1
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Arsene D, Tchaptchet SY, Hansen JJ. The global stress response regulator oxyS in an adherent-invasive Escherichia coli strain attenuates experimental colitis. Gut Microbes 2025; 17:2473518. [PMID: 40022675 PMCID: PMC11875499 DOI: 10.1080/19490976.2025.2473518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 01/13/2025] [Accepted: 02/21/2025] [Indexed: 03/03/2025] Open
Abstract
Crohn's disease and ulcerative colitis in humans and experimental immune-mediated colitis in mice are likely due in part to overactive immune responses to resident intestinal bacteria, including certain strains of adherent-invasive Escherichia coli (E. coli) such as E. coli NC101. We have previously shown that specific E. coli NC101 stress responses are upregulated during experimental colitis and attenuate inflammation. However, the roles of broader stress response pathways in E. coli NC101 during experimental colitis are unknown. We hypothesize that the global stress response regulator in E. coli, oxyS, also reduces experimental colitis. We show that intestinal E. coli NC101 upregulate oxyS expression during colitis in monocolonized interleukin-10 deficient mice. Furthermore, we demonstrate that oxyS-sufficient E. coli NC101 have decreased motility and biofilm formation in vitro and attenuated intestinal translocation and colitogenic potential in vivo compared with oxyS-deficient E. coli. These data suggest that activation of a generalized E. coli stress response, oxyS, reduces experimental colitis and may be a potential therapeutic target.
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Affiliation(s)
- Diana Arsene
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sandrine Y. Tchaptchet
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jonathan J. Hansen
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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2
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Ju Y, Ma C, Huang L, Tao Y, Li T, Li H, Huycke MM, Yang Y, Wang X. Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis. Gut Microbes 2025; 17:2451090. [PMID: 39819335 PMCID: PMC11740687 DOI: 10.1080/19490976.2025.2451090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 11/08/2024] [Accepted: 01/02/2025] [Indexed: 01/30/2025] Open
Abstract
Enterococcus faecalis-infected macrophages produce 4-hydroxynonenal (4-HNE) that mediates microbiota-induced bystander effect (MIBE) leading to colorectal cancer (CRC). Glutathione S-transferase alpha 4 (Gsta4), a specific detoxifying enzyme for 4-HNE, is overexpressed in human CRC and E. faecalis-induced murine CRC. However, the roles of Gsta4 in E. faecalis-induced colitis and CRC remain unclear. Herein, we demonstrate that Gsta4 is essential for MIBE by protecting macrophages from E. faecalis-induced ferroptosis. E. faecalis OG1RFSS was used to induce colitis in Gsta4-/- and Il10-/-/Gsta4-/- mice by orogastric gavage. Ferroptosis was assessed in Gsta4-deficient murine macrophages. We found that, unlike Il10-/- mice, Gsta4-/- and Il10-/-/Gsta4-/- mice colonized with E. faecalis failed to develop colitis or CRC. Immunofluorescent staining showed a reduction of macrophages in the lamina propria of E. faecalis-colonized Il10-/-/Gsta4-/- mice, as well as decreased Gpx4 expression, indicating the occurrence of ferroptosis. Ferroptosis was further confirmed in Gsta4-deficient murine macrophages infected with E. faecalis. Moreover, Gsta4 inactivation induced the upregulation of Hmox1 and phosphorylated c-Jun while blocked Nos2 expression, leading to the accumulation of intracellular ferrous iron, lipid peroxidation and, eventually, ferroptosis. Finally, Mapk8, as a ferroptosis driver, was remarkably elevated in E. faecalis-infected Gsta4-deficient macrophages. These results suggest that Gsta4 inactivation blocks MIBE by eliminating macrophages, thereby attenuates E. faecalis-induced colitis and CRC.
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Affiliation(s)
- Yuanyuan Ju
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, China
- Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, Jiangsu, China
| | - Chunhua Ma
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, China
- Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, Jiangsu, China
| | - Lin Huang
- Department of Gastroenterology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yumei Tao
- Department of Pathology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, China
| | - Tianqi Li
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, China
- Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, Jiangsu, China
| | - Haibo Li
- Department of Clinical Laboratory, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, China
| | - Mark M. Huycke
- Stephenson Cancer Center, Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Yonghong Yang
- Department of Nephrology, Rheumatology, and Immunology, Nantong Children’s Hospital, Nantong, Jiangsu, China
- Department of Pediatrics, Nantong Maternity and Child Healthcare Hospital, Nantong, Jiangsu, China
| | - Xingmin Wang
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, China
- Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, Jiangsu, China
- Stephenson Cancer Center, Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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3
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Sartor RB. Beyond Random Fecal Microbial Transplants: Next Generation Personalized Approaches to Normalize Dysbiotic Microbiota for Treating IBD. Gastroenterol Clin North Am 2025; 54:333-350. [PMID: 40348491 DOI: 10.1016/j.gtc.2024.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
This review and commentary outline the strong rationale for normalizing the abnormal microbiota of patients with ulcerative colitis, Crohn's disease, and pouchitis and focus on strategies to improve current variable outcomes of fecal microbial transplant (FMT) in ulcerative colitis. Applying lessons from successful FMT therapy of recurrent Clostridioides difficile and insights from basic scientific understanding of host/microbial interactions provide strategies to enhance clinical outcomes in IBD. We outline promising approaches to develop novel-defined consortia of live biotherapeutic products and combination treatments to improve current results and to optimize and personalize treatment approaches in individual patients and disease subsets.
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Affiliation(s)
- R Balfour Sartor
- Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina - Chapel Hill, Chapel Hill, NC 27517, USA; Department of Microbiology & Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina - Chapel Hill, Chapel Hill, NC 27517, USA.
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4
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Ahn JH, da Silva Pedrosa M, Lopez LR, Tibbs TN, Jeyachandran JN, Vignieri EE, Rothemich A, Cumming I, Irmscher AD, Haswell CJ, Zamboni WC, Yu YRA, Ellermann M, Denson LA, Arthur JC. Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease. Cell Host Microbe 2025; 33:71-88.e9. [PMID: 39701098 DOI: 10.1016/j.chom.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 11/11/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.
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Affiliation(s)
- Ju-Hyun Ahn
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Marlus da Silva Pedrosa
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lacey R Lopez
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Taylor N Tibbs
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Joanna N Jeyachandran
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Emily E Vignieri
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Aaron Rothemich
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ian Cumming
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA
| | - Alexander D Irmscher
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Corey J Haswell
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - William C Zamboni
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yen-Rei A Yu
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Melissa Ellermann
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Lee A Denson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Janelle C Arthur
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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5
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Zhao Y, Liu Y, Jia L. Gut microbial dysbiosis and inflammation: Impact on periodontal health. J Periodontal Res 2025; 60:30-43. [PMID: 38991951 DOI: 10.1111/jre.13324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/28/2024] [Accepted: 07/01/2024] [Indexed: 07/13/2024]
Abstract
Periodontitis is widely acknowledged as the most prevalent type of oral inflammation, arising from the dynamic interplay between oral pathogens and the host's immune responses. It is also recognized as a contributing factor to various systemic diseases. Dysbiosis of the oral microbiota can significantly alter the composition and diversity of the gut microbiota. Researchers have delved into the links between periodontitis and systemic diseases through the "oral-gut" axis. However, whether the associations between periodontitis and the gut microbiota are simply correlative or driven by causative mechanistic interactions remains uncertain. This review investigates how dysbiosis of the gut microbiota impacts periodontitis, drawing on existing preclinical and clinical data. This study highlights potential mechanisms of this interaction, including alterations in subgingival microbiota, oral mucosal barrier function, neutrophil activity, and abnormal T-cell recycling, and offers new perspectives for managing periodontitis, especially in cases linked to systemic diseases.
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Affiliation(s)
- Yifan Zhao
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Lu Jia
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
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6
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Kelly C, Sartor RB, Rawls JF. Early subclinical stages of the inflammatory bowel diseases: insights from human and animal studies. Am J Physiol Gastrointest Liver Physiol 2025; 328:G17-G31. [PMID: 39499254 PMCID: PMC11901386 DOI: 10.1152/ajpgi.00252.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 10/30/2024] [Accepted: 10/31/2024] [Indexed: 11/07/2024]
Abstract
The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals that mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. The natural history of IBD progression begins with early subclinical stages of disease that occur before clinical diagnosis. Improved understanding of those early subclinical stages could lead to new or improved strategies for IBD diagnosis, prognostication, or prevention. Here, we review our current understanding of the early subclinical stages of IBD in humans including studies from first-degree relatives of patients with IBD and members of the general population who go on to develop IBD. We also discuss representative mouse models of IBD that can be used to investigate disease dynamics and host-microbiota relationships during these early stages. In particular, we underscore how mouse models of IBD that develop disease later in life with variable penetrance may present valuable opportunities to discern early subclinical mechanisms of disease before histological inflammation and other severe symptoms become apparent.
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Affiliation(s)
- Cecelia Kelly
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina, United States
| | - R Balfour Sartor
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, United States
| | - John F Rawls
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina, United States
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7
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Biagioli M, Di Giorgio C, Massa C, Marchianò S, Bellini R, Bordoni M, Urbani G, Roselli R, Lachi G, Morretta E, Piaz FD, Charlier B, Fiorillo B, Catalanotti B, Cari L, Nocentini G, Ricci P, Distrutti E, Festa C, Sepe V, Zampella A, Monti MC, Fiorucci S. Microbial-derived bile acid reverses inflammation in IBD via GPBAR1 agonism and RORγt inverse agonism. Biomed Pharmacother 2024; 181:117731. [PMID: 39657506 DOI: 10.1016/j.biopha.2024.117731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/22/2024] [Accepted: 12/03/2024] [Indexed: 12/12/2024] Open
Abstract
The interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reverses disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated that intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and in models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Martina Bordoni
- Bar Pharmaceuticals s.r.l., Via Gramsci 88/A, Reggio Emilia 42124, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Rosalinda Roselli
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Ginevra Lachi
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Fabrizio Dal Piaz
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy
| | - Bruno Charlier
- University hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy
| | - Bianca Fiorillo
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Bruno Catalanotti
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Luigi Cari
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giuseppe Nocentini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Patrizia Ricci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Carmen Festa
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
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8
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DeLira-Bustillos N, Angulo-Zamudio UA, Leon-Sicairos N, Flores-Villaseñor H, Velazquez-Roman J, Tapia-Pastrana G, Canizales-Quinteros S, Velázquez-Cruz R, Cortez-Hernández JA, Canizalez-Roman A. Cyclomodulins-harboring Escherichia coli isolated from obese and normal-weight subjects induces intestinal dysplasia in a mouse model. World J Microbiol Biotechnol 2024; 40:371. [PMID: 39487241 DOI: 10.1007/s11274-024-04176-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/18/2024] [Indexed: 11/04/2024]
Abstract
Recently, cyclomodulins have been identified in Escherichia coli (E. coli), which can induce dysplastic damage. This work aimed to determine the dysplastic activity of cyclomodulin-harboring E. coli isolated from CRC patients, obese and normal-weight subjects in a mouse model. Forty-two mice were pretreated with streptomycin, azoxymethane, and dextran sodium sulfate. Mice were infected with E. coli pks + isolated from a CRC patient, with E. coli pks + cif + isolated from obese or normal-weight subjects, or with E. coli HB101. The presence of cyclomodulin-harboring E. coli in the feces, weight loss, changes in fecal consistency, and the presence of blood in the feces were monitored and used to assess the disease activity index (DAI). After 62 days, the mice were sacrificed to evaluate the presence of intestinal polyps and dysplastic damage by histologic sections. Cyclomodulin-harboring E. coli colonized the mice; these mice exhibited weight loss and watery diarrhea, and isolated normal-weight E. coli had a higher DAI. Polyps were observed in mice infected with cyclomodulin-harboring E. coli in the ileum but to a greater extent in obese isolates. E. coli isolated from CRC showed more significant endothelial damage associated with dysplasia in the ileum in equal proportions from obese and normal-weight isolates. In conclusion, E. coli harboring cyclomodulins isolated from CRC, obesity, or normal weight can cause dysplastic damage in the ileum of mice and may be a risk factor for CRC development.
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Affiliation(s)
- Nora DeLira-Bustillos
- Programa de Doctorado, Posgrado Integral en Biotecnología, FCQB, UAS, Culiacan Sinaloa, 80030, Mexico
| | | | - Nidia Leon-Sicairos
- School of Medicine, Autonomous University of Sinaloa, Culiacan, Sinaloa, 80019, Mexico
- Pediatric Hospital of Sinaloa, Culiacan Sinaloa, 80200, Mexico
| | - Hector Flores-Villaseñor
- School of Medicine, Autonomous University of Sinaloa, Culiacan, Sinaloa, 80019, Mexico
- The Sinaloa State Public Health Laboratory, Secretariat of Health, Culiacan Sinaloa, 80058, Mexico
| | - Jorge Velazquez-Roman
- School of Medicine, Autonomous University of Sinaloa, Culiacan, Sinaloa, 80019, Mexico
| | - Gabriela Tapia-Pastrana
- Laboratorio de Investigación Biomédica, Servicios de Salud del Instituto Mexicano del Seguro Social para el Bienestar (IMSS- BIENESTAR) Hospital Regional de Alta Especialidad de Oaxaca, Oaxaca, 71256, Mexico
| | - Samuel Canizales-Quinteros
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, 14610, Mexico
| | - Rafael Velázquez-Cruz
- Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, 14610, Mexico
| | | | - Adrian Canizalez-Roman
- School of Medicine, Autonomous University of Sinaloa, Culiacan, Sinaloa, 80019, Mexico.
- The Women's Hospital, Secretariat of Health, Culiacan Sinaloa, 80020, Mexico.
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9
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Muñiz Pedrogo DA, Sears CL, Melia JMP. Colorectal Cancer in Inflammatory Bowel Disease: A Review of the Role of Gut Microbiota and Bacterial Biofilms in Disease Pathogenesis. J Crohns Colitis 2024; 18:1713-1725. [PMID: 38703073 DOI: 10.1093/ecco-jcc/jjae061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/31/2024] [Accepted: 05/03/2024] [Indexed: 05/06/2024]
Abstract
The risk of colorectal cancer [CRC] is increased in patients with inflammatory bowel disease [IBD], particularly in extensive ulcerative colitis [UC] and Crohn's colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation, as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and proinflammatory properties by organising into biofilms, potentially making them more resistant to the host's immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumour-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histological inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. Commonly used in the treatment of UC, 5-aminosalicylates have antimicrobial and anticarcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially of biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC, via mechanisms independent of inflammation, is still unknown. Further research is warranted to identify potential new microbial targets in therapy for chemoprevention of dysplasia and CRC in IBD.
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Affiliation(s)
- David A Muñiz Pedrogo
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Cynthia L Sears
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joanna M P Melia
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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10
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Madani WAM, Ramos Y, Cubillos-Ruiz JR, Morales DK. Enterococcal-host interactions in the gastrointestinal tract and beyond. FEMS MICROBES 2024; 5:xtae027. [PMID: 39391373 PMCID: PMC11466040 DOI: 10.1093/femsmc/xtae027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 08/05/2024] [Accepted: 09/06/2024] [Indexed: 10/12/2024] Open
Abstract
The gastrointestinal tract (GIT) is typically considered the natural niche of enterococci. However, these bacteria also inhabit extraintestinal tissues, where they can disrupt organ physiology and cause life-threatening infections. Here, we discuss how enterococci, primarily Enterococcus faecalis, interact with the intestine and other host anatomical locations such as the oral cavity, heart, liver, kidney, and vaginal tract. The metabolic flexibility of these bacteria allows them to quickly adapt to new environments, promoting their persistence in diverse tissues. In transitioning from commensals to pathogens, enterococci must overcome harsh conditions such as nutrient competition, exposure to antimicrobials, and immune pressure. Therefore, enterococci have evolved multiple mechanisms to adhere, colonize, persist, and endure these challenges in the host. This review provides a comprehensive overview of how enterococci interact with diverse host cells and tissues across multiple organ systems, highlighting the key molecular pathways that mediate enterococcal adaptation, persistence, and pathogenic behavior.
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Affiliation(s)
- Wiam Abdalla Mo Madani
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, NY 10065, United States
| | - Yusibeska Ramos
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, NY 10065, United States
| | - Juan R Cubillos-Ruiz
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, NY 10065, United States
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, NY 10065, United States
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, NY 10065, United States
| | - Diana K Morales
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, NY 10065, United States
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11
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Gray SM, Moss AD, Herzog JW, Kashiwagi S, Liu B, Young JB, Sun S, Bhatt AP, Fodor AA, Balfour Sartor R. Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment. MICROBIOME 2024; 12:147. [PMID: 39113097 PMCID: PMC11304999 DOI: 10.1186/s40168-024-01857-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/10/2024] [Indexed: 08/10/2024]
Abstract
BACKGROUND Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. RESULTS Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. CONCLUSIONS Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract.
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Affiliation(s)
- Simon M Gray
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anh D Moss
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Jeremy W Herzog
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Saori Kashiwagi
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Bo Liu
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jacqueline B Young
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Shan Sun
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Aadra P Bhatt
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anthony A Fodor
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA.
| | - R Balfour Sartor
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- National Gnotobiotic Rodent Resource Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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12
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Ge J, Li M, Yao J, Guo J, Li X, Li G, Han X, Li Z, Liu M, Zhao J. The potential of EGCG in modulating the oral-gut axis microbiota for treating inflammatory bowel disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155643. [PMID: 38820660 DOI: 10.1016/j.phymed.2024.155643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 04/07/2024] [Accepted: 04/13/2024] [Indexed: 06/02/2024]
Abstract
Inflammatory bowel disease (IBD) is a recurrent chronic intestinal disorder that includes ulcerative colitis (UC) and Crohn's disease (CD). Its pathogenesis involves intricate interactions between pathogenic microorganisms, native intestinal microorganisms, and the intestinal immune system via the oral-gut axis. The strong correlation observed between oral diseases and IBD indicates the potential involvement of oral pathogenic microorganisms in IBD development. Consequently, therapeutic strategies targeting the proliferation, translocation, intestinal colonization and exacerbated intestinal inflammation of oral microorganisms within the oral-gut axis may partially alleviate IBD. Tea consumption has been identified as a contributing factor in reducing IBD, with epigallocatechin gallate (EGCG) being the primary bioactive compound used for IBD treatment. However, the precise mechanism by which EGCG mediates microbial crosstalk within the oral-gut axis remains unclear. In this review, we provide a comprehensive overview of the diverse oral microorganisms implicated in the pathogenesis of IBD and elucidate their colonization pathways and mechanisms. Subsequently, we investigated the antibacterial properties of EGCG and its potential to attenuate microbial translocation and colonization in the gut, emphasizing its role in attenuating exacerbations of IBD. We also elucidated the toxic and side effects of EGCG. Finally, we discuss current strategies for enhancing EGCG bioavailability and propose novel multi-targeted nano-delivery systems for the more efficacious management of IBD. This review elucidates the role and feasibility of EGCG-mediated modulation of the oral-gut axis microbiota in the management of IBD, contributing to a better understanding of the mechanism of action of EGCG in the treatment of IBD and the development of prospective treatment strategies.
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Affiliation(s)
- Jiaming Ge
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Mengyuan Li
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jingwen Yao
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jinling Guo
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiankuan Li
- Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Gang Li
- State Key Laboratory of Precision Measurement Technology and Instruments, Tianjin University, Tianjin 300072, China
| | - Xiangli Han
- Department of Geriatric, Fourth Teaching Hospital of Tianjin University of TCM, Tianjin 300450, China
| | - Zheng Li
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ming Liu
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, 236 Baidi Road, Nankai District, Tianjin 300192, China.
| | - Jing Zhao
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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13
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Geropoulos G, Psarras K, Koimtzis G, Fornasiero M, Anestiadou E, Geropoulos V, Michopoulou A, Papaioannou M, Kouzi-Koliakou K, Galanis I. Knockout Genes in Bowel Anastomoses: A Systematic Review of Literature Outcomes. J Pers Med 2024; 14:553. [PMID: 38929776 PMCID: PMC11205243 DOI: 10.3390/jpm14060553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/12/2024] [Accepted: 04/16/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND The intestinal wound healing process is a complex event of three overlapping phases: exudative, proliferative, and remodeling. Although some mechanisms have been extensively described, the intestinal healing process is still not fully understood. There are some similarities but also some differences compared to other tissues. The aim of this systematic review was to summarize all studies with knockout (KO) experimental models in bowel anastomoses, underline any recent knowledge, and clarify further the cellular and molecular mechanisms of the intestinal healing process. A systematic review protocol was performed. MATERIALS AND METHODS Medline, EMBASE, and Scopus were comprehensively searched. RESULTS a total of eight studies were included. The silenced genes included interleukin-10, the four-and-one-half LIM domain-containing protein 2 (FHL2), cyclooxygenase-2 (COX-2), annexin A1 (ANXA-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and heparin-binding epidermal growth factor (HB-EGF) gene. Surgically, an end-to-end bowel anastomosis was performed in the majority of the studies. Increased inflammatory cell infiltration in the anastomotic site was found in IL-10-, annexin-A1-, and TAFI-deficient mice compared to controls. COX-1 deficiency showed decreased angiogenesis at the anastomotic site. Administration of prostaglandin E2 in COX-2-deficient mice partially improved anastomotic leak rates, while treatment of ANXA1 KO mice with Ac2-26 nanoparticles reduced colitis activity and increased weight recovery following surgery. CONCLUSIONS our findings provide new insights into improving intestinal wound healing by amplifying the aforementioned genes using appropriate gene therapies. Further research is required to clarify further the cellular and micromolecular mechanisms of intestinal healing.
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Affiliation(s)
- Georgios Geropoulos
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
| | - Kyriakos Psarras
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
| | - Georgios Koimtzis
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
| | | | - Elissavet Anestiadou
- Fourth Surgical Department, School of Medicine, Aristotle University of Thessaloniki, 57010 Thessaloniki, Greece;
| | - Vasileios Geropoulos
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
| | - Anna Michopoulou
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
- Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Maria Papaioannou
- Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Kokkona Kouzi-Koliakou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Ioannis Galanis
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
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14
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Gray SM, Moss AD, Herzog JW, Kashiwagi S, Liu B, Young JB, Sun S, Bhatt A, Fodor AA, Balfour Sartor R. Mouse Adaptation of Human Inflammatory Bowel Diseases Microbiota Enhances Colonization Efficiency and Alters Microbiome Aggressiveness Depending on Recipient Colonic Inflammatory Environment. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.23.576862. [PMID: 38328082 PMCID: PMC10849574 DOI: 10.1101/2024.01.23.576862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.
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Affiliation(s)
- Simon M. Gray
- These authors contributed equally to this work
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anh D. Moss
- These authors contributed equally to this work
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Jeremy W. Herzog
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Saori Kashiwagi
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Bo Liu
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jacqueline B. Young
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Shan Sun
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Aadra Bhatt
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anthony A. Fodor
- These authors contributed equally to this work
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - R. Balfour Sartor
- These authors contributed equally to this work
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- National Gnotobiotic Rodent Resource Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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15
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Bleich RM, Li C, Sun S, Ahn JH, Dogan B, Barlogio CJ, Broberg CA, Franks AR, Bulik-Sullivan E, Carroll IM, Simpson KW, Fodor AA, Arthur JC. A consortia of clinical E. coli strains with distinct in vitro adherent/invasive properties establish their own co-colonization niche and shape the intestinal microbiota in inflammation-susceptible mice. MICROBIOME 2023; 11:277. [PMID: 38124090 PMCID: PMC10731797 DOI: 10.1186/s40168-023-01710-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 10/26/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) patients experience recurrent episodes of intestinal inflammation and often follow an unpredictable disease course. Mucosal colonization with adherent-invasive Escherichia coli (AIEC) are believed to perpetuate intestinal inflammation. However, it remains unclear if the 24-year-old AIEC in vitro definition fully predicts mucosal colonization in vivo. To fill this gap, we have developed a novel molecular barcoding approach to distinguish strain variants in the gut and have integrated this approach to explore mucosal colonization of distinct patient-derived E. coli isolates in gnotobiotic mouse models of colitis. RESULTS Germ-free inflammation-susceptible interleukin-10-deficient (Il10-/-) and inflammation-resistant WT mice were colonized with a consortium of AIEC and non-AIEC strains, then given a murine fecal transplant to provide niche competition. E. coli strains isolated from human intestinal tissue were each marked with a unique molecular barcode that permits identification and quantification by barcode-targeted sequencing. 16S rRNA sequencing was used to evaluate the microbiome response to E. coli colonization. Our data reveal that specific AIEC and non-AIEC strains reproducibly colonize the intestinal mucosa of WT and Il10-/- mice. These E. coli expand in Il10-/- mice during inflammation and induce compositional dysbiosis to the microbiome in an inflammation-dependent manner. In turn, specific microbes co-evolve in inflamed mice, potentially diversifying E. coli colonization patterns. We observed no selectivity in E. coli colonization patterns in the fecal contents, indicating minimal selective pressure in this niche from host-microbe and interbacterial interactions. Because select AIEC and non-AIEC strains colonize the mucosa, this suggests the in vitro AIEC definition may not fully predict in vivo colonization potential. Further comparison of seven E. coli genomes pinpointed unique genomic features contained only in highly colonizing strains (two AIEC and two non-AIEC). Those colonization-associated features may convey metabolic advantages (e.g., iron acquisition and carbohydrate consumption) to promote efficient mucosal colonization. CONCLUSIONS Our findings establish the in vivo mucosal colonizer, not necessarily AIEC, as a principal dysbiosis driver through crosstalk with host and associated microbes. Furthermore, we highlight the utility of high-throughput screens to decode the in vivo colonization dynamics of patient-derived bacteria in murine models. Video Abstract.
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Affiliation(s)
- Rachel M Bleich
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Biology, Appalachian State University, Boone, NC, USA
| | - Chuang Li
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Shan Sun
- College of Computing and Informatics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Ju-Hyun Ahn
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Belgin Dogan
- Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Cassandra J Barlogio
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Christopher A Broberg
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Adrienne R Franks
- Center for Gastrointestinal Biology & Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Emily Bulik-Sullivan
- Center for Gastrointestinal Biology & Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ian M Carroll
- Center for Gastrointestinal Biology & Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kenneth W Simpson
- Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Anthony A Fodor
- College of Computing and Informatics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Janelle C Arthur
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Center for Gastrointestinal Biology & Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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16
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Unni R, Andreani NA, Vallier M, Heinzmann SS, Taubenheim J, Guggeis MA, Tran F, Vogler O, Künzel S, Hövener JB, Rosenstiel P, Kaleta C, Dempfle A, Unterweger D, Baines JF. Evolution of E. coli in a mouse model of inflammatory bowel disease leads to a disease-specific bacterial genotype and trade-offs with clinical relevance. Gut Microbes 2023; 15:2286675. [PMID: 38059748 PMCID: PMC10730162 DOI: 10.1080/19490976.2023.2286675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/17/2023] [Indexed: 12/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a persistent inflammatory condition that affects the gastrointestinal tract and presents significant challenges in its management and treatment. Despite the knowledge that within-host bacterial evolution occurs in the intestine, the disease has rarely been studied from an evolutionary perspective. In this study, we aimed to investigate the evolution of resident bacteria during intestinal inflammation and whether- and how disease-related bacterial genetic changes may present trade-offs with potential therapeutic importance. Here, we perform an in vivo evolution experiment of E. coli in a gnotobiotic mouse model of IBD, followed by multiomic analyses to identify disease-specific genetic and phenotypic changes in bacteria that evolved in an inflamed versus a non-inflamed control environment. Our results demonstrate distinct evolutionary changes in E. coli specific to inflammation, including a single nucleotide variant that independently reached high frequency in all inflamed mice. Using ex vivo fitness assays, we find that these changes are associated with a higher fitness in an inflamed environment compared to isolates derived from non-inflamed mice. Further, using large-scale phenotypic assays, we show that bacterial adaptation to inflammation results in clinically relevant phenotypes, which intriguingly include collateral sensitivity to antibiotics. Bacterial evolution in an inflamed gut yields specific genetic and phenotypic signatures. These results may serve as a basis for developing novel evolution-informed treatment approaches for patients with intestinal inflammation.
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Affiliation(s)
- Rahul Unni
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Nadia Andrea Andreani
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Marie Vallier
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Silke S. Heinzmann
- Research Unit Analytical BioGeoChemistry, Helmholtz Munich, Neuherberg, Germany
| | - Jan Taubenheim
- Research Group Medical Systems Biology, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Martina A. Guggeis
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Florian Tran
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Olga Vogler
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - Sven Künzel
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - Jan-Bernd Hövener
- Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Kiel, Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Christoph Kaleta
- Research Group Medical Systems Biology, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Astrid Dempfle
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
| | - Daniel Unterweger
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - John F. Baines
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
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17
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Pös O, Styk J, Buglyó G, Zeman M, Lukyova L, Bernatova K, Hrckova Turnova E, Rendek T, Csók Á, Repiska V, Nagy B, Szemes T. Cross-Kingdom Interaction of miRNAs and Gut Microbiota with Non-Invasive Diagnostic and Therapeutic Implications in Colorectal Cancer. Int J Mol Sci 2023; 24:10520. [PMID: 37445698 DOI: 10.3390/ijms241310520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Colorectal cancer (CRC) has one of the highest incidences among all types of malignant diseases, affecting millions of people worldwide. It shows slow progression, making it preventable. However, this is not the case due to shortcomings in its diagnostic and management procedure and a lack of effective non-invasive biomarkers for screening. Here, we discuss CRC-associated microRNAs (miRNAs) and gut microbial species with potential as CRC diagnostic and therapy biomarkers. We provide rich evidence of cross-kingdom miRNA-mediated interactions between the host and gut microbiome. miRNAs have emerged with the ability to shape the composition and dynamics of gut microbiota. Intestinal microbes can uptake miRNAs, which in turn influence microbial growth and provide the ability to regulate the abundance of various microbial species. In the context of CRC, targeting miRNAs could aid in manipulating the balance of the microbiota. Our findings suggest the need for correlation analysis between the composition of the gut microbiome and the miRNA expression profile.
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Affiliation(s)
- Ondrej Pös
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
| | - Jakub Styk
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Gergely Buglyó
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Michal Zeman
- Comenius University Science Park, 841 04 Bratislava, Slovakia
| | - Lydia Lukyova
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
| | - Kamila Bernatova
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
| | - Evelina Hrckova Turnova
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Slovgen Ltd., 841 04 Bratislava, Slovakia
| | - Tomas Rendek
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Ádám Csók
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Vanda Repiska
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
- Medirex Group Academy, n.p.o., 949 05 Nitra, Slovakia
| | - Bálint Nagy
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Tomas Szemes
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
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18
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Lopez LR, Miller CM, Jeyachandran JN, Li C, Simpson KW, Arthur JC. Heterogeneity among Clinical Intestinal Escherichia coli Isolates upon Acquired Streptomycin Resistance. Microbiol Spectr 2023; 11:e0350022. [PMID: 37184392 PMCID: PMC10269711 DOI: 10.1128/spectrum.03500-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/25/2023] [Indexed: 05/16/2023] Open
Abstract
Escherichia coli isolates from inflammatory bowel disease (IBD) patients are often multidrug resistant, including to streptomycin. Streptomycin resistance (StrR) mutations can alter bacterial behavior, which may influence intestinal disease. We generated a spontaneous StrR strain of the intestinal adherent-invasive E. coli (AIEC) strain NC101. Whole-genome sequencing revealed a single missense mutation in rpsL that commonly confers StrR, rpsL-K43N. StrR NC101 exhibited a striking loss of aggregation and significantly increased motility, behaviors that can impact host-microbe interactions. Behavioral changes were associated with reduced transcription of csgA, encoding the biofilm component curli, and increased transcription of fliC, encoding flagellin. Scanning electron microscopy (SEM) detailed morphologic changes consistent with the observed alterations in multicellular behavior. Because intestinal E. coli isolates exhibit remarkable strain-specific differences, we generated spontaneous StrR mutants of 10 clinical E. coli phylotype B2 strains from patients with IBD, colorectal cancer, and urinary tract infection. Out of these 10 StrR clinical strains, two had altered colony morphology on Congo red agar (suggesting changes in extracellular products), and three had significant changes in motility. These changes were not associated with a particular rpsL mutation nor with the presence of virulence genes encoding the inflammation-associated E. coli metabolites yersiniabactin or colibactin. We conclude that common mutations in rpsL, which confer StrR, can differentially alter disease-associated phenotypes across intestinal E. coli strains. These findings highlight the heterogeneity among seemingly similar intestinal E. coli strains and reveal the need to carefully study the strain-specific effects of antibiotic resistance mutations, particularly when using these mutations during strain selection studies. IMPORTANCE We demonstrate that StrR, commonly acquired through a single point mutation in rpsL (a gene encoding part of the 30S bacterial ribosome), strikingly alters the morphology and behavior of a key intestinal AIEC strain, NC101. These changes include remarkably diminished aggregation and significantly increased motility, traits that are linked to AIEC-defining features and disease development. Phenotypic changes were heterogeneous among other StrR clinical E. coli strains, underscoring the need to evaluate the strain-specific effects of commonly acquired antibiotic resistance mutations. This is important, as the results of studies using mutant StrR Enterobacteriaceae strains (e.g., for cloning or in vivo selection) may be confounded beyond our demonstrated effects. Long term, these findings can help researchers better distinguish the contribution of specific E. coli traits to functional changes in the microbiota. Evaluating these strain-level differences could provide insight into the diversity of IBD symptoms and lead to improved therapies for microbiota-driven intestinal disorders.
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Affiliation(s)
- Lacey R. Lopez
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Claire M. Miller
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Joanna N. Jeyachandran
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Chuang Li
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Kenneth W. Simpson
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
| | - Janelle C. Arthur
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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19
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Bleich RM, Li C, Sun S, Barlogio CJ, Broberg CA, Franks AR, Bulik-Sullivan E, Dogan B, Simpson KW, Carroll IM, Fodor AA, Arthur JC. A consortia of clinical E. coli strains with distinct in-vitro adherent/invasive properties establish their own co-colonization niche and shape the intestinal microbiota in inflammation-susceptible mice. RESEARCH SQUARE 2023:rs.3.rs-2899665. [PMID: 37214858 PMCID: PMC10197778 DOI: 10.21203/rs.3.rs-2899665/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Background Inflammatory bowel disease (IBD) patients experience recurrent episodes of intestinal inflammation and often follow an unpredictable disease course. Mucosal colonization with adherent-invasive Escherichia coli (AIEC) are believed to perpetuate intestinal inflammation. However, it remains unclear if the 24-year-old AIEC in-vitro definition fully predicts mucosal colonization in-vivo. To fill this gap, we have developed a novel molecular barcoding approach to distinguish strain variants in the gut and have integrated this approach to explore mucosal colonization of distinct patient-derived E. coli isolates in gnotobiotic mouse models of colitis. Results Germ-free inflammation-susceptible interleukin-10-deficient (Il10-/-) and inflammation-resistant WT mice were colonized with a consortia of AIEC and non-AIEC strains, then given a murine fecal transplant to provide niche competition. E. coli strains isolated from human intestinal tissue were each marked with a unique molecular barcode that permits identification and quantification by barcode-targeted sequencing. 16S rRNA sequencing was used to evaluate the microbiome response to E. coli colonization. Our data reveal that specific AIEC and non-AIEC strains reproducibly colonize the intestinal mucosa of WT and Il10-/- mice. These E. coli expand in Il10-/- mice during inflammation and induce compositional dysbiosis to the microbiome in an inflammation-dependent manner. In turn, specific microbes co-evolve in inflamed mice, potentially diversifying E. coli colonization patterns. We observed no selectivity in E. coli colonization patterns in the fecal contents, indicating minimal selective pressure in this niche from host-microbe and interbacterial interactions. Because select AIEC and non-AIEC strains colonize the mucosa, this suggests the in vitro AIEC definition may not fully predict in vivo colonization potential. Further comparison of seven E. coli genomes pinpointed unique genomic features contained only in highly colonizing strains (two AIEC and two non-AIEC). Those colonization-associated features may convey metabolic advantages (e.g., iron acquisition and carbohydrate consumption) to promote efficient mucosal colonization. Conclusions Our findings establish the in-vivo mucosal colonizer, not necessarily AIEC, as a principal dysbiosis driver through crosstalk with host and associated microbes. Furthermore, we highlight the utility of high-throughput screens to decode the in-vivo colonization dynamics of patient-derived bacteria in murine models.
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Affiliation(s)
| | - Chuang Li
- University of North Carolina at Chapel Hill
| | - Shan Sun
- University of North Carolina at Charlotte
| | | | | | | | | | - Belgin Dogan
- Cornell University College of Veterinary Medicine
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20
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Verburgt CM, Dunn KA, Otley A, Heyman MB, Verstraete S, Sunseri W, Sylvester F, de Meij T, Comeau A, Langille M, de Jonge WJ, Benninga MA, Van Limbergen JE. Personalised azithromycin+metronidazole (PAZAZ), in combination with standard induction therapy, to achieve a faecal microbiome community structure and metagenome changes associated with sustained remission in paediatric Crohn's disease (CD): protocol of a pilot study. BMJ Open 2023; 13:e064944. [PMID: 36725090 PMCID: PMC9896212 DOI: 10.1136/bmjopen-2022-064944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
INTRODUCTION Early relapse in Crohn's disease (CD) is associated with a more severe disease course. The microbiome plays a crucial role, yet strategies targeting the microbiome are underrepresented in current guidelines. We hypothesise that early manipulation of the microbiome will improve clinical response to standard-of-care (SOC) induction therapy in patients with a relapse-associated microbiome profile. We describe the protocol of a pilot study assessing feasibility of treatment allocation based on baseline faecal microbiome profiles. METHODS AND ANALYSIS This is a 52-week, multicentre, randomised, controlled, open-label, add-on pilot study to test the feasibility of a larger multicontinent trial evaluating the efficacy of adjuvant antibiotic therapy in 20 paediatric patients with mild-to-moderate-CD (10<PCDAI≤37.5; PCDAI, Pediatric Crohn's Disease Activity Index). SOC induction treatment will be Crohn's Disease Exclusion Diet+Partial Enteral Nutrition (CDED+PEN). Relapse-associated microbiome signatures will be evaluated using 16S rRNA gene sequencing and a previously generated Bayesian predictive model (BioMiCo) based on baseline stool. At week 4, patients in remission with relapse-associated signatures (group A) will be randomised to CDED+antibiotics (A2) or CDED+PEN alone (A1). Patients in remission without this signature will continue CDED+PEN alone (B). Patients not in remission will receive CDED+antibiotics regardless of their microbiome signature (C). Subjects in group A2 or C will receive a combination of azithromycin 7.5 mg/kg (weeks 4-8: 5 days/week; weeks 9-12: 3 days/week) with metronidazole 20 mg/kg/day (weeks 4-12). Primary outcomes will assess feasibility of treatment allocation and possible efficacy to sustain remission (PCDAI≤10, no need for reinduction). Exploratory outcomes will include changes in PCDAI, inflammatory markers and patient-reported outcomes. We will additionally explore changes in faecal microbiome taxonomic composition between groups. ETHICS AND DISSEMINATION This study was approved by METC-AMC and CCMO (Netherlands) and IWK Health Centre (Canada). The first version of this protocol was approved by North Carolina Children's Hospital (USA), Wolfson Medical Centre (Israel). The FDA (USA), Health Canada and Ministry of Health (Israel) have reviewed and approved the protocol. Results will be published in international peer-reviewed journals and summaries will be provided to the funders and participants. TRIAL REGISTRATION NUMBER NCT04186247.
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Affiliation(s)
- Charlotte M Verburgt
- Department of Paediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers - location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction & Development Research Institute, Paediatric Gastroenterology, Amsterdam, The Netherlands
| | - Katherine A Dunn
- Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Paediatrics, Division of Hematology & Oncology, IWK Health Centre, Halifax, Nova Scotia, Canada
- Institute for Comparative Genomics, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Anthony Otley
- Department of Paediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Melvin B Heyman
- Department of Paediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, California, USA
| | - Sofia Verstraete
- Department of Paediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, California, USA
| | - Withney Sunseri
- Department of Paediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA
| | - Francisco Sylvester
- Division of Paediatric Gastroenterology, UNC Children's Hospital, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Tim de Meij
- Department of Paediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers - location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands
| | - Andre Comeau
- Integrated Microbiome Resource (IMR) and Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Morgan Langille
- Integrated Microbiome Resource (IMR) and Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Amsterdam, The Netherlands
- Department of Surgery, University of Bonn, Bonn, Nordrhein-Westfalen, Germany
| | - Marc A Benninga
- Department of Paediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers - location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands
| | - Johan E Van Limbergen
- Department of Paediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers - location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Amsterdam, The Netherlands
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21
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Zádori ZS, Király K, Al-Khrasani M, Gyires K. Interactions between NSAIDs, opioids and the gut microbiota - Future perspectives in the management of inflammation and pain. Pharmacol Ther 2023; 241:108327. [PMID: 36473615 DOI: 10.1016/j.pharmthera.2022.108327] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
The composition of intestinal microbiota is influenced by a number of factors, including medications, which may have a substantial impact on host physiology. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics are among those widely used medications that have been shown to alter microbiota composition in both animals and humans. Although much effort has been devoted to identify microbiota signatures associated with these medications, much less is known about the underlying mechanisms. Mucosal inflammation, changes in intestinal motility, luminal pH and bile acid metabolism, or direct drug-induced inhibitory effect on bacterial growth are all potential contributors to NSAID- and opioid-induced dysbiosis, however, only a few studies have addressed directly these issues. In addition, there is a notable overlap between the microbiota signatures of these drugs and certain diseases in which they are used, such as spondyloarthritis (SpA), rheumatoid arthritis (RA) and neuropathic pain associated with type 2 diabetes (T2D). The aims of the present review are threefold. First, we aim to provide a comprehensive up-to-date summary on the bacterial alterations caused by NSAIDs and opioids. Second, we critically review the available data on the possible underlying mechanisms of dysbiosis. Third, we review the current knowledge on gut dysbiosis associated with SpA, RA and neuropathic pain in T2D, and highlight the similarities between them and those caused by NSAIDs and opioids. We posit that drug-induced dysbiosis may contribute to the persistence of these diseases, and may potentially limit the therapeutic effect of these medications by long-term use. In this context, we will review the available literature data on the effect of probiotic supplementation and fecal microbiota transplantation on the therapeutic efficacy of NSAIDs and opioids in these diseases.
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Affiliation(s)
- Zoltán S Zádori
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
| | - Kornél Király
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Mahmoud Al-Khrasani
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Klára Gyires
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
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22
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Ardura MI, Kim SC. Infectious Complications of Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:687-697. [DOI: 10.1007/978-3-031-14744-9_49] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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23
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van Lier YF, Vos J, Blom B, Hazenberg MD. Allogeneic hematopoietic cell transplantation, the microbiome, and graft-versus-host disease. Gut Microbes 2023; 15:2178805. [PMID: 36794370 PMCID: PMC9980553 DOI: 10.1080/19490976.2023.2178805] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/17/2023] Open
Abstract
Many patients with hematological malignancies, such as acute myeloid leukemia, receive an allogeneic hematopoietic cell transplantation (HCT) to cure their underlying condition. Allogeneic HCT recipients are exposed to various elements during the pre-, peri- and post-transplant period that can disrupt intestinal microbiota, including chemo- and radiotherapy, antibiotics, and dietary changes. The dysbiotic post-HCT microbiome is characterized by low fecal microbial diversity, loss of anaerobic commensals, and intestinal domination, particularly by Enterococcus species, and is associated with poor transplant outcomes. Graft-versus-host disease (GvHD) is a frequent complication of allogeneic HCT caused by immunologic disparity between donor and host cells and results in tissue damage and inflammation. Microbiota injury is particularly pronounced in allogeneic HCT recipients who go on to develop GvHD. At present, manipulation of the microbiome for example, via dietary interventions, antibiotic stewardship, prebiotics, probiotics, or fecal microbiota transplantation, is widely being explored to prevent or treat gastrointestinal GvHD. This review discusses current insights into the role of the microbiome in GvHD pathogenesis and summarizes interventions to prevent and treat microbiota injury.
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Affiliation(s)
- Yannouck F. van Lier
- Department of Hematology, Amsterdam UMC location AMC, Amsterdam, The Netherlands,Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity Institute, Cancer Center Amsterdam, Amsterdam UMC location AMC, Amsterdam, The Netherlands
| | - Jaël Vos
- Department of Hematology, Amsterdam UMC location AMC, Amsterdam, The Netherlands,Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity Institute, Cancer Center Amsterdam, Amsterdam UMC location AMC, Amsterdam, The Netherlands
| | - Bianca Blom
- Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity Institute, Cancer Center Amsterdam, Amsterdam UMC location AMC, Amsterdam, The Netherlands
| | - Mette D. Hazenberg
- Department of Hematology, Amsterdam UMC location AMC, Amsterdam, The Netherlands,Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity Institute, Cancer Center Amsterdam, Amsterdam UMC location AMC, Amsterdam, The Netherlands,Department of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands,CONTACT Mette D. Hazenberg Department of Hematology, Amsterdam UMC, Meibergdreef 9, Amsterdam1105 AZ, The Netherlands
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24
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Yu J, Cheon JH. Microbial Modulation in Inflammatory Bowel Diseases. Immune Netw 2022; 22:e44. [PMID: 36627937 PMCID: PMC9807960 DOI: 10.4110/in.2022.22.e44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/30/2022] [Accepted: 11/02/2022] [Indexed: 12/30/2022] Open
Abstract
Gut dysbiosis is one of prominent features in inflammatory bowel diseases (IBDs) which are of an unknown etiology. Although the cause-and-effect relationship between IBD and gut dysbiosis remains to be elucidated, one area of research has focused on the management of IBD by modulating and correcting gut dysbiosis. The use of antibiotics, probiotics either with or without prebiotics, and fecal microbiota transplantation from healthy donors are representative methods for modulating the intestinal microbiota ecosystem. The gut microbiota is not a simple assembly of bacteria, fungi, and viruses, but a complex organ-like community system composed of numerous kinds of microorganisms. Thus, studies on specific changes in the gut microbiota depending on which treatment option is applied are very limited. Here, we review previous studies on microbial modulation as a therapeutic option for IBD and its significance in the pathogenesis of IBD.
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Affiliation(s)
- Jongwook Yu
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
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25
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Surman SL, Crawford J, Dash P, Tonkonogy SL, Thomas PG, Hurwitz JL. Microbiome Shapes the T Cell Receptor Repertoire among CD4+CD8+ Thymocytes. Biomedicines 2022; 10:3015. [PMID: 36551771 PMCID: PMC9775422 DOI: 10.3390/biomedicines10123015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 11/08/2022] [Accepted: 11/11/2022] [Indexed: 11/24/2022] Open
Abstract
The microbiome shapes the mature T cell receptor (TCR) repertoire and thereby influences pathogen control. To investigate microbiome influences on T cells at an earlier, immature stage, we compared single-cell TCR transcript sequences between CD4+CD8+ (double-positive) thymocytes from gnotobiotic [E. coli mono-associated (Ec)] and germ-free (GF) mice. Identical TCRβ transcripts (termed repeat, REP) were more often shared between cells of individual Ec mice compared to GF mice (Fishers Exact test, p < 0.0001). Among Ec REPs, a cluster of Vβ genes (Vβ12-1, 12-2, 13-1, and 13-2, termed 12-13) was well represented, whereas 12-13 sequences were not detected among GF REPs (Fishers Exact test, p = 0.046). Vα genes located in the distal region of the TCRα locus were more frequently expressed in Ec mice compared to GF mice, both among REPs and total sequences (Fishers Exact test, p = 0.009). Results illustrate how gut bacteria shape the TCR repertoire, not simply among mature T cells, but among immature CD4+CD8+ thymocytes.
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Affiliation(s)
- Sherri L. Surman
- Department of Infectious Diseases, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
| | - Jeremy Crawford
- Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
| | - Pradyot Dash
- Lentigen, a Miltenyi Biotec Company, Gaithersburg, MD 20878, USA
| | - Susan L. Tonkonogy
- College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
| | - Paul G. Thomas
- Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Julia L. Hurwitz
- Department of Infectious Diseases, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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26
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Viladomiu M, Khounlotham M, Dogan B, Lima SF, Elsaadi A, Cardakli E, Castellanos JG, Ng C, Herzog J, Schoenborn AA, Ellermann M, Liu B, Zhang S, Gulati AS, Sartor RB, Simpson KW, Lipkin SM, Longman RS. Agr2-associated ER stress promotes adherent-invasive E. coli dysbiosis and triggers CD103 + dendritic cell IL-23-dependent ileocolitis. Cell Rep 2022; 41:111637. [PMID: 36384110 PMCID: PMC9805753 DOI: 10.1016/j.celrep.2022.111637] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/06/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Endoplasmic reticulum (ER) stress is associated with Crohn's disease (CD), but its impact on host-microbe interaction in disease pathogenesis is not well defined. Functional deficiency in the protein disulfide isomerase anterior gradient 2 (AGR2) has been linked with CD and leads to epithelial cell ER stress and ileocolitis in mice and humans. Here, we show that ileal expression of AGR2 correlates with mucosal Enterobactericeae abundance in human inflammatory bowel disease (IBD) and that Agr2 deletion leads to ER-stress-dependent expansion of mucosal-associated adherent-invasive Escherichia coli (AIEC), which drives Th17 cell ileocolitis in mice. Mechanistically, our data reveal that AIEC-induced epithelial cell ER stress triggers CD103+ dendritic cell production of interleukin-23 (IL-23) and that IL-23R is required for ileocolitis in Agr2-/- mice. Overall, these data reveal a specific and reciprocal interaction of the expansion of the CD pathobiont AIEC with ER-stress-associated ileocolitis and highlight a distinct cellular mechanism for IL-23-dependent ileocolitis.
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Affiliation(s)
- Monica Viladomiu
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Manirath Khounlotham
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Belgin Dogan
- College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Svetlana F. Lima
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ahmed Elsaadi
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Emre Cardakli
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jim G. Castellanos
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Charles Ng
- Department of Pathology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jeremy Herzog
- Departments of Medicine and Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Alexi A. Schoenborn
- Department of Pediatrics, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Melissa Ellermann
- Departments of Medicine and Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA,Present address: Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Bo Liu
- Departments of Medicine and Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Shiying Zhang
- College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Ajay S. Gulati
- Department of Pediatrics, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - R. Balfour Sartor
- Departments of Medicine and Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kenneth W. Simpson
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA,College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Steven M. Lipkin
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA,Correspondence: (S.M.L.), (R.S.L.)
| | - Randy S. Longman
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA,Jill Roberts Center for IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA,Lead contact,Correspondence: (S.M.L.), (R.S.L.)
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27
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Wolstenholme JT, Saunders JM, Smith M, Kang JD, Hylemon PB, González-Maeso J, Fagan A, Zhao D, Sikaroodi M, Herzog J, Shamsaddini A, Peña-Rodríguez M, Su L, Tai YL, Zheng J, Cheng PC, Sartor RB, Gillevet PM, Zhou H, Bajaj JS. Reduced alcohol preference and intake after fecal transplant in patients with alcohol use disorder is transmissible to germ-free mice. Nat Commun 2022; 13:6198. [PMID: 36261423 PMCID: PMC9581985 DOI: 10.1038/s41467-022-34054-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 10/07/2022] [Indexed: 01/11/2023] Open
Abstract
Alcohol use disorder is a major cause of morbidity, which requires newer treatment approaches. We previously showed in a randomized clinical trial that alcohol craving and consumption reduces after fecal transplantation. Here, to determine if this could be transmitted through microbial transfer, germ-free male C57BL/6 mice received stool or sterile supernatants collected from the trial participants pre-/post-fecal transplant. We found that mice colonized with post-fecal transplant stool but not supernatants reduced ethanol acceptance, intake and preference versus pre-fecal transplant colonized mice. Microbial taxa that were higher in post-fecal transplant humans were also associated with lower murine alcohol intake and preference. A majority of the differentially expressed genes (immune response, inflammation, oxidative stress response, and epithelial cell proliferation) occurred in the intestine rather than the liver and prefrontal cortex. These findings suggest a potential for therapeutically targeting gut microbiota and the microbial-intestinal interface to alter gut-liver-brain axis and reduce alcohol consumption in humans.
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Affiliation(s)
- Jennifer T Wolstenholme
- VCU-Alcohol Research Center and Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
| | - Justin M Saunders
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA
| | - Maren Smith
- VCU-Alcohol Research Center and Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
| | - Jason D Kang
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Phillip B Hylemon
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA
| | - Javier González-Maeso
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA
| | - Andrew Fagan
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, VA, USA
| | - Derrick Zhao
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Jeremy Herzog
- National Gnotobiotic Rodent Research Center, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Marcela Peña-Rodríguez
- University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Lianyong Su
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Yun-Ling Tai
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Jing Zheng
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Po-Cheng Cheng
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - R Balfour Sartor
- National Gnotobiotic Rodent Research Center, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Huiping Zhou
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, VA, USA.
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Inflammatory Bowel Disease: A Review of Pre-Clinical Murine Models of Human Disease. Int J Mol Sci 2022; 23:ijms23169344. [PMID: 36012618 PMCID: PMC9409205 DOI: 10.3390/ijms23169344] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 12/11/2022] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are both highly inflammatory diseases of the gastrointestinal tract, collectively known as inflammatory bowel disease (IBD). Although the cause of IBD is still unclear, several experimental IBD murine models have enabled researchers to make great inroads into understanding human IBD pathology. Here, we discuss the current pre-clinical experimental murine models for human IBD, including the chemical-induced trinitrobenzene sulfonic acid (TNBS) model, oxazolone and dextran sulphate sodium (DSS) models, the gene-deficient I-kappa-B kinase gamma (Iκκ-γ) and interleukin(IL)-10 models, and the CD4+ T-cell transfer model. We offer a comprehensive review of how these models have been used to dissect the etiopathogenesis of disease, alongside their limitations. Furthermore, the way in which this knowledge has led to the translation of experimental findings into novel clinical therapeutics is also discussed.
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Federici S, Kredo-Russo S, Valdés-Mas R, Kviatcovsky D, Weinstock E, Matiuhin Y, Silberberg Y, Atarashi K, Furuichi M, Oka A, Liu B, Fibelman M, Weiner IN, Khabra E, Cullin N, Ben-Yishai N, Inbar D, Ben-David H, Nicenboim J, Kowalsman N, Lieb W, Kario E, Cohen T, Geffen YF, Zelcbuch L, Cohen A, Rappo U, Gahali-Sass I, Golembo M, Lev V, Dori-Bachash M, Shapiro H, Moresi C, Cuevas-Sierra A, Mohapatra G, Kern L, Zheng D, Nobs SP, Suez J, Stettner N, Harmelin A, Zak N, Puttagunta S, Bassan M, Honda K, Sokol H, Bang C, Franke A, Schramm C, Maharshak N, Sartor RB, Sorek R, Elinav E. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell 2022; 185:2879-2898.e24. [PMID: 35931020 DOI: 10.1016/j.cell.2022.07.003] [Citation(s) in RCA: 282] [Impact Index Per Article: 94.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/17/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023]
Abstract
Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.
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Affiliation(s)
- Sara Federici
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Sharon Kredo-Russo
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Rafael Valdés-Mas
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Denise Kviatcovsky
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Eyal Weinstock
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA; Molecular Genetics Department, Weizmann Institute of Science, Rehovot, Israel
| | - Yulia Matiuhin
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Yael Silberberg
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Koji Atarashi
- RIKEN Center for Integrative Medical Sciences (IMS), Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
| | - Munehiro Furuichi
- RIKEN Center for Integrative Medical Sciences (IMS), Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
| | - Akihiko Oka
- Department of Internal Medicine II, Shimane University, Shimane, Japan; Division of Gastroenterology and Hepatology, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599-7032, USA
| | - Bo Liu
- Division of Gastroenterology and Hepatology, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599-7032, USA
| | - Morine Fibelman
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Internal Medicine "A", Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Iddo Nadav Weiner
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Efrat Khabra
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Nyssa Cullin
- Division of Microbiome & Cancer, DKFZ, Heidelberg, Germany
| | - Noa Ben-Yishai
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Dana Inbar
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Hava Ben-David
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Julian Nicenboim
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Noga Kowalsman
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Wolfgang Lieb
- Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Edith Kario
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Tal Cohen
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Yael Friedman Geffen
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Lior Zelcbuch
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Ariel Cohen
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Urania Rappo
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Inbar Gahali-Sass
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Myriam Golembo
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Vered Lev
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Mally Dori-Bachash
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Hagit Shapiro
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Claudia Moresi
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | | | - Gayatree Mohapatra
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Lara Kern
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Danping Zheng
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Samuel Philip Nobs
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Jotham Suez
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Noa Stettner
- Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel
| | - Alon Harmelin
- Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel
| | - Naomi Zak
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Sailaja Puttagunta
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Merav Bassan
- BiomX Ltd., 22 Einstein St., Ness Ziona, 7414001, Israel; BiomX Inc., 36 E Industrial Road, Branford, CT 06405, USA
| | - Kenya Honda
- RIKEN Center for Integrative Medical Sciences (IMS), Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
| | - Harry Sokol
- Sorbonne Université, INSERM UMRS-938, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Paris, France; Paris Center for Microbiome Medicine, Fédération Hospitalo-Universitaire, Paris, France; INRAE, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France
| | - Corinna Bang
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; University Hospital of Schleswig-Holstein (UKSH), Kiel Campus, Kiel, Germany
| | - Christoph Schramm
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nitsan Maharshak
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ryan Balfour Sartor
- Division of Gastroenterology and Hepatology, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599-7032, USA
| | - Rotem Sorek
- Molecular Genetics Department, Weizmann Institute of Science, Rehovot, Israel
| | - Eran Elinav
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel; Division of Microbiome & Cancer, DKFZ, Heidelberg, Germany.
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Xing C, Du Y, Duan T, Nim K, Chu J, Wang HY, Wang RF. Interaction between microbiota and immunity and its implication in colorectal cancer. Front Immunol 2022; 13:963819. [PMID: 35967333 PMCID: PMC9373904 DOI: 10.3389/fimmu.2022.963819] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the world. Besides genetic causes, colonic inflammation is one of the major risk factors for CRC development, which is synergistically regulated by multiple components, including innate and adaptive immune cells, cytokine signaling, and microbiota. The complex interaction between CRC and the gut microbiome has emerged as an important area of current CRC research. Metagenomic profiling has identified a number of prominent CRC-associated bacteria that are enriched in CRC patients, linking the microbiota composition to colitis and cancer development. Some microbiota species have been reported to promote colitis and CRC development in preclinical models, while a few others are identified as immune modulators to induce potent protective immunity against colitis and CRC. Mechanistically, microbiota regulates the activation of different immune cell populations, inflammation, and CRC via crosstalk between innate and adaptive immune signaling pathways, including nuclear factor kappa B (NF-κB), type I interferon, and inflammasome. In this review, we provide an overview of the potential interactions between gut microbiota and host immunity and how their crosstalk could synergistically regulate inflammation and CRC, thus highlighting the potential roles and mechanisms of gut microbiota in the development of microbiota-based therapies to prevent or alleviate colitis and CRC.
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Affiliation(s)
- Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Kelly Nim
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Junjun Chu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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Buttimer C, Sutton T, Colom J, Murray E, Bettio PH, Smith L, Bolocan AS, Shkoporov A, Oka A, Liu B, Herzog JW, Sartor RB, Draper LA, Ross RP, Hill C. Impact of a phage cocktail targeting Escherichia coli and Enterococcus faecalis as members of a gut bacterial consortium in vitro and in vivo. Front Microbiol 2022; 13:936083. [PMID: 35935217 PMCID: PMC9355613 DOI: 10.3389/fmicb.2022.936083] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 07/01/2022] [Indexed: 01/14/2023] Open
Abstract
Escherichia coli and Enterococcus faecalis have been implicated as important players in human gut health that have been associated with the onset of inflammatory bowel disease (IBD). Bacteriophage (phage) therapy has been used for decades to target pathogens as an alternative to antibiotics, but the ability of phage to shape complex bacterial consortia in the lower gastrointestinal tract is not clearly understood. We administered a cocktail of six phages (either viable or heat-inactivated) targeting pro-inflammatory Escherichia coli LF82 and Enterococcus faecalis OG1RF as members of a defined community in both a continuous fermenter and a murine colitis model. The two target strains were members of a six species simplified human microbiome consortium (SIHUMI-6). In a 72-h continuous fermentation, the phage cocktail caused a 1.1 and 1.5 log (log10 genome copies/mL) reduction in E. faecalis and E. coli numbers, respectively. This interaction was accompanied by changes in the numbers of other SIHUMI-6 members, with an increase of Lactiplantibacillus plantarum (1.7 log) and Faecalibacterium prausnitzii (1.8 log). However, in germ-free mice colonized by the same bacterial consortium, the same phage cocktail administered twice a week over nine weeks did not cause a significant reduction of the target strains. Mice treated with active or inactive phage had similar levels of pro-inflammatory cytokines (IFN-y/IL12p40) in unstimulated colorectal colonic strip cultures. However, histology scores of the murine lower GIT (cecum and distal colon) were lower in the viable phage-treated mice, suggesting that the phage cocktail did influence the functionality of the SIHUMI-6 consortium. For this study, we conclude that the observed potential of phages to reduce host populations in in vitro models did not translate to a similar outcome in an in vivo setting, with this effect likely brought about by the reduction of phage numbers during transit of the mouse GIT.
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Affiliation(s)
- Colin Buttimer
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Tom Sutton
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Joan Colom
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Ellen Murray
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Pedro H. Bettio
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Linda Smith
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | | | | | - Akihiko Oka
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Internal Medicine II, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Bo Liu
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jeremy W. Herzog
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - R. Balfour Sartor
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | | | - R. Paul Ross
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Colin Hill
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- School of Microbiology, University College Cork, Cork, Ireland
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32
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Lopez LR, Ahn JH, Alves T, Arthur JC. Microenvironmental Factors that Shape Bacterial Metabolites in Inflammatory Bowel Disease. Front Cell Infect Microbiol 2022; 12:934619. [PMID: 35959366 PMCID: PMC9362432 DOI: 10.3389/fcimb.2022.934619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/21/2022] [Indexed: 11/17/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a significant global health problem that involves chronic intestinal inflammation and can involve severe comorbidities, including intestinal fibrosis and inflammation-associated colorectal cancer (CRC). Disease-associated alterations to the intestinal microbiota often include fecal enrichment of Enterobacteriaceae, which are strongly implicated in IBD development. This dysbiosis of intestinal flora accompanies changes in microbial metabolites, shaping host:microbe interactions and disease risk. While there have been numerous studies linking specific bacterial taxa with IBD development, our understanding of microbial function in the context of IBD is limited. Several classes of microbial metabolites have been directly implicated in IBD disease progression, including bacterial siderophores and genotoxins. Yet, our microbiota still harbors thousands of uncharacterized microbial products. In-depth discovery and characterization of disease-associated microbial metabolites is necessary to target these products in IBD treatment strategies. Towards improving our understanding of microbiota metabolites in IBD, it is important to recognize how host relevant factors influence microbiota function. For example, changes in host inflammation status, metal availability, interbacterial community structure, and xenobiotics all play an important role in shaping gut microbial ecology. In this minireview, we outline how each of these factors influences gut microbial function, with a specific focus on IBD-associated Enterobacteriaceae metabolites. Importantly, we discuss how altering the intestinal microenvironment could improve the treatment of intestinal inflammation and associated disorders, like intestinal fibrosis and CRC.
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Affiliation(s)
- Lacey R. Lopez
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ju-Hyun Ahn
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Tomaz Alves
- Division of Comprehensive Oral Health, Adams School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Janelle C. Arthur
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Center for Gastrointestinal Biology and Disease, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- *Correspondence: Janelle C. Arthur,
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Liu Y, Yang M, Tang L, Wang F, Huang S, Liu S, Lei Y, Wang S, Xie Z, Wang W, Zhao X, Tang B, Yang S. TLR4 regulates RORγt + regulatory T-cell responses and susceptibility to colon inflammation through interaction with Akkermansia muciniphila. MICROBIOME 2022; 10:98. [PMID: 35761415 PMCID: PMC9235089 DOI: 10.1186/s40168-022-01296-x] [Citation(s) in RCA: 95] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 05/25/2022] [Indexed: 05/05/2023]
Abstract
BACKGROUND Well-balanced interactions between gut microbiota and the immune system are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). Toll-like receptor 4 (TLR4) functions as a sensor mediating the crosstalk between the intestinal commensal microbiome and host immunity, but the influence of TLR4 on the shaping of intestinal microbiota and immune responses during colon inflammation remains poorly characterized. We investigated whether the different susceptibilities to colitis between wild-type (WT) and TLR4-/- mice were gut microbiota-dependent and aimed to identify the potential immunity modulation mechanism. METHODS We performed antibiotic depletion of the microbiota, cohousing experiments, and faecal microbiota transplantation (FMT) in WT and TLR4-/- mice to assess the influence of TLR4 on intestinal microbial ecology. 16S rRNA sequencing was performed to dissect microbial discrepancies, and dysbiosis-associated immune perturbation was investigated by flow cytometry. Akkermansia muciniphila (A. muciniphila)-mediated immune modulation was confirmed through the T-cell transfer colitis model and bone marrow chimaera construction. RESULTS TLR4-/- mice experienced enhanced susceptibility to DSS-induced colitis. 16S rRNA sequencing showed notable discrepancy in the gut microbiota between WT and TLR4-/- mice. In particular, A. muciniphila contributed most to distinguishing the two groups. The T-cell transfer colitis model and bone marrow transplantation (BMT) consistently demonstrated that A. muciniphila ameliorated colitis by upregulating RORγt+ Treg cell-mediated immune responses. Mucosal biopsies from human manifested parallel outcomes with colon tissue from WT mice, as evidenced by the positive correlation between TLR4 expression and intestinal A. muciniphila colonization during homeostasis. CONCLUSIONS Our results demonstrate a novel protective role of TLR4 against intestinal inflammation, wherein it can modulate A. muciniphila-associated immune responses. These findings provide a new perspective on host-commensal symbiosis, which may be beneficial for developing potential therapeutic strategies. Video abstract.
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Affiliation(s)
- Yaojiang Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Min Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Li Tang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Fengchao Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, College of Preventive Medicine, Third Military Medical University, Chongqing, 400037, China
| | - Shengjie Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Shuang Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Yuanyuan Lei
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Sumin Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Zhuo Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Wei Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Xiaoyan Zhao
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China.
| | - Bo Tang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China.
| | - Shiming Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China.
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Lee SY, Byun HJ, Choi H, Won JI, Han J, Park S, Kim D, Sung JH. Development of a Pumpless Microfluidic System to Study the Interaction between Gut Microbes and Intestinal Epithelial Cells. BIOTECHNOL BIOPROC E 2022. [DOI: 10.1007/s12257-021-0268-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Zhang Z, Tanaka I, Pan Z, Ernst PB, Kiyono H, Kurashima Y. Intestinal homeostasis and inflammation: gut microbiota at the crossroads of pancreas-intestinal barrier axis. Eur J Immunol 2022; 52:1035-1046. [PMID: 35476255 PMCID: PMC9540119 DOI: 10.1002/eji.202149532] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 11/24/2022]
Abstract
The pancreas contains exocrine glands, which release enzymes (e.g., amylase, trypsin, and lipase) that are important for digestion and islets, which produce hormones. Digestive enzymes and hormones are secreted from the pancreas into the duodenum and bloodstream, respectively. Growing evidence suggests that the roles of the pancreas extend to not only the secretion of digestive enzymes and hormones but also to the regulation of intestinal homeostasis and inflammation (e.g., mucosal defense to pathogens and pathobionts). Organ crosstalk between the pancreas and intestine is linked to a range of physiological, immunological, and pathological activities, such as the regulation of the gut microbiota by the pancreatic proteins and lipids, the retroaction of the gut microbiota on the pancreas, the relationship between inflammatory bowel disease, and pancreatic diseases. We herein discuss the current understanding of the pancreas–intestinal barrier axis and the control of commensal bacteria in intestinal inflammation.
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Affiliation(s)
- Zhongwei Zhang
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Izumi Tanaka
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Zhen Pan
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Peter B Ernst
- Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, CA, 92093-0956, USA.,Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, CA, 92093-0956, USA.,Departments of Medicine and Pathology, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), University of California, San Diego, CA, 92093-0956, USA.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Hiroshi Kiyono
- Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, CA, 92093-0956, USA.,Departments of Medicine and Pathology, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), University of California, San Diego, CA, 92093-0956, USA.,Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,Department of Human Mucosal Vaccinology, Chiba University, Chiba, 260-8670, Japan
| | - Yosuke Kurashima
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.,Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, CA, 92093-0956, USA.,Departments of Medicine and Pathology, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), University of California, San Diego, CA, 92093-0956, USA.,Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,Department of Human Mucosal Vaccinology, Chiba University, Chiba, 260-8670, Japan.,Institute for Advanced Academic Research, Chiba University, Chiba, 260-8670, Japan
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Hayashi Y, Nakase H. The Molecular Mechanisms of Intestinal Inflammation and Fibrosis in Crohn’s Disease. Front Physiol 2022; 13:845078. [PMID: 35222098 PMCID: PMC8874128 DOI: 10.3389/fphys.2022.845078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 01/26/2022] [Indexed: 12/20/2022] Open
Abstract
Crohn’s disease (CD) is an inflammatory bowel disease (IBD) with repeated remissions and relapses. As the disease progresses, fibrosis and narrowing of the intestine occur, leading to severe complications such as intestinal obstruction. Endoscopic balloon dilatation, surgical stricture plasty, and bowel resection have been performed to treat intestinal stenosis. The clinical issue is that some patients with CD have a recurrence of intestinal stenosis even after the medical treatments. On the other hand, there exist no established medical therapies to prevent stenosis. With the progressive intestinal inflammation, cytokines and growth factors, including transforming growth factor (TGF-β), stimulate intestinal myofibroblasts, contributing to fibrosis of the intestine, smooth muscle hypertrophy, and mesenteric fat hypertrophy. Therefore, chronically sustained inflammation has long been considered a cause of intestinal fibrosis and stenosis. Still, even after the advent of biologics and tighter control of inflammation, intestinal fibrosis’s surgical rate has not necessarily decreased. It is essential to elucidate the mechanisms involved in intestinal fibrosis in CD from a molecular biological level to overcome clinical issues. Recently, much attention has been paid to several key molecules of intestinal fibrosis: peroxisome proliferator-activating receptor gamma (PPARγ), toll-like receptor 4 (TLR4), adherent-invasive Escherichia coli (AIEC), Th17 immune response, and plasminogen activator inhibitor 1 (PAI-1). As a major problem in the treatment of CD, the pathophysiology of patients with CD is not the same and varies depending on each patient. It is necessary to integrate these key molecules for a better understanding of the mechanism of intestinal inflammation and fibrosis.
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Dietary Alaska Pollock Protein Attenuates the Experimental Colitis Induced by Dextran Sulfate Sodium via Regulation of Gut Microbiota and Its Metabolites in Mice. Metabolites 2022; 12:metabo12010044. [PMID: 35050166 PMCID: PMC8779829 DOI: 10.3390/metabo12010044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 02/07/2023] Open
Abstract
Protein derived from fish has not only nutritional properties but also health-promoting properties. Few studies have examined the effect of dietary Alaska pollock protein (APP) on the anticolitis effect reported to be associated with metabolic syndrome (MetS). This study investigated the effect of APP intake on colitis symptoms, gut microbiota, and its metabolites in the experimental colitis mouse model induced by dextran sulfate sodium (DSS). Male C57BL/6J mice were divided into three groups: (1) DSS-untreated mice fed an American Institute of Nutrition (AIN) 93G diet (protein source is casein), (2) DSS-treated mice fed an AIN93G diet, and (3) DSS-treated mice fed an APP diet. After the mice were fed the diets for 21 days, experimental colitis was induced by three cycles of 2% DSS administration for 5 days followed by washouts over the course of 5 days. APP-reduced body weight loss increased the disease activity index, and elevated spleen weight and alleviated colon length shortening and colonic tissue damage. Furthermore, APP altered the structure and composition of the microbiota and short-chain fatty acids in feces. Since APP intake alleviates experimental colitis induced by DSS administration through alterations in the gut microbiota and its metabolites, we deduced that APP would inhibit MetS progression via colitis suppression.
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Gut microbiome dysbiosis in inflammatory bowel disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2022; 192:179-204. [DOI: 10.1016/bs.pmbts.2022.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Zhang J, Xu X, Li N, Cao L, Sun Y, Wang J, He S, Si J, Qing D. Licoflavone B, an isoprene flavonoid derived from licorice residue, relieves dextran sodium sulfate-induced ulcerative colitis by rebuilding the gut barrier and regulating intestinal microflora. Eur J Pharmacol 2021; 916:174730. [PMID: 34968462 DOI: 10.1016/j.ejphar.2021.174730] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 11/23/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022]
Abstract
Ulcerative colitis (UC) is a major inflammatory disease worldwide. We previously demonstrated that licorice residue flavones (LFs) showed satisfactory efficacy in the treatment of UC. Therefore, research into the ingredients of LFs may lead to the discovery of novel anti-UC targets. In the current study, we separated licoflavone B (LB) from LFs and administered it to dextran sodium sulfate (DSS)-exposed C57BL/6 mice for 14 days. Our results demonstrated that high dose LB (120mg/kg) significantly prevented DSS-induced weight loss, disease activity index (DAI) increase, histological damage, and colonic inflammation, indicating that LB has ameliorative effects on UC. We also investigated the composition of the intestinal barrier and microflora in an attempt to explore the mechanisms of LB against UC. As a result, we found that LB preserved the integrity of the colonic barrier by inhibiting colonic cell apoptosis and protecting the expression of occludin, claudin-1, and ZO-1. Moreover, LB reshaped the microflora composition by suppressing harmful bacteria (Enterococcus et al.) and boosting beneficial microorganisms (Bacteroides et al.). Further molecular exploration implied that LB exerted anti-UC activity through blocking the MAPK pathway. Here, we explored anti-UC activity of LB for the first time and clarified its mechanisms. These results will provide valuable clues for the discovery of novel anti-UC agents.
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Affiliation(s)
- Juan Zhang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China; XinJiang Institute of Chinese Materia Medica and Ethnodrug, Urumqi, 830002, China
| | - Xiaoqin Xu
- XinJiang Institute of Chinese Materia Medica and Ethnodrug, Urumqi, 830002, China
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Li Cao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Yu Sun
- XinJiang Institute of Chinese Materia Medica and Ethnodrug, Urumqi, 830002, China
| | - Junchi Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Shuaibing He
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou Central Hospital, Huzhou, 313000, China
| | - Jianyong Si
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China.
| | - Degang Qing
- XinJiang Institute of Chinese Materia Medica and Ethnodrug, Urumqi, 830002, China.
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Long-read sequencing to interrogate strain-level variation among adherent-invasive Escherichia coli isolated from human intestinal tissue. PLoS One 2021; 16:e0259141. [PMID: 34710159 PMCID: PMC8553045 DOI: 10.1371/journal.pone.0259141] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/13/2021] [Indexed: 01/19/2023] Open
Abstract
Adherent-invasive Escherichia coli (AIEC) is a pathovar linked to inflammatory bowel diseases (IBD), especially Crohn’s disease, and colorectal cancer. AIEC are genetically diverse, and in the absence of a universal molecular signature, are defined by in vitro functional attributes. The relative ability of difference AIEC strains to colonize, persist, and induce inflammation in an IBD-susceptible host is unresolved. To evaluate strain-level variation among tissue-associated E. coli in the intestines, we develop a long-read sequencing approach to identify AIEC by strain that excludes host DNA. We use this approach to distinguish genetically similar strains and assess their fitness in colonizing the intestine. Here we have assembled complete genomes using long-read nanopore sequencing for a model AIEC strain, NC101, and seven strains isolated from the intestinal mucosa of Crohn’s disease and non-Crohn’s tissues. We show these strains can colonize the intestine of IBD susceptible mice and induce inflammatory cytokines from cultured macrophages. We demonstrate that these strains can be quantified and distinguished in the presence of 99.5% mammalian DNA and from within a fecal population. Analysis of global genomic structure and specific sequence variation within the ribosomal RNA operon provides a framework for efficiently tracking strain-level variation of closely-related E. coli and likely other commensal/pathogenic bacteria impacting intestinal inflammation in experimental settings and IBD patients.
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Ferchichi M, Sebei K, Boukerb AM, Karray-Bouraoui N, Chevalier S, Feuilloley MGJ, Connil N, Zommiti M. Enterococcus spp.: Is It a Bad Choice for a Good Use-A Conundrum to Solve? Microorganisms 2021; 9:2222. [PMID: 34835352 PMCID: PMC8622268 DOI: 10.3390/microorganisms9112222] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Since antiquity, the ubiquitous lactic acid bacteria (LAB) Enterococci, which are just as predominant in both human and animal intestinal commensal flora, have been used (and still are) as probiotics in food and feed production. Their qualities encounter several hurdles, particularly in terms of the array of virulence determinants, reflecting a notorious reputation that nearly prevents their use as probiotics. Additionally, representatives of the Enterococcus spp. genus showed intrinsic resistance to several antimicrobial agents, and flexibility to acquire resistance determinants encoded on a broad array of conjugative plasmids, transposons, and bacteriophages. The presence of such pathogenic aspects among some species represents a critical barrier compromising their use as probiotics in food. Thus, the genus neither has Generally Recognized as Safe (GRAS) status nor has it been included in the Qualified Presumption of Safety (QPS) list implying drastic legislation towards these microorganisms. To date, the knowledge of the virulence factors and the genetic structure of foodborne enterococcal strains is rather limited. Although enterococcal infections originating from food have never been reported, the consumption of food carrying virulence enterococci seems to be a risky path of transfer, and hence, it renders them poor choices as probiotics. Auspiciously, enterococcal virulence factors seem to be strain specific suggesting that clinical isolates carry much more determinants that food isolates. The latter remain widely susceptible to clinically relevant antibiotics and subsequently, have a lower potential for pathogenicity. In terms of the ideal enterococcal candidate, selected strains deemed for use in foods should not possess any virulence genes and should be susceptible to clinically relevant antibiotics. Overall, implementation of an appropriate risk/benefit analysis, in addition to the case-by-case assessment, the establishment of a strain's innocuity, and consideration for relevant guidelines, legislation, and regulatory aspects surrounding functional food development seem to be the crucial elements for industries, health-staff and consumers to accept enterococci, like other LAB, as important candidates for useful and beneficial applications in food industry and food biotechnology. The present review aims at shedding light on the world of hurdles and limitations that hampers the Enterococcus spp. genus and its representatives from being used or proposed for use as probiotics. The future of enterococci use as probiotics and legislation in this field are also discussed.
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Affiliation(s)
- Mounir Ferchichi
- Unité de Protéomique Fonctionnelle et Potentiel Nutraceutique de la Biodiversité de Tunisie, Institut Supérieur des Sciences Biologiques Appliquées de Tunis, Université de Tunis El Manar, Tunis 1006, Tunisia; (M.F.); (K.S.)
| | - Khaled Sebei
- Unité de Protéomique Fonctionnelle et Potentiel Nutraceutique de la Biodiversité de Tunisie, Institut Supérieur des Sciences Biologiques Appliquées de Tunis, Université de Tunis El Manar, Tunis 1006, Tunisia; (M.F.); (K.S.)
| | - Amine Mohamed Boukerb
- Laboratoire de Microbiologie, Signaux et Microenvironnement (LMSM) EA 4312, Université de Rouen Normandie, 27000 Evreux, France; (A.M.B.); (S.C.); (M.G.J.F.); (N.C.)
| | - Najoua Karray-Bouraoui
- Laboratoire de Productivité Végétale et Contraintes Abiotiques, LR18ES04, Faculté des Sciences de Tunis, Université Tunis El Manar, Tunis 2092, Tunisia;
| | - Sylvie Chevalier
- Laboratoire de Microbiologie, Signaux et Microenvironnement (LMSM) EA 4312, Université de Rouen Normandie, 27000 Evreux, France; (A.M.B.); (S.C.); (M.G.J.F.); (N.C.)
| | - Marc G. J. Feuilloley
- Laboratoire de Microbiologie, Signaux et Microenvironnement (LMSM) EA 4312, Université de Rouen Normandie, 27000 Evreux, France; (A.M.B.); (S.C.); (M.G.J.F.); (N.C.)
| | - Nathalie Connil
- Laboratoire de Microbiologie, Signaux et Microenvironnement (LMSM) EA 4312, Université de Rouen Normandie, 27000 Evreux, France; (A.M.B.); (S.C.); (M.G.J.F.); (N.C.)
| | - Mohamed Zommiti
- Laboratoire de Microbiologie, Signaux et Microenvironnement (LMSM) EA 4312, Université de Rouen Normandie, 27000 Evreux, France; (A.M.B.); (S.C.); (M.G.J.F.); (N.C.)
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Rousta E, Oka A, Liu B, Herzog J, Bhatt AP, Wang J, Habibi Najafi MB, Sartor RB. The Emulsifier Carboxymethylcellulose Induces More Aggressive Colitis in Humanized Mice with Inflammatory Bowel Disease Microbiota Than Polysorbate-80. Nutrients 2021; 13:3565. [PMID: 34684567 PMCID: PMC8540676 DOI: 10.3390/nu13103565] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/27/2021] [Accepted: 10/08/2021] [Indexed: 12/11/2022] Open
Abstract
Commonly used synthetic dietary emulsifiers, including carboxymethylcellulose (CMC) and polysorbate-80 (P80), promote intestinal inflammation. We compared abilities of CMC vs. P80 to potentiate colitis and impact human microbiota in an inflammatory environment using a novel colitis model of ex-germ-free (GF) IL10-/- mice colonized by pooled fecal transplant from three patients with active inflammatory bowel diseases. After three days, mice received 1% CMC or P80 in drinking water or water alone for four weeks. Inflammation was quantified by serial fecal lipocalin 2 (Lcn-2) and after four weeks by blinded colonic histologic scores and colonic inflammatory cytokine gene expression. Microbiota profiles in cecal contents were determined by shotgun metagenomic sequencing. CMC treatment significantly increased fecal Lcn-2 levels compared to P80 and water treatment by one week and throughout the experiment. Likewise, CMC treatment increased histologic inflammatory scores and colonic inflammatory cytokine gene expression compared with P80 and water controls. The two emulsifiers differentially affected specific intestinal microbiota. CMC did not impact bacterial composition but significantly decreased Caudoviricetes (bacteriophages), while P80 exposure non-significantly increased the abundance of both Actinobacteria and Proteobacteria. Commonly used dietary emulsifiers have different abilities to induce colitis in humanized mice. CMC promotes more aggressive inflammation without changing bacterial composition.
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Affiliation(s)
- Esmat Rousta
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA; (E.R.); (A.O.); (B.L.); (J.H.); (A.P.B.)
- Department of Food Science and Technology, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
| | - Akihiko Oka
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA; (E.R.); (A.O.); (B.L.); (J.H.); (A.P.B.)
- Department of Internal Medicine II, Faculty of Medicine, Shimane University, 89-1, Enya, Izumo, Shimane 693-8501, Japan
| | - Bo Liu
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA; (E.R.); (A.O.); (B.L.); (J.H.); (A.P.B.)
| | - Jeremy Herzog
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA; (E.R.); (A.O.); (B.L.); (J.H.); (A.P.B.)
| | - Aadra P. Bhatt
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA; (E.R.); (A.O.); (B.L.); (J.H.); (A.P.B.)
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA;
| | - Jeremy Wang
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA;
- Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA
| | - Mohammad B. Habibi Najafi
- Department of Food Science and Technology, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
| | - Ryan Balfour Sartor
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA; (E.R.); (A.O.); (B.L.); (J.H.); (A.P.B.)
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA;
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC 27599, USA
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Kidess E, Kleerebezem M, Brugman S. Colonizing Microbes, IL-10 and IL-22: Keeping the Peace at the Mucosal Surface. Front Microbiol 2021; 12:729053. [PMID: 34603258 PMCID: PMC8484919 DOI: 10.3389/fmicb.2021.729053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/25/2021] [Indexed: 12/15/2022] Open
Abstract
Our world is filled with microbes. Each multicellular organism has developed ways to interact with this microbial environment. Microbes do not always pose a threat; they can contribute to many processes that benefit the host. Upon colonization both host and microbes adapt resulting in dynamic ecosystems in different host niches. Regulatory processes develop within the host to prevent overt inflammation to beneficial microbes, yet keeping the possibility to respond when pathogens attempt to adhere and invade tissues. This review will focus on microbial colonization and the early (innate) host immune response, with special emphasis on the microbiota-modifying roles of IL-10 and IL-22 in the intestine. IL-10 knock out mice show an altered microbial composition, and spontaneously develop enterocolitis over time. IL-22 knock out mice, although not developing enterocolitis spontaneously, also have an altered microbial composition and increase of epithelial-adherent bacteria, mainly caused by a decrease in mucin and anti-microbial peptide production. Recently interesting links have been found between the IL-10 and IL-22 pathways. While IL-22 can function as a regulatory cytokine at the mucosal surface, it also has inflammatory roles depending on the context. For example, lack of IL-22 in the IL-10–/– mice model prevents spontaneous colitis development. Additionally, the reduced microbial diversity observed in IL-10–/– mice was also reversed in IL-10/IL-22 double mutant mice (Gunasekera et al., 2020). Since in early life, host immunity develops in parallel and in interaction with colonizing microbes, there is a need for future studies that focus on the effect of the timing of colonization in relation to the developmental phase of the host. To illustrate this, examples from zebrafish research will be compared with studies performed in mammals. Since zebrafish develop from eggs and are directly exposed to the outside microbial world, timing of the development of host immunity and subsequent control of microbial composition, is different from mammals that develop in utero and only get exposed after birth. Likewise, colonization studies using adult germfree mice might yield different results from those using neonatal germfree mice. Lastly, special emphasis will be given to the need for host genotype and environmental (co-housing) control of experiments.
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Affiliation(s)
- Evelien Kidess
- Animal Sciences Group, Host-Microbe Interactomics, Wageningen University and Research, Wageningen, Netherlands
| | - Michiel Kleerebezem
- Animal Sciences Group, Host-Microbe Interactomics, Wageningen University and Research, Wageningen, Netherlands
| | - Sylvia Brugman
- Animal Sciences Group, Host-Microbe Interactomics, Wageningen University and Research, Wageningen, Netherlands
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Gupta T, Kaur H, Kapila S, Kapila R. Potential probiotic Lacticaseibacillus rhamnosus MTCC-5897 attenuates Escherichia coli induced inflammatory response in intestinal cells. Arch Microbiol 2021; 203:5703-5713. [PMID: 34476513 DOI: 10.1007/s00203-021-02541-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/31/2021] [Accepted: 08/18/2021] [Indexed: 12/31/2022]
Abstract
Probiotics are microbes having tremendous potential to prevent gastrointestinal disorders. In current investigation, immunomodulatory action of probiotic Lacticaseibacillus rhamnosus MTCC-5897 was studied during exclusion, competition and displacement of Escherichia coli on intestinal epithelial (Caco-2) cells. The incubation of intestinal cells with Escherichia coli, enhanced downstream signalling and activated nuclear factor kappa B (NF-κB). This significantly increased (p < 0.01) the pro-inflammatory cytokines (IL-8, TNF-α, IFN-ϒ) expression. While, incubation of epithelial cells with Lacticaseibacillus rhamnosus during exclusion and competition with Escherichia coli, counteracted these enhanced expressions. The immunomodulatory feature of Lacticaseibacillus rhamnosus was also highlighted with increased (p < 0.05) transcription of toll-like receptor-2 (TLR-2) and single Ig IL-1-related receptor (SIGIRR) along with diminished expression of TLR-4. Likewise, attenuation (p < 0.05) of E. coli-mediated enhanced nuclear translocation of NF-κB p-65 subunit by Lacticaseibacillus rhamnosus during exclusion was confirmed with western blotting. Thus, present finding establishes the prophylactic potential of Lacticaseibacillus rhamnosus against exclusion of Escherichia coli in intestinal cells.
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Affiliation(s)
- Taruna Gupta
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India
| | - Harpreet Kaur
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India
| | - Suman Kapila
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India
| | - Rajeev Kapila
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India.
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45
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Pierre N, Salée C, Vieujean S, Bequet E, Merli AM, Siegmund B, Meuwis MA, Louis E. Review article: distinctions between ileal and colonic Crohn's disease: from physiology to pathology. Aliment Pharmacol Ther 2021; 54:779-791. [PMID: 34297423 DOI: 10.1111/apt.16536] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/15/2021] [Accepted: 07/05/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Ileal and colonic Crohn's disease seem to be two separate entities. AIMS To describe the main physiological distinctions between the small and the large intestine and to analyse the differences between ileal and colonic Crohn's disease. METHODS The relevant literature was critically examined and synthesised. RESULTS The small and large intestine have fundamental distinctions (anatomy, cellular populations, immune defence, microbiota). The differences between ileal and colonic Crohn's disease are highlighted by a heterogeneous body of evidence including clinical features (natural history of the disease, efficacy of treatments, and monitoring), epidemiological data (smoking status, age, gender) and biological data (genetics, microbiota, immunity, mesenteric fat). However, the contribution of these factors to disease location remains poorly understood. CONCLUSION The classification of ileal and colonic Crohn's disease as distinct subphenotypes is well supported by the literature. Understanding of these differences could be exploited to develop more individualised patient care.
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Affiliation(s)
- Nicolas Pierre
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium
| | - Catherine Salée
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium
| | - Sophie Vieujean
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
| | - Emeline Bequet
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Liège University Hospital, Liège, Belgium
| | - Angela-Maria Merli
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium
| | - Britta Siegmund
- Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Marie-Alice Meuwis
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
| | - Edouard Louis
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
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46
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Intestinal immunoregulation: lessons from human mendelian diseases. Mucosal Immunol 2021; 14:1017-1037. [PMID: 33859369 DOI: 10.1038/s41385-021-00398-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 02/04/2023]
Abstract
The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.
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Verburgt CM, Heutink WP, Kuilboer LIM, Dickmann JD, van Etten-Jamaludin FS, Benninga MA, de Jonge WJ, Van Limbergen JE, Tabbers MM. Antibiotics in pediatric inflammatory bowel diseases: a systematic review. Expert Rev Gastroenterol Hepatol 2021; 15:891-908. [PMID: 34148466 DOI: 10.1080/17474124.2021.1940956] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Current therapies in pediatric Inflammatory Bowel Diseases (IBD) target the immune system and often fail to sustain long-term remission. There is a high need for development of alternative treatment strategies such as antibiotics in pediatric IBD.Areas covered: This study systematically assessed efficacy and safety of antibiotics in pediatric IBD. CENTRAL, EMBASE, and Medline were searched for Randomized Controlled Trials (RCTs). Quality assessment was conducted with the Cochrane risk-of-bias tool.Expert opinion: Two RCTs (n = 101, 4.4-18 years, 43% male) were included. Both studies had overall low risk of bias. In mild-to-moderate Crohn's disease, azithromycin+metronidazole (AZ+MET) (n = 35) compared to metronidazole (MET) alone (n = 38) did not induce a significantly different response (PCDAI drop ≥12.5 or remission) (p = 0.07). For induction of remission (PCDAI≤10), AZ+MET was more effective than MET (p = 0.025). In Acute Severe Colitis, mean 5-day-PUCAI was significantly lower in the antibiotic (vancomycin, amoxicillin, metronidazole, doxycycline)+intravenous-corticosteroids group (AB+IVCS) (n = 16) compared to IVCS alone (n=12) (p = 0.037), whereas remission (PUCAI<10) did not differ (p = 0.61). No significant drug-related adverse events were reported. Results of this systematic review of antibiotic use highlight the lack of evidence in pediatric IBD. More evidence is needed before widespread implementation in daily practice.
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Affiliation(s)
- Charlotte M Verburgt
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands.,Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.,Amsterdam Reproduction & Development Research Institute, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - W Pepijn Heutink
- Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lot I M Kuilboer
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Julie D Dickmann
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Faridi S van Etten-Jamaludin
- Research Support, Medical Library, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Marc A Benninga
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.,Department of Surgery, University of Bonn, Bonn, Germany
| | - Johan E Van Limbergen
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands.,Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.,Department of Pediatrics, Dalhousie University, Halifax, Canada
| | - Merit M Tabbers
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands
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48
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The potential of Akkermansia muciniphila in inflammatory bowel disease. Appl Microbiol Biotechnol 2021; 105:5785-5794. [PMID: 34312713 DOI: 10.1007/s00253-021-11453-1] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 12/19/2022]
Abstract
Akkermansia muciniphila is a next-generation probiotic with significant application prospects. The role of A. muciniphila in metabolic diseases and tumor immunotherapy has been widely recognized. Recent clinical trials further confirmed its safety and therapeutic value in human metabolic diseases. A. muciniphila also shows potential in the treatment of intestinal inflammatory diseases, especially for inflammatory bowel disease (IBD). The improvement in the efficacy of washed microbiota transplantation (WMT) in treating IBD is closely related to the increase in the abundance of A. muciniphila in patients' gut. However, there is still controversy regarding the pro-inflammatory or anti-inflammatory effect of A. muciniphila on IBD. Currently, several studies targeting the correlation between A. muciniphila and IBD have demonstrated opposite conclusions. Similarly, the interventional studies exploring causality between them also come to conflicting results. This article therefore aims to review the relationship between A. muciniphila and IBD, the effect of intervention of A. muciniphila on IBD, and the possible reasons for the contradictory role of A. muciniphila in the treatment of IBD. KEY POINTS: The effect of A. muciniphila on inflammatory bowel disease is controversy. A. muciniphila shows anti-inflammatory potential in IBD. The colitogenicity of A. muciniphila is context dependent.
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49
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Zhan S, Li N, Liu C, Mao R, Wu D, Li T, Chen M, Zhuang X, Zeng Z. Intestinal Fibrosis and Gut Microbiota: Clues From Other Organs. Front Microbiol 2021; 12:694967. [PMID: 34335525 PMCID: PMC8322786 DOI: 10.3389/fmicb.2021.694967] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/24/2021] [Indexed: 12/11/2022] Open
Abstract
Fibrosis is a complex and difficult to elucidate pathological process with no available therapies. Growing evidence implicates intestinal microbiota in the occurrence and development of fibrosis, and the potential mechanisms involved in different organs have been explored in several studies. In this review, we summarize the causative and preventive effects of gut microbiota on intestinal fibrosis, as well as the relationships between gut microbiota and fibrosis in other organs. Interestingly, several colonized microbes are associated with fibrosis via their structural components and metabolic products. They may also play essential roles in regulating inflammation and fibroblast activation or differentiation, which modulates extracellular matrix formation. While the relationships between intestinal fibrosis and gut microbiota remain unclear, lessons can be drawn from the effects of gut microbiota on hepatic, cardiac, nephritic, and pulmonary fibrosis. Various intestinal microbes alterations have been detected in different fibrotic organs; however, the results were heterogeneous. Mechanisms by which the intestinal microbiota regulate fibrotic processes in other organs, such as novel metabolic products or specific microbes, are also discussed. The specific microbiota associated with fibrosis in other organs could instruct future studies aiming to discover prospective mechanisms regulating intestinal fibrosis.
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Affiliation(s)
- Shukai Zhan
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Na Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Caiguang Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dongxuan Wu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tong Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaojun Zhuang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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50
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Sadecki PW, Balboa SJ, Lopez LR, Kedziora KM, Arthur JC, Hicks LM. Evolution of Polymyxin Resistance Regulates Colibactin Production in Escherichia coli. ACS Chem Biol 2021; 16:1243-1254. [PMID: 34232632 PMCID: PMC8601121 DOI: 10.1021/acschembio.1c00322] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The complex reservoir of metabolite-producing bacteria in the gastrointestinal tract contributes tremendously to human health and disease. Bacterial composition, and by extension gut metabolomic composition, is undoubtably influenced by the use of modern antibiotics. Herein, we demonstrate that polymyxin B, a last resort antibiotic, influences the production of the genotoxic metabolite colibactin from adherent-invasive Escherichia coli (AIEC) NC101. Colibactin can promote colorectal cancer through DNA double stranded breaks and interstrand cross-links. While the structure and biosynthesis of colibactin have been elucidated, chemical-induced regulation of its biosynthetic gene cluster and subsequent production of the genotoxin by E. coli are largely unexplored. Using a multiomic approach, we identified that polymyxin B stress enhances the abundance of colibactin biosynthesis proteins (Clb's) in multiple pks+ E. coli strains, including pro-carcinogenic AIEC, NC101; the probiotic strain, Nissle 1917; and the antibiotic testing strain, ATCC 25922. Expression analysis via qPCR revealed that increased transcription of clb genes likely contributes to elevated Clb protein levels in NC101. Enhanced production of Clb's by NC101 under polymyxin stress matched an increased production of the colibactin prodrug motif, a proxy for the mature genotoxic metabolite. Furthermore, E. coli with a heightened tolerance for polymyxin induced greater mammalian DNA damage, assessed by quantification of γH2AX staining in cultured intestinal epithelial cells. This study establishes a key link between the polymyxin B stress response and colibactin production in pks+ E. coli. Ultimately, our findings will inform future studies investigating colibactin regulation and the ability of seemingly innocuous commensal microbes to induce host disease.
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Affiliation(s)
- Patric W. Sadecki
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Samantha J. Balboa
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Lacey R. Lopez
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Katarzyna M. Kedziora
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Bioinformatics and Analytics Research Collaborative (BARC), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Janelle C. Arthur
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Leslie M. Hicks
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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