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Liu K, Liu J, Su Y, Wang M, Long T, Fang L, Zhou Y, Sun J, Liao X. IncI2 plasmid transfer and changes of intestinal microbiota in mice under β-lactam antibiotic pressure. BMC Vet Res 2025; 21:343. [PMID: 40375072 DOI: 10.1186/s12917-025-04808-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 05/06/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND β-lactam antibiotics represent the most widely utilized class of antimicrobial agents in livestock and poultry breeding. However, the effects of β-lactam antibiotics on conjugation transfer of IncI2 plasmids and the homeostasis of the mouse intestinal microbiota have not been thoroughly investigated. RESULTS The results revealed that the transfer of IncI2 plasmid was the highest for intra-specific E. coli and inter-specific transfer to Salmonella and K. pneumoniae occurred at much lower levels in the absence of β-lactam antibiotic selective pressure. Furthermore, inter-species and intra-species transfer of IncI2 plasmid was enhanced in the presence of sub-MIC levels of amoxicillin/clavulanate and cephalexin whereas ampicillin promoted only inter-species transfer. These results were consistent with in vivo observations where amoxicillin/clavulanate and cephalexin but not ampicillin promoted conjugation. Meanwhile, the intestinal microbiota was also disturbed following antibiotic treatment and Proteobacteria abundance increased while Bacteroides decreased. The gut microbiota could also be partially restored to initial levels after antibiotic cessation for 14 days. CONCLUSIONS These findings highlight the potential risk of β-lactam antibiotics in promoting the spread of resistance plasmids and causing disruption to the intestinal microbiota.
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Affiliation(s)
- Kaidi Liu
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, P. R. China
| | - Junqi Liu
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, P. R. China
| | - Yuting Su
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, P. R. China
| | - Minge Wang
- School of Agricultural Science and Engineering, Liaocheng University, No.1 Hunan Road, Liaocheng, Shandong, 252000, China
| | - Tengfei Long
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, P. R. China
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, P. R. China
| | - Liangxing Fang
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, P. R. China
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, P. R. China
| | - Yufeng Zhou
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, P. R. China
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, P. R. China
| | - Jian Sun
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, P. R. China
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, P. R. China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, P. R. China
| | - Xiaoping Liao
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, P. R. China.
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, P. R. China.
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, P. R. China.
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Chen Y, Li X, Sun X, Kou Y, Ma X, Song L, Zhang H, Xie F, Song Z, Yuan C, Huang S, Wu Y. Joint transcriptomics and metabolomics unveil the protective mechanism of tamarind seed polysaccharide against antibiotic-induced intestinal barrier damage. Int J Biol Macromol 2025; 305:140999. [PMID: 39952497 DOI: 10.1016/j.ijbiomac.2025.140999] [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: 11/14/2024] [Revised: 01/13/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Intestinal barrier damage is frequently caused by antibiotic therapy, potentially leading to bacterial translocation and toxin leakage, which triggers inflammation and increases the risk of various diseases. In this study, Tamarind seed polysaccharides (TSP) with different molecular weights were administered to mice during the recovery phase from clindamycin-induced intestinal barrier damage. The results indicated that TSP restored the shortened colon length, reduced the enlarged cecum index, and decreased the elevated level of inflammatory infiltration. Biochemical testing revealed that TSP decreased the levels of intestinal permeability biomarkers and inflammatory factors that were elevated by clindamycin treatment. Transcriptomics and non-targeted metabolomics analyses respectively uncovered changes in colon gene expression and fecal metabolites. The joint analysis of these omics data identified critical pathways, including arachidonic acid metabolism, retinol metabolism, and steroid hormone biosynthesis. These findings suggest that TSP could be a promising dietary supplement for protecting the intestinal barrier and alleviating inflammation.
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Affiliation(s)
- Yinan Chen
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xujiao Li
- Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China
| | - Xianbao Sun
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yuxing Kou
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xuan Ma
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Lihua Song
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Hui Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Fan Xie
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Zibo Song
- Yunnan Maoduoli Group Food Co., Ltd., Yuxi 653100, China; Yunnan Special Favor Biotechnology Co., Ltd., Yuxi 653100, China
| | - Chunmei Yuan
- Yunnan Maoduoli Group Food Co., Ltd., Yuxi 653100, China; Yunnan Special Favor Biotechnology Co., Ltd., Yuxi 653100, China
| | - Siyan Huang
- Yunnan Maoduoli Group Food Co., Ltd., Yuxi 653100, China; Yunnan Special Favor Biotechnology Co., Ltd., Yuxi 653100, China
| | - Yan Wu
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
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Behl A, Sharma KK. Xenobiotics mediated modulation of gut microbiota and its role in lifestyle diseases: a critical appraisal on exposomics. Lett Appl Microbiol 2025; 78:ovaf067. [PMID: 40312786 DOI: 10.1093/lambio/ovaf067] [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: 01/31/2025] [Revised: 04/23/2025] [Accepted: 04/30/2025] [Indexed: 05/03/2025]
Abstract
Gastrointestinal tract of humans provides a niche to thousands of microbes, referred as gut microbiota (GM). GM establishes an intricate relationship with other organs via gut-organ axis, and modulates host health. The structure and functioning of these gut microbes can be influenced by the type of external exposome an individual experiences. Depending upon GM perturbations and host genotype, this can result in variable health implications. On the other hand, the huge arsenal of enzymes possessed by GM can chemically alter the xenobiotic structure. Its consequences can be numerous, including formation of harmful metabolites that cause organ damage, reversal of host detoxification pathways, or favourable health effects. Additionally, GM-mediated bio-transformation of pharmaceuticals can alter their pharmacokinetics and pharmacodynamics, potentially yielding variable drug responses, resulting into prolonged or ineffective treatments. To address this bi-facial relationship and the pivotal role of GM, this review incorporates recent in vitro, in vivo, and multiomics studies. It also suggests the need of machine learning approaches to decode the complex host-microbiota-xenobiotics interactions. These knowledge will aid in comprehending recent rise in chronic lifestyle-diseases which poses a huge burden on the health sector, and can also be a learning curve in making formulations and therapies for personalized treatment.
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Affiliation(s)
- Arush Behl
- Laboratory of Enzymology and Gut Microbiology, Maharshi Dayanand University, Rohtak 124001, India
| | - Krishna Kant Sharma
- Laboratory of Enzymology and Gut Microbiology, Maharshi Dayanand University, Rohtak 124001, India
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4
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Chen S, Dan L, Xiang L, He Q, Hu D, Gao Y. The role of gut flora-driven Th cell responses in preclinical rheumatoid arthritis. J Autoimmun 2025; 154:103426. [PMID: 40300482 DOI: 10.1016/j.jaut.2025.103426] [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: 12/03/2024] [Revised: 03/24/2025] [Accepted: 04/22/2025] [Indexed: 05/01/2025]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with an immune pathogenesis that evolves over decades. Preclinical RA (PreRA) represents a dynamic immune phase preceding clinical RA, marked by the loss of autoimmune tolerance, the appearance of tissue-invasive effector T cells, and the production of autoantibodies (such as antibodies against citrullinated proteins and rheumatoid factors). Extensive research has demonstrated that gut microbiota influence mucosal T-cell responses, driving the progression of PreRA through multiple mechanisms, including altered intestinal permeability, gene-environment interactions, bacterial antigenic specificity, molecular mimicry, and metabolite production. Environmental risk factors such as smoking, hormonal changes, and high-sodium (Na) diets, may contribute to RA pathogenesis via the gut microbiome. The next challenge in RA research lies in developing therapeutic strategies to intervene during the asymptomatic autoimmune phase, where dietary adjustments, natural compounds, probiotics, and other approaches could effectively modulate gut flora to prevent or delay RA onset.
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Affiliation(s)
- Shuanglan Chen
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Lijuan Dan
- Department of Infection, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Li Xiang
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Qingman He
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Dongsen Hu
- Sichuan Jinxin Xi'nan Women's and Children's Hospital Co., Ltd, Chengdu, 610023, China
| | - Yongxiang Gao
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
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Park J, Kim S, Im JP, Lee HJ, Kim JS, Park H, Han YM, Koh SJ. Clinical Outcome of Inflammatory Bowel Disease with Clostridioides difficile Polymerase Chain Reaction Toxin-Positive/Enzyme Immunoassay Toxin-Negative: A Retrospective Cohort Study. Dig Dis Sci 2025:10.1007/s10620-025-09045-4. [PMID: 40259149 DOI: 10.1007/s10620-025-09045-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 04/04/2025] [Indexed: 04/23/2025]
Abstract
BACKGROUND Clostridioides difficile infection (CDI) frequently occurs concurrently in patients with inflammatory bowel disease (IBD), and differential diagnosis from IBD flares is critical. However, clinical management of C. difficile in IBD patients with polymerase chain reaction toxin-positive (tPCR+)/enzyme immunoassay toxin-negative (tEIA-) results has not yet been investigated. AIMS We aimed to assess the clinical significance of C. difficile tPCR+/tEIA- in patients with IBD and the impact of antibiotic treatment on IBD outcomes. METHODS This single-center, retrospective cohort study included patients with IBD with CDI test results between January 01, 2018, and August 01, 2022. First, the clinical outcomes of IBD, such as medication escalation, hospitalization, and surgery, were compared between patients with IBD with tPCR-/tEIA- and those with tPCR+/tEIA- using Cox regression and propensity score matching. Next, the clinical outcomes of IBD were assessed based on whether antibiotic treatment for CDI was administered to both groups. RESULTS Among 412 patients with IBD with PCR test, 71 (17.2%) showed tPCR+/tEIA- results. The tPCR+/tEIA- group showed no statistically significant difference in IBD outcomes compared to the tPCR-/tEIA- group. The antibiotic-treated tPCR+/tEIA- group showed a higher risk of drug escalation and admission than the tPCR-/tEIA- group, while the antibiotic-untreated tPCR+/tEIA- group did not. After drug escalation during the follow-up, the treated tPCR+/tEIA- group showed IBD outcomes similar to those of the tPCR-/tEIA- group. CONCLUSIONS In patients with IBD with indeterminate CDI, the need for antibiotics should be thoroughly assessed and proper management of underlying IBD such as drug escalation may lead to favorable outcomes.
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Affiliation(s)
- Junseok Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Seulji Kim
- Department of Internal Medicine, Korea Institute of Radiological and Medical Sciences, Korea Cancer Center Hospital, Seoul, Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Jung Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyunsun Park
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea
| | - Yoo Min Han
- Department of Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Seong-Joon Koh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
- Department of Internal Medicine and Liver Research Institute, Laboratory of Intestinal Mucosa and SkinImmunology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea.
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Bonomo MG, D’Angelo S, Picerno V, Carriero A, Salzano G. Recent Advances in Gut Microbiota in Psoriatic Arthritis. Nutrients 2025; 17:1323. [PMID: 40284188 PMCID: PMC12030176 DOI: 10.3390/nu17081323] [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: 03/06/2025] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by joint inflammation and skin lesions. Recent research has underscored the critical role of gut microbiota-comprising bacteria, fungi, viruses, and archaea-in the pathogenesis and progression of PsA. This narrative review synthesizes the latest findings on the influence of gut microbiota on PsA, focusing on mechanisms such as immune modulation, microbial dysbiosis, the gut-joint axis, and its impact on treatment. Advances in high-throughput sequencing and metagenomics have revealed distinct microbial profiles associated with PsA. Studies show that individuals with PsA have a unique gut microbiota composition, differing significantly from healthy controls. Alterations in the abundance of specific bacterial taxa, including a decrease in beneficial bacteria and an increase in potentially pathogenic microbes, contribute to systemic inflammation by affecting the intestinal barrier and promoting immune responses. This review explores the impact of various factors on gut microbiota composition, including age, hygiene, comorbidities, and medication use. Additionally, it highlights the role of diet, probiotics, and fecal microbiota transplantation as promising strategies to modulate gut microbiota and alleviate PsA symptoms. The gut-skin-joint axis concept illustrates how gut microbiota influences not only gastrointestinal health but also skin and joint inflammation. Understanding the complex interplay between gut microbiota and PsA could lead to novel, microbiome-based therapeutic approaches. These insights offer hope for improved patient outcomes through targeted manipulation of the gut microbiota, enhancing both diagnosis and treatment strategies for PsA.
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Affiliation(s)
- Maria Grazia Bonomo
- Department of Health Sciences, University of Basilicata, Viale dell’ Ateneo Lucano 10, 85100 Potenza, Italy; (S.D.); (G.S.)
| | - Salvatore D’Angelo
- Department of Health Sciences, University of Basilicata, Viale dell’ Ateneo Lucano 10, 85100 Potenza, Italy; (S.D.); (G.S.)
- Rheumatology Department of Lucania, San Carlo Hospital of Potenza, Via Potito Petrone, 85100 Potenza, Italy; (V.P.); (A.C.)
| | - Valentina Picerno
- Rheumatology Department of Lucania, San Carlo Hospital of Potenza, Via Potito Petrone, 85100 Potenza, Italy; (V.P.); (A.C.)
| | - Antonio Carriero
- Rheumatology Department of Lucania, San Carlo Hospital of Potenza, Via Potito Petrone, 85100 Potenza, Italy; (V.P.); (A.C.)
| | - Giovanni Salzano
- Department of Health Sciences, University of Basilicata, Viale dell’ Ateneo Lucano 10, 85100 Potenza, Italy; (S.D.); (G.S.)
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7
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Wolfe TM, Jo J, Pinkham NV, Garey KW, Walk ST. The impact of ibezapolstat and other Clostridioides difficile infection-relevant antibiotics on the microbiome of humanized mice. Antimicrob Agents Chemother 2025; 69:e0160424. [PMID: 39998294 PMCID: PMC11963539 DOI: 10.1128/aac.01604-24] [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] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/29/2025] [Indexed: 02/26/2025] Open
Abstract
Ibezapolstat (IBZ) is a competitive inhibitor of the bacterial Pol IIIC enzyme in clinical development for the treatment of Clostridioides difficile infection (CDI). Previous studies demonstrated that IBZ carries a favorable microbiome diversity profile compared to vancomycin (VAN). However, head-to-head comparisons with other CDI antibiotics have not been done. The purpose of this study was to compare microbiome changes associated with IBZ to other clinically used CDI antibiotics. Groups of germ-free (GF) mice received a fecal microbiota transplant from one of two healthy human donors and were subsequently exposed to either IBZ, VAN, fidaxomicin (FDX), metronidazole (MET), or no antibiotic (control). 16S rRNA encoding gene sequencing of temporally collected stool samples was used to compare the gut microbiome perturbations between treatment and no-drug control groups. Among the tested antibiotics, the most significant change in microbiome diversity was observed in MET-treated mice. Each antibiotic had a unique effect, but changes in alpha and beta diversities following FDX- and IBZ-treated groups were less pronounced than those observed in VAN- or MET-treated groups. By the end of therapy, both IBZ and FDZ increased the relative abundance of Bacteroidota (phylum), with IBZ additionally increasing the relative abundance of Actinomycetota (phylum). In microbiome-humanized mice, IBZ and FDX had smaller effects on gut microbiome diversity than VAN and MET. Notable differences were observed between the microbiome of IBZ- and FDX-treated groups, which may allow for differentiation of these two antibiotics in future studies.
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Affiliation(s)
- Trenton M. Wolfe
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana, USA
| | - Jinhee Jo
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Nick V. Pinkham
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana, USA
| | - Kevin W. Garey
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Seth T. Walk
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana, USA
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8
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Groenewegen B, van Lingen E, Kovynev A, van den Berg AJ, Berssenbrugge EKL, Sanders IMJG, van Prehn J, van Nood E, Goorhuis A, Kuijper EJ, Smits WK, Wiese M, Keller JJ, Ducarmon QR, Terveer EM. The presence of Clostridioides difficile in faeces before and after faecal microbiota transplantation and its relation with recurrent C. difficile infection and the gut microbiota in a Dutch cohort. Clin Microbiol Infect 2025; 31:568-574. [PMID: 39662821 DOI: 10.1016/j.cmi.2024.12.003] [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: 04/19/2024] [Revised: 11/19/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024]
Abstract
OBJECTIVES The objectives of this study are to investigate the presence of Clostridioides difficile in faeces of patients with recurrent C. difficile infection (rCDI) before and after faecal microbiota transplantation (FMT) and to identify risk factors for faecal C. difficile and C. difficile infection (CDI) recurrence. METHODS n = 83 faecal sample triads (pre-FMT [∼1 day], post-FMT [∼3 weeks], and a corresponding FMT donor sample), and n = 22 long-term (∼1-3 years) follow-up faecal samples were collected from FMT-treated patients. The presence of C. difficile in faeces was assessed by enrichment broth culture and PCR (tcdB gene) and associated with patient characteristics, FMT outcome, duration of pre-FMT vancomycin, FMT donor, post-FMT antibiotic use, and faecal microbiota composition (shotgun metagenomics). RESULTS The FMT cure rate for rCDI was 92.8% (77/83), with six early CDI recurrences (<2 months post-FMT). Toxigenic C. difficile was cultured in 27.7% (23/83) of all patients post-FMT, 23.4% (18/77) of patients cured 2 months post-FMT, and 13.6% (3/22) at long-term follow-up. Early CDI recurrence (n = 6) was associated with positive C. difficile culture post-FMT (21.7% [5/23] vs. 1.7% [1/60], p 0.01), post-FMT antibiotics (30.0% [3/10] vs. 4.6% [3/65], p 0.03), and a short course of pre-FMT vancomycin (median 6.0 days, IQR [5-12] vs. 18 days, IQR [10.8-29], p < 0.05). Additionally, positive C. difficile culture directly pre-FMT was associated with a short course of pre-FMT vancomycin (median 9 days IQR [5-18] vs. 17 days, IQR [10-29.2], p 0.04). Gut microbiota analyses did not reveal signatures associated with C. difficile culture result, despite statistically non-significant trends in relative abundances of the Enterobacteriaceae family, and Dorea, Roseburia, and Clostridiales species. DISCUSSION Although eradication of C. difficile is not required for clinical cure of rCDI by FMT, it is associated with reduced prevalence of early CDI recurrence, as are the full completion of pre-FMT vancomycin (at least 10 days) and avoiding post-FMT antibiotics.
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Affiliation(s)
- Bas Groenewegen
- Netherlands Donor Feces Bank, Leiden University Center of Infectious Diseases Medical Microbiology and Infection Prevention, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Emilie van Lingen
- Netherlands Donor Feces Bank, Leiden University Center of Infectious Diseases Medical Microbiology and Infection Prevention, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Artemiy Kovynev
- Center for Microbiome Analyses and Therapeutics, Leiden University Center of Infectious Diseases Research, Leiden University Medical Center, Leiden, The Netherlands
| | - Alexander J van den Berg
- Netherlands Donor Feces Bank, Leiden University Center of Infectious Diseases Medical Microbiology and Infection Prevention, Leiden University Medical Center, Leiden, The Netherlands
| | - Eric K L Berssenbrugge
- Netherlands Donor Feces Bank, Leiden University Center of Infectious Diseases Medical Microbiology and Infection Prevention, Leiden University Medical Center, Leiden, The Netherlands
| | - Ingrid M J G Sanders
- Leiden University Center of Infectious Diseases Research, Leiden University Medical Center, Leiden, The Netherlands
| | - Joffrey van Prehn
- Netherlands Donor Feces Bank, Leiden University Center of Infectious Diseases Medical Microbiology and Infection Prevention, Leiden University Medical Center, Leiden, The Netherlands; Center for Microbiome Analyses and Therapeutics, Leiden University Center of Infectious Diseases Research, Leiden University Medical Center, Leiden, The Netherlands
| | - Els van Nood
- Department of Medical Microbiology and Infectious Diseases and Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Abraham Goorhuis
- Department of Internal Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands
| | - Ed J Kuijper
- Netherlands Donor Feces Bank, Leiden University Center of Infectious Diseases Medical Microbiology and Infection Prevention, Leiden University Medical Center, Leiden, The Netherlands; Center for Microbiome Analyses and Therapeutics, Leiden University Center of Infectious Diseases Research, Leiden University Medical Center, Leiden, The Netherlands
| | - Wiep Klaas Smits
- Center for Microbiome Analyses and Therapeutics, Leiden University Center of Infectious Diseases Research, Leiden University Medical Center, Leiden, The Netherlands
| | - Maria Wiese
- Center for Microbiome Analyses and Therapeutics, Leiden University Center of Infectious Diseases Research, Leiden University Medical Center, Leiden, The Netherlands; Department of Microbiology and Systems Biology, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Josbert J Keller
- Netherlands Donor Feces Bank, Leiden University Center of Infectious Diseases Medical Microbiology and Infection Prevention, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastroenterology and Hepatology, Haaglanden Medical Center, Den Haag, The Netherlands
| | - Quinten R Ducarmon
- Center for Microbiome Analyses and Therapeutics, Leiden University Center of Infectious Diseases Research, Leiden University Medical Center, Leiden, The Netherlands
| | - Elisabeth M Terveer
- Netherlands Donor Feces Bank, Leiden University Center of Infectious Diseases Medical Microbiology and Infection Prevention, Leiden University Medical Center, Leiden, The Netherlands; Center for Microbiome Analyses and Therapeutics, Leiden University Center of Infectious Diseases Research, Leiden University Medical Center, Leiden, The Netherlands.
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Alshannaq A, Henning M, Dixon J, Riley C, Choi D, Yu JH, Safdar N. Potent Antimicrobial Activity of Aspergillus oryzae Fermentate Against Toxigenic Strains of Clostridioides difficile. Antibiotics (Basel) 2025; 14:333. [PMID: 40298462 PMCID: PMC12023927 DOI: 10.3390/antibiotics14040333] [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: 02/28/2025] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 04/30/2025] Open
Abstract
Background:Clostridioides difficile infection (CDI) remains a significant public health challenge in the United States, with limited treatment options currently available. Objectives: This study investigated the antimicrobial efficacy of a fungal-based fermentate derived from Aspergillus oryzae, cultivated in a proprietary food-grade medium, against toxigenic strains of C. difficile. Methods and Results: The ethyl acetate extract of A. oryzae fermentate (fungal extract) exhibited potent bactericidal activity, producing a significant zone of inhibition across all tested C. difficile strains, including hypervirulent Ribotype 027. Notably, 80% of the tested strains (four out of five) exhibited greater susceptibility to the fungal extract than to 5 µg vancomycin discs. Inner colony formation within the zone of inhibition was observed for all strains treated with vancomycin but only one strain was exposed to fungal extract. Time kill assays further confirmed the rapid bactericidal effect of the fungal extract, achieving complete C. difficile eradication within six hours. Mechanistic studies using scanning electron microscopy (SEM) and flow cytometry revealed that the fungal extract induced severe membrane disruption, leading to intracellular leakage and complete lysis. Flow cytometry analysis confirmed membrane depolarization and permeability loss on C. difficile cells. Conclusions: These findings highlight that the fungal extract of A. oryzae exhibits a promising antimicrobial activity against C. difficile. Future studies will focus on identifying its active components, evaluating its efficacy in vivo, and assessing its impact on gut microbiota to establish its potential clinical application in managing CDI.
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Affiliation(s)
- Ahmad Alshannaq
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Morgan Henning
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
- Department of Medicine, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA
| | - Jonah Dixon
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
- Department of Medicine, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA
| | - Colleen Riley
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
- Department of Medicine, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA
| | - Dasol Choi
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Jae-Hyuk Yu
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Nasia Safdar
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
- Department of Medicine, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA
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10
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Kaur N, Kumar P, Dhami M, Aran KR. Antibiotic-induced gut dysbiosis: unraveling the gut-heart axis and its impact on cardiovascular health. Mol Biol Rep 2025; 52:319. [PMID: 40095156 DOI: 10.1007/s11033-025-10425-2] [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: 02/10/2025] [Accepted: 03/10/2025] [Indexed: 03/19/2025]
Abstract
Cardiovascular diseases (CVDs) remain the major cause of morbidity and mortality amongst people of all ages across the world. Research suggests that the initiation and progression of CVDs are associated with antibiotic-induced gut dysbiosis. Antibiotics are primarily intended to be used to treat bacterial infections, which can alter gut microbiota (GM) composition, by lowering the abundance of beneficial bacteria, like Firmicutes, Bacteroidetes, and increasing the profusion of Enterobacteriaceae, leading to harm on gut health. Additionally, it reduces short-chain fatty acids (SCFAs) and bile acid metabolism, increases trimethylamine N-oxide (TMAO) production, intestinal permeability allowing lipopolysaccharide (LPS) and TMAO into systemic circulation. SCFAs play a key role in lipid metabolism, inflammation, and strengthening of the intestinal barrier, and participate in CVDs through FFAR2 and FFAR3 receptors, whereas dysbiosis reduces SCFAs levels and worsens these effects. TMAO enhances oxidative stress, inflammation, endothelial dysfunction, and cholesterol dysregulation, thus worsening CVDs. Furthermore, LPS develops systemic inflammation, insulin resistance, and endothelial dysfunction by activating the NF-κB pathway. Dysbiosis also affects bile acid synthesis, disrupting lipid and glucose metabolism, further participating in the progression of CVDs. This article aims to explore the role of gut dysbiosis in various CVDs, including congenital heart disease, hypertension, valvular heart disease, coronary heart disease, and heart failure. Furthermore, this article aims to bridge the knowledge gap regarding the gut-heart axis by exploring how antibiotics alter the gut microbiota homeostasis, further contributing to the development of CVDs and therapeutic interventions that reduce cardiovascular risks and restore the gut microbiota homeostasis.
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Affiliation(s)
- Navpreet Kaur
- Department of Pharmacy Practice, ISF College of Pharmacy, Moga, Punjab, India
| | - Pankaj Kumar
- Department of Pharmacology, Himachal Institute of Pharmaceutical Education and Research (HIPER), Tehsil-Nadaun, Hamirpur, Himachal Pradesh, 177033, India
| | - Mahadev Dhami
- Bhimdatta Polytechnic Institute, Patan, Baitadi, 10200, Nepal
| | - Khadga Raj Aran
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India.
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11
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Szajewska H, Scott KP, de Meij T, Forslund-Startceva SK, Knight R, Koren O, Little P, Johnston BC, Łukasik J, Suez J, Tancredi DJ, Sanders ME. Antibiotic-perturbed microbiota and the role of probiotics. Nat Rev Gastroenterol Hepatol 2025; 22:155-172. [PMID: 39663462 DOI: 10.1038/s41575-024-01023-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 12/13/2024]
Abstract
The disruptive effect of antibiotics on the composition and function of the human microbiota is well established. However, the hypothesis that probiotics can help restore the antibiotic-disrupted microbiota has been advanced, with little consideration of the strength of evidence supporting it. Some clinical data suggest that probiotics can reduce antibiotic-related side effects, including Clostridioides difficile-associated diarrhoea, but there are no data that causally link these clinical effects to microbiota protection or recovery. Substantial challenges hinder attempts to address this hypothesis, including the absence of consensus on the composition of a 'normal' microbiota, non-standardized and evolving microbiome measurement methods, and substantial inter-individual microbiota variation. In this Review, we explore these complexities. First, we review the known benefits and risks of antibiotics, the effect of antibiotics on the human microbiota, the resilience and adaptability of the microbiota, and how microbiota restoration might be defined and measured. Subsequently, we explore the evidence for the efficacy of probiotics in preventing disruption or aiding microbiota recovery post-antibiotic treatment. Finally, we offer insights into the current state of research and suggest directions for future research.
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Affiliation(s)
- Hania Szajewska
- Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
| | - Karen P Scott
- Rowett Institute, University of Aberdeen, Aberdeen, UK
| | - Tim de Meij
- Department of Paediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands
| | - Sofia K Forslund-Startceva
- Experimental and Clinical Research Center, a joint cooperation of Max Delbruck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Max Delbruck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Rob Knight
- Department of Pediatrics, University of California San Diego, San Diego, CA, USA
- Department of Computer Science & Engineering, University of California San Diego, San Diego, CA, USA
- Shu Chien - Gene Lay Department of Bioengineering, University of California San Diego, San Diego, CA, USA
- Halıcıoğlu Data Science Institute, University of California San Diego, San Diego, CA, USA
- Center for Microbiome Innovation, University of California San Diego, San Diego, CA, USA
| | - Omry Koren
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
| | - Paul Little
- Primary Care Research Centre, University of Southampton, Southampton, UK
| | - Bradley C Johnston
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA
- Department of Epidemiology and Biostatistics, School of Public Health, Texas A&M University, College Station, TX, USA
| | - Jan Łukasik
- Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
| | - Jotham Suez
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Daniel J Tancredi
- Department of Pediatrics, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Mary Ellen Sanders
- International Scientific Association for Probiotics and Prebiotics, Consulting Scientific Advisor, Centennial, CO, USA.
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12
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Gurung B, Courreges MC, Pollak J, Malgor R, Jiang L, Wang B, Wang S. Non-invasive treatment of Clostridioides difficile infection with a human-origin probiotic cocktail through gut microbiome-gut metabolome modulations. Front Microbiol 2025; 16:1555220. [PMID: 40078549 PMCID: PMC11897039 DOI: 10.3389/fmicb.2025.1555220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
Clostridioides difficile (C. difficile) is a leading cause of hospital-associated diarrhea, primarily due to gut dysbiosis following antibiotic use. Probiotics have been found to provide several benefits to hosts via modulation of the gut microbiota and their metabolites. However, till now, no conventional probiotics have been clearly proven to be an effective prophylactic option for CDI prevention. Therefore, more studies on developing specific probiotic candidates targeting CDI and improving diversity of probiotics administrated are needed. In this study, a human-origin highly diverse and highly targeted probiotic cocktail (Pro11) containing 11 various probiotic species was developed against C. difficile. Pro11 protected mice against CDI with lower clinical scores and higher survival rates, and inhibited C. difficile in vivo with less C. difficile burden and toxins production determined in colon. Histological analysis demonstrated that Pro11 strengthened gut barrier, reducing gut permeability (less secreted sCD14 in serum) and gut inflammation. In addition, gut microbiome analysis demonstrated that Pro11 increased gut microbiome diversity and beneficial species. Along with gut microbiome modulation, gut metabolites including butyrate, were significantly increased in the probiotics-fed group. Results from this study highlighted probiotics as a promising CDI therapy as gut microbiota modulators, which will lay the foundation for translating probiotics in mitigating CDI and other intestinal pathogens for clinical use.
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Affiliation(s)
- Bijay Gurung
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
- Infectious and Tropical Disease Institute, Ohio University, Athens, OH, United States
| | - Maria C. Courreges
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
| | - Julie Pollak
- Department of Chemistry and Chemical Engineering, Florida Institute of Technology, Melbourne, FL, United States
| | - Ramiro Malgor
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
| | - Lin Jiang
- Division of Natural Sciences, New College of Florida, Sarasota, FL, United States
| | - Bo Wang
- Department of Chemistry and Chemical Engineering, Florida Institute of Technology, Melbourne, FL, United States
| | - Shaohua Wang
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
- Infectious and Tropical Disease Institute, Ohio University, Athens, OH, United States
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13
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Jo J, Hu C, Horvath TD, Haidacher SJ, Begum K, Alam MJ, Garey KW. Phase I trial comparing bile acid and short-chain fatty acid alterations in stool collected from human subjects treated with omadacycline or vancomycin. Antimicrob Agents Chemother 2025; 69:e0125124. [PMID: 39819014 PMCID: PMC11823362 DOI: 10.1128/aac.01251-24] [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: 12/06/2024] [Indexed: 01/19/2025] Open
Abstract
Omadacycline, an aminomethylcycline tetracycline, has a low propensity to cause Clostridioides difficile infection (CDI) in clinical trials. Omadacycline exhibited a reduced bactericidal effect compared with vancomycin on key microorganisms implicated in bile acid homeostasis and short-chain fatty acids (SCFAs), key components of CDI pathogenesis. The purpose of this study was to assess bile acid and SCFA changes in stool samples from healthy volunteers given omadacycline or vancomycin. Stool samples were collected daily from 16 healthy volunteers, who were given oral omadacycline or vancomycin for 10 days. Daily stool samples were assessed for bile acids and SCFA concentrations using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bile acids changed significantly over time for all subjects (P < 0.01 for each bile acid), with vancomycin causing a larger change in the primary bile acids, cholic acid (P < 0.001) and chenodeoxycholic acid (P < 0.001), and a reduced change in the secondary bile acid, lithocholic acid (P < 0.001). The secondary bile acid ursodeoxycholic acid was reduced less by vancomycin than by omadacycline (P < 0.001). All SCFA concentrations were reduced from baseline with a larger effect observed with vancomycin for isobutyric acid (P = 0.0034), propionic acid (P = 0.0012), and acetic acid (P = 0.047). Microbial changes associated with the use of vancomycin versus omadacycline were also associated with changes in bile acid homeostasis and SCFA concentrations. Oral omadacycline produced a distinctive metabolomic profile compared with vancomycin when administered to healthy subjects. The metabolic findings help further our understanding of the lower CDI risk properties of omadacycline and warrant phase 2 investigations using omadacycline as a CDI antibiotic. IMPORTANCE The purpose of this study was to assess bile acid and SCFA changes in stool samples obtained from healthy volunteers given omadacycline or vancomycin. Stool samples were collected daily from 16 healthy volunteers given a 10-day oral course of omadacycline or vancomycin. Vancomycin caused a larger change in the primary bile acids and SCFA concentrations compared with omadacycline. The metabolic findings help further our understanding of the mechanistic basis for the lower-risk properties of omadacycline causing CDI and warrant phase 2 investigations using omadacycline as a CDI antibiotic. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT06030219.
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Affiliation(s)
- Jinhee Jo
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Chenlin Hu
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Thomas D. Horvath
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Sigmund J. Haidacher
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Khurshida Begum
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - M. Jahangir Alam
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
| | - Kevin W. Garey
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA
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14
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Kellogg TD, Ceglia S, Mortzfeld BM, Tanna TM, Zeamer AL, Mancini MR, Foley SE, Ward DV, Bhattarai SK, McCormick BA, Reboldi A, Bucci V. Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile. J Exp Med 2025; 222:e20232055. [PMID: 39589553 PMCID: PMC11602550 DOI: 10.1084/jem.20232055] [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: 11/08/2023] [Revised: 09/26/2024] [Accepted: 10/23/2024] [Indexed: 11/27/2024] Open
Abstract
The role of microbes and their metabolites in modulating tuft cell (TC) dynamics in the large intestine and the relevance of this pathway to infections is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia protects against Clostridioides difficile infection. Using selective antibiotics, we demonstrate increased type 2 cytokines and TC hyperplasia in the colon but not in the ileum. We demonstrate the causal role of the microbiome in modulating this phenotype using fecal matter transplantation and administration of consortia of succinate-producing bacteria. Administration of succinate production-deficient microbes shows a reduced response in a Pou2f3-dependent manner despite similar intestinal colonization. Finally, antibiotic-treated mice prophylactically administered with succinate-producing bacteria show increased protection against C. difficile-induced morbidity and mortality. This effect is nullified in Pou2f3-/- mice, confirming that the protection occurs via the TC pathway. We propose that activation of TCs by the microbiota in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by pathogens.
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Affiliation(s)
- Tasia D. Kellogg
- Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
| | - Simona Ceglia
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
- Department of Pathology, UMass Chan Medical School, Worcester, MA, USA
| | - Benedikt M. Mortzfeld
- Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
| | - Tanvi M. Tanna
- Department of Pathology, UMass Chan Medical School, Worcester, MA, USA
| | - Abigail L. Zeamer
- Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
| | - Matthew R. Mancini
- Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
| | - Sage E. Foley
- Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA
| | - Doyle V. Ward
- Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
| | - Shakti K. Bhattarai
- Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
| | - Beth A. McCormick
- Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
| | - Andrea Reboldi
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
- Department of Pathology, UMass Chan Medical School, Worcester, MA, USA
| | - Vanni Bucci
- Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
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15
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Duman H, Karav S. Fiber and the gut microbiome and its impact on inflammation. NUTRITION IN THE CONTROL OF INFLAMMATION 2025:51-76. [DOI: 10.1016/b978-0-443-18979-1.00004-6] [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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16
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Tiseo G, Yahav D, Atamna A, Avni T, Causse M, Pérez-Nadales E, Mularoni A, Reigadas E, Olmedo-Samperio M, Fernández-Ruiz M, Palacios-Baena ZR, Rodríguez-Baño J, De Simone P, Biancofiore G, Sabik EF, Paul M, Aguado JM, Boggi U, Muñoz P, Torres-Cisneros J, Farcomeni A, Falcone M. Recurrent Clostridioides difficile infections in solid organ transplant recipients: The international CALIPSO study. J Infect 2024; 89:106306. [PMID: 39374859 DOI: 10.1016/j.jinf.2024.106306] [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: 08/18/2024] [Revised: 09/27/2024] [Accepted: 09/29/2024] [Indexed: 10/09/2024]
Abstract
OBJECTIVE To evaluate the risk of recurrent Clostridioides difficile infection (CDI) in solid-organ transplant (SOT) recipients. METHODS Retrospective multicenter study including SOT recipients with a first CDI episode in the year after transplantation (Jan 2017-June 2020). The primary outcome measure was recurrence, defined as a new CDI ≤56 days from the first episode. A competing risk analysis was performed using the sub-distribution hazard model multivariable analysis. RESULTS 191 SOT recipients were included: 101 (52.9%) were kidney, 66 (34.6%) liver, 11 (5.8%) lung, 8 (4.2%) simultaneous pancreas-kidney, 4 (2.1%) heart and 1 (0.5%) pancreas alone recipients. Treatment for the first CDI were: vancomycin (n = 114,59.7%), vancomycin+metronidazole (n = 39,20.4%), metronidazole (n = 26,13.6%), fidaxomicin (n = 9,4.7%), 3 patients did not receive any therapy. After the first CDI, 17/191 (8.9%) patients died within 56-day mortality without having a recurrence, while 23/191 (12%) patients had a recurrence. Among patients with recurrent CDI, 56-day mortality rate was 30.4% (7/23 patients). On multivariable analysis, severe CDI (sHR4.01, 95% CI 1.77-9.08, p < .001) and metronidazole monotherapy (sHR 3.65, 95% CI 1.64-8.14, p = .001) were factors independently associated with recurrence. CONCLUSIONS Metronidazole monotherapy is associated with increased risk of recurrent CDI in SOT recipients. Therapeutic strategies aimed to reduce the risk of recurrence should be implemented in this setting.
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Affiliation(s)
- Giusy Tiseo
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Dafna Yahav
- Infectious Diseases Unit, Sheba Medical Center, Ramat Gan, Israel
| | - Alaa Atamna
- Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
| | - Tomer Avni
- Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
| | - Manuel Causse
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Clinical Units of Microbiology and Infectious Diseases, Reina Sofia University Hospital, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Department of Agricultural Chemistry, Edaphology and Microbiology and Department of Medical and Surgical Science, University of Cordoba, Cordoba, Spain
| | - Elena Pérez-Nadales
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Clinical Units of Microbiology and Infectious Diseases, Reina Sofia University Hospital, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Department of Agricultural Chemistry, Edaphology and Microbiology and Department of Medical and Surgical Science, University of Cordoba, Cordoba, Spain
| | - Alessandra Mularoni
- Infectious Diseases Unit, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), Palermo, Italy
| | - Elena Reigadas
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Health Research Institute Hospital "12 de Octubre" (imas12), Department of Medicine, School of Medicine, Universidad Complutense, CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
| | - María Olmedo-Samperio
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Health Research Institute Hospital "12 de Octubre" (imas12), Department of Medicine, School of Medicine, Universidad Complutense, CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Health Research Institute Hospital "12 de Octubre" (imas12), Department of Medicine, School of Medicine, Universidad Complutense, CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
| | - Zaira R Palacios-Baena
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Infectious Diseases and Microbiology Clinical Unit, University Hospital Virgen Macarena, Instute of Biomedicine of Seville (IBiS)/CSIC, Department of Medicine, University of Seville, Seville, Spain
| | - Jesus Rodríguez-Baño
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Infectious Diseases and Microbiology Clinical Unit, University Hospital Virgen Macarena, Instute of Biomedicine of Seville (IBiS)/CSIC, Department of Medicine, University of Seville, Seville, Spain
| | - Paolo De Simone
- Liver Transplant Program, University of Pisa Medical School Hospital, Pisa, Italy
| | - Giandomenico Biancofiore
- Division of Transplant Anesthesia and Critical Care, Department of Anesthesia, Azienda Ospedaliero Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Eman Fares Sabik
- Infectious Diseases Instute, Rambam Health Care Campus, Haifa, Israel
| | - Mical Paul
- Infectious Diseases Instute, Rambam Health Care Campus, Haifa, Israel
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Health Research Institute Hospital "12 de Octubre" (imas12), Department of Medicine, School of Medicine, Universidad Complutense, CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
| | - Ugo Boggi
- Division of General and Transplant Surgery, University of Pisa, Pisa, Italy
| | - Patricia Muñoz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Health Research Institute Hospital "12 de Octubre" (imas12), Department of Medicine, School of Medicine, Universidad Complutense, CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
| | - Julián Torres-Cisneros
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Clinical Units of Microbiology and Infectious Diseases, Reina Sofia University Hospital, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Department of Agricultural Chemistry, Edaphology and Microbiology and Department of Medical and Surgical Science, University of Cordoba, Cordoba, Spain
| | - Alessio Farcomeni
- Department of Economics and Finance, Tor Vergata University of Rome, Rome, Italy
| | - Marco Falcone
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
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17
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Wolfe TM, Jo J, Pinkham NV, Garey KW, Walk ST. Microbiome impact of ibezapolstat and other Clostridioides difficile infection relevant antibiotics using humanized mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.06.622322. [PMID: 39574673 PMCID: PMC11580883 DOI: 10.1101/2024.11.06.622322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Background Ibezapolstat (IBZ) is a competitive inhibitor of the bacterial Pol IIIC enzyme in clinical development for treatment of Clostridioides difficile infection (CDI). Previous studies demonstrated IBZ carries a favorable microbiome diversity profile compared to vancomycin (VAN). However, head-to-head comparisons with other CDI antibiotics have not been done. The purpose of this study was to compare microbiome changes associated with IBZ to other clinically used CDI antibiotics. Methods Groups of germ-free (GF) mice received a fecal microbiota transplant from one of two healthy human donors and were subsequently exposed to either IBZ, VAN, fidaxomicin (FDX), metronidazole (MET), or no antibiotic (control). 16S rRNA encoding gene sequencing of temporally collected stool samples was used to compare gut microbiome perturbation between treatment and no-drug control groups. Results Among the tested antibiotics, the most significant change in microbiome diversity was observed in MET-treated mice. Each antibiotic had a unique effect, but changes in alpha and beta diversity following FDX- and IBZ-treated groups were less pronounced compared to those observed in VAN-or MET-treated groups. By the end of therapy, both IBZ and FDZ increased the relative abundance of Bacteroidota (phylum), with IBZ additionally increasing the relative abundance of Actinomycetota (phylum). Conclusion In microbiome-humanized mice, IBZ and FDX had smaller effects on gut microbiome diversity compared to VAN and MET. Notable differences were observed between the microbiome of IBZ- and FDX-treated groups, which may allow for differentiation of these two antibiotics in future studies.
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18
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Baghdadi JD, Wessel M, Dubberke ER, Lydecker A, Claeys KC, Alonso C, Coffey K, Durkin M, Gonzales-Luna AJ, Guh AY, Kwon JH, Martin E, Mehrotra P, Polage CR, Pulia MS, Rock C, Skinner AM, Vaughn VM, Vijayan T, Yarrington ME, Morgan DJ, for the CDC Prevention Epicenters Program. Informing estimates of probability of Clostridioides difficile infection for testing and treatment: expert consensus from a modified-Delphi procedure. ANTIMICROBIAL STEWARDSHIP & HEALTHCARE EPIDEMIOLOGY : ASHE 2024; 4:e168. [PMID: 39411667 PMCID: PMC11474763 DOI: 10.1017/ash.2024.387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/31/2024] [Accepted: 05/31/2024] [Indexed: 10/19/2024]
Abstract
Background Clostridioides difficile infection (CDI) may be misdiagnosed if testing is performed in the absence of signs or symptoms of disease. This study sought to support appropriate testing by estimating the impact of signs, symptoms, and healthcare exposures on pre-test likelihood of CDI. Methods A panel of fifteen experts in infectious diseases participated in a modified UCLA/RAND Delphi study to estimate likelihood of CDI. Consensus, defined as agreement by >70% of panelists, was assessed via a REDCap survey. Items without consensus were discussed in a virtual meeting followed by a second survey. Results All fifteen panelists completed both surveys (100% response rate). In the initial survey, consensus was present on 6 of 15 (40%) items related to risk of CDI. After panel discussion and clarification of questions, consensus (>70% agreement) was reached on all remaining items in the second survey. Antibiotics were identified as the primary risk factor for CDI and grouped into three categories: high-risk (likelihood ratio [LR] 7, 93% agreement among panelists in first survey), low-risk (LR 3, 87% agreement in first survey), and minimal-risk (LR 1, 71% agreement in first survey). Other major factors included new or unexplained severe diarrhea (e.g., ≥ 10 liquid bowel movements per day; LR 5, 100% agreement in second survey) and severe immunosuppression (LR 5, 87% agreement in second survey). Conclusion Infectious disease experts concurred on the importance of signs, symptoms, and healthcare exposures for diagnosing CDI. The resulting risk estimates can be used by clinicians to optimize CDI testing and treatment.
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Affiliation(s)
| | - Mia Wessel
- University of Maryland, Baltimore, Baltimore, MD, USA
| | | | | | | | | | - K.C. Coffey
- University of Maryland, Baltimore, Baltimore, MD, USA
| | - Michael Durkin
- Washington University School of Medicine, St. Louis, MO, USA
| | | | - Alice Y. Guh
- Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Jennie H. Kwon
- Washington University School of Medicine, St. Louis, MO, USA
| | - Elise Martin
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | | | | | - Michael S. Pulia
- University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Clare Rock
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Zaheer J, Khan MN, Rahman AU, Shahzad MA, Yaasir Z, Lateef M, Gujar N. Identification and Epidemiological Analysis of Antibiotic-Resistant Bacteria in the Oral Microbiome of the Population in Pakistan. Cureus 2024; 16:e70666. [PMID: 39493182 PMCID: PMC11528176 DOI: 10.7759/cureus.70666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2024] [Indexed: 11/05/2024] Open
Abstract
Background Antibiotic resistance in the oral microbiome poses serious health risks worldwide, particularly in developing countries like Pakistan. Public health efforts are challenged by the potential of the oral cavity to serve as a reservoir for resistant bacteria due to its frequent exposure to antibiotics. Objective This study aimed to identify and analyze the prevalence and epidemiology of antibiotic-resistant bacteria within the oral microbiome of the Pakistani population. Methodology A cross-sectional study was conducted at Akhtar Saeed Medical and Dental College, Lahore, and Gomal Medical College, Dera Ismail Khan, from January 2023 to December 2023. A total of 290 participants, aged 18 years or older, were recruited based on specific inclusion and exclusion criteria. Oral swabs were collected and analyzed using conventional culture methods. All descriptive and inferential statistical analyses were performed using SPSS version 25 (IBM Corp., Armonk, NY), with a significance level set at p <0.05. Results The most common antibiotic-resistant bacteria identified were Enterococcus faecalis (24.48%, n = 71), Staphylococcus aureus (27.24%, n = 79), and Streptococcus mutans (35.86%, n = 104). The most frequent resistances were to penicillin (32.14%, n = 93), tetracycline (23.45%, n = 68), and erythromycin (22.07%, n = 64). Recent antibiotic use was significantly associated with higher rates of resistance (p = 0.01), with 75.19% of individuals (n = 97) who had used antibiotics within the past three to six months showing resistance. Conclusion The study reveals a high prevalence of antibiotic-resistant bacteria, particularly to penicillin and tetracycline, in the oral microbiome of the Pakistani population.
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Affiliation(s)
- Javeria Zaheer
- Department of Microbiology, Akhtar Saeed Medical and Dental College, Lahore, PAK
| | | | - Atiq Ur Rahman
- Department of Maxillofacial Surgery, Gomal Medical College, Dera Ismail Khan, PAK
| | - Muhammad Asif Shahzad
- Department of Oral and Maxillofacial Surgery, Azra Naheed Dental College, The Superior University, Lahore, PAK
| | - Zenab Yaasir
- Department of Dental Materials, Akhtar Saeed Medical and Dental College, Lahore, PAK
| | - Madeeha Lateef
- Department of Biochemistry, Sardar Begum Dental College, Gandhara University, Peshawar, PAK
| | - Nida Gujar
- Department of Internal Medicine, Punjab Medical College, Allied Hospital, Faisalabad, PAK
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Benech N, Cassir N, Galperine T, Alric L, Scanzi J, Sokol H. Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection Can Be the Best Therapeutic Option in Severely Immunocompromised Patients Depending on a Case-by-Case Assessment of the Benefit-to-Risk Ratio. Gastroenterology 2024; 167:627-628. [PMID: 38679396 DOI: 10.1053/j.gastro.2024.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 04/01/2024] [Indexed: 05/01/2024]
Affiliation(s)
- Nicolas Benech
- Hepato-Gastroenterology Department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France; Lyon GEM Microbiota Study Group, Lyon, France; ESCMID Study Group for Host and Microbiota Interactions (ESGHAMI), Basel, Switzerland; Claude Bernard Lyon 1 University, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, France
| | - Nadim Cassir
- Pôle Maladies Infectieuses et Tropicales, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix-Marseille Université, Institut de Recherche pour le Développement (IRD), Microbes, Evolution, Phylogénie et Infection (MEPHI), Marseille, France
| | - Tatiana Galperine
- Services des Maladies Infectieuses, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Laurent Alric
- Digestive Department, Internal Medicine, Rangueil Hospital, Toulouse 3 University, Toulouse, France
| | - Julien Scanzi
- Service de Gastroentérologie, Centre Hospitalier de Thiers, Thiers, France; Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire Clermont-Ferrand, Clermont-Ferrand, France
| | - Harry Sokol
- Assistance Publique-Hopitaux de Paris FMT Center, Paris, France; Paris Center for Microbiome Medicine FHU, Paris, France; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Assistance Publique-Hopitaux, Gastroenterology Department, Saint-Antoine Hospital, Paris, France; Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
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21
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Bogatic D, Bryant RV. Letter: Microbial manipulation for primary sclerosing cholangitis-associated inflammatory bowel disease-hope on the horizon. Aliment Pharmacol Ther 2024; 60:535-536. [PMID: 39014921 DOI: 10.1111/apt.18098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/18/2024]
Abstract
LINKED CONTENTThis article is linked to Ricciuto et al paper. To view this article, visit https://doi.org/10.1111/apt.17936
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Affiliation(s)
- D Bogatic
- Department of Gastroenterology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia
- School of Medicine, Faculty of Helath Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - R V Bryant
- Department of Gastroenterology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia
- School of Medicine, Faculty of Helath Sciences, University of Adelaide, Adelaide, South Australia, Australia
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22
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Taguer M, Xiao J, Crawford R, Shi H, Cheng MP, Citron M, Hannigan GD, Kasper SH. Spatial recovery of the murine gut microbiota after antibiotics perturbation. mBio 2024; 15:e0070724. [PMID: 38832780 PMCID: PMC11253616 DOI: 10.1128/mbio.00707-24] [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: 03/12/2024] [Accepted: 03/31/2024] [Indexed: 06/05/2024] Open
Abstract
Bacterial communities are highly complex, with interaction networks dictating ecosystem function. Bacterial interactions are constrained by the spatial organization of these microbial communities, yet studying the spatial organization of microbial communities at the single-cell level has been technically challenging. Here, we use the recently developed high-phylogenetic-resolution microbiota mapping by fluorescence in situ hybridization technology to image the gut microbiota at the species and single-cell level. We simultaneously image 63 different bacterial species to spatially characterize the perturbation and recovery of the gut microbiota to ampicillin and vancomycin in the cecum and distal colon of mice. To decipher the biology in this complex imaging data, we developed an analytical framework to characterize the spatial changes of the gut microbiota to a perturbation. The three-tiered analytical approach includes image-level diversity, pairwise colocalization analysis, and hypothesis-driven neighborhood analysis. Through this workflow, we identify biogeographic and antibiotic-based differences in the spatial organization of the gut microbiota. We demonstrate that the cecal microbiota has increased micrometer-scale diversity than the colon at baseline and recovers better from perturbation. Also, we identify potential foundation and keystone species that have high baseline neighborhood richness and that are associated with recovery from antibiotics. Through this workflow, we add a spatial layer to the characterization of bacterial communities and progress toward a better understanding of bacterial interactions leading to improved microbiome modulation strategies. IMPORTANCE Antibiotics have broad off-target effects on the gut microbiome. When the microbial community is unable to recover from antibiotics, it can lead to increased susceptibility to gastrointestinal infections and increased risk of immunological and metabolic diseases. In this study, we work to better understand how the gut microbiota recovers from antibiotics by employing a recent technology to image the entire bacterial community at once. Through this approach, we characterize the spatial changes in the gut microbiota after treatment with model antibiotics in both the cecum and colon of mice. We find antibiotic- and biogeographic-dependent spatial changes between bacterial species and that many of these spatial colocalizations do not recover to baseline levels even 35 days after antibiotic administration.
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Affiliation(s)
- M. Taguer
- Discovery Immunology, MRL, Merck & Co., Inc., Cambridge, Massachusetts, USA
| | - J. Xiao
- Infectious Diseases and Vaccine Research, MRL, Merck & Co., Inc., West Point, Pennsylvania, USA
| | - R. Crawford
- Informatics Technology, MRL, Merck & Co., Inc., West Point, Pennsylvania, USA
| | - H. Shi
- Kanvas Biosciences, Inc., Monmouth Junction, New Jersey, USA
| | - M. P. Cheng
- Kanvas Biosciences, Inc., Monmouth Junction, New Jersey, USA
| | - M. Citron
- Infectious Diseases and Vaccine Research, MRL, Merck & Co., Inc., West Point, Pennsylvania, USA
| | - G. D. Hannigan
- Informatics Technology, MRL, Merck & Co., Inc., Cambridge, Massachusetts, USA
| | - S. H. Kasper
- Discovery Immunology, MRL, Merck & Co., Inc., Cambridge, Massachusetts, USA
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Quan M, Zhang X, Fang Q, Lv X, Wang X, Zong Z. Fighting against Clostridioides difficile infection: Current medications. Int J Antimicrob Agents 2024; 64:107198. [PMID: 38734214 DOI: 10.1016/j.ijantimicag.2024.107198] [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: 12/08/2023] [Revised: 04/18/2024] [Accepted: 05/04/2024] [Indexed: 05/13/2024]
Abstract
Clostridioides difficile (formerly Clostridium difficile) has been regarded as an 'urgent threat' and a significant global health problem, as life-threatening diarrhoea and refractory recurrence are common in patients with C. difficile infection (CDI). Unfortunately, the available anti-CDI drugs are limited. Recent guidelines recommend fidaxomicin and vancomycin as first-line drugs to treat CDI, bezlotoxumab to prevent recurrence, and faecal microbiota transplantation for rescue treatment. Currently, researchers are investigating therapeutic antibacterial drugs (e.g. teicoplanin, ridinilazole, ibezapolstat, surotomycin, cadazolid, and LFF571), preventive medications against recurrence (e.g. Rebyota, Vowst, VP20621, VE303, RBX7455, and MET-2), primary prevention strategies (e.g. vaccine, ribaxamase, and DAV132) and other anti-CDI medications in the preclinical stage (e.g. Raja 42, Myxopyronin B, and bacteriophage). This narrative review summarises current medications, including newly marketed drugs and products in development against CDI, to help clinicians treat CDI appropriately and to call for more research on innovation.
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Affiliation(s)
- Min Quan
- Center for Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoxia Zhang
- Center for Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Qingqing Fang
- Center for Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoju Lv
- Center for Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaohui Wang
- Center for Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
| | - Zhiyong Zong
- Center for Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
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Reveles KR, Gonzales-Luna AJ, Golan Y, Alonso CD, Guthmueller B, Tan X, Bidell MR, Pokhilko V, Crawford CV, Skinner AM. Efficacy of Fecal Microbiota, Live-jslm (REBYOTA®), Among Patients Exposed to Non- Clostridioides difficile Infection Antibiotics: Post Hoc Subgroup Analysis of a Phase 2 Open-Label Study. Open Forum Infect Dis 2024; 11:ofae341. [PMID: 39006315 PMCID: PMC11244191 DOI: 10.1093/ofid/ofae341] [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: 01/12/2024] [Accepted: 06/13/2024] [Indexed: 07/16/2024] Open
Abstract
Background Antibiotic use is a major risk factor for recurrent Clostridioides difficile infection (CDI) due to the associated disruption in gut microbiota. Fecal microbiota, live-jslm (REBYOTA®; RBL, previously RBX2660), is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent CDI in adults following standard-of-care antibiotic treatment. To investigate the impact of non-CDI antibiotics on the durability of RBL, a subgroup analysis was conducted on PUNCH™ Open-Label study participants who received non-CDI antibiotics during the period between RBL administration and up to 2 years after. Methods Participants in PUNCH™ Open-Label who received non-CDI antibiotics after RBL administration were included in this subgroup analysis. Treatment response was defined as the absence of CDI diarrhea needing retreatment at the last evaluable time point (8 weeks, 6 months, 1 year, or 2 years) after RBL administration. Results Among participants from PUNCH™ Open-Label, 43 received non-CDI antibiotics after RBL administration but before CDI recurrence as evaluated over a 2-year period. Across all evaluable time points, 86% (37/43) of participants had a treatment response regardless of when non-CDI antibiotic exposure occurred. Treatment response was sustained for a median 470 days (IQR, 212-648) from the first day of non-CDI antibiotic use. Most participants (5/6) with CDI recurrences received a high-risk antibiotic. Conclusions RBL remained efficacious in participants with a history of recurrent CDI after subsequent non-CDI antibiotic exposure. Clinical Trials Registration NCT02589847 (https://clinicaltrials.gov/study/NCT02589847).
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Affiliation(s)
- Kelly R Reveles
- College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - Anne J Gonzales-Luna
- Department of Pharmacy Practice and Translational Research, College of Pharmacy, University of Houston, Houston, Texas, USA
| | - Yoav Golan
- Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA
| | - Carolyn D Alonso
- Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | | | - Xing Tan
- Ferring Pharmaceuticals, Parsippany, New Jersey, USA
| | | | | | - Carl V Crawford
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York, USA
| | - Andrew M Skinner
- Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah, USA
- Infectious Diseases Section, George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah, USA
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25
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Salvadori M, Rosso G. Update on the gut microbiome in health and diseases. World J Methodol 2024; 14:89196. [PMID: 38577200 PMCID: PMC10989414 DOI: 10.5662/wjm.v14.i1.89196] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/18/2023] [Accepted: 01/27/2024] [Indexed: 03/07/2024] Open
Abstract
The Human Microbiome Project, Earth Microbiome Project, and next-generation sequencing have advanced novel genome association, host genetic linkages, and pathogen identification. The microbiome is the sum of the microbes, their genetic information, and their ecological niche. This study will describe how millions of bacteria in the gut affect the human body in health and disease. The gut microbiome changes in relation with age, with an increase in Bacteroidetes and Firmicutes. Host and environmental factors affecting the gut microbiome are diet, drugs, age, smoking, exercise, and host genetics. In addition, changes in the gut microbiome may affect the local gut immune system and systemic immune system. In this study, we discuss how the microbiome may affect the metabolism of healthy subjects or may affect the pathogenesis of metabolism-generating metabolic diseases. Due to the high number of publications on the argument, from a methodologically point of view, we decided to select the best papers published in referred journals in the last 3 years. Then we selected the previously published papers. The major goals of our study were to elucidate which microbiome and by which pathways are related to healthy and disease conditions.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Tuscany, Italy
| | - Giuseppina Rosso
- Division of Nephrology, San Giovanni di Dio Hospital, Florence 50143, Toscana, Italy
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26
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Bhardwaj G, Riadi Y, Afzal M, Bansal P, Kaur H, Deorari M, Tonk RK, Almalki WH, Kazmi I, Alzarea SI, Kukreti N, Thangavelu L, Saleem S. The hidden threat: Environmental toxins and their effects on gut microbiota. Pathol Res Pract 2024; 255:155173. [PMID: 38364649 DOI: 10.1016/j.prp.2024.155173] [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: 12/11/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/18/2024]
Abstract
The human gut microbiota (GM), which consists of a complex and diverse ecosystem of bacteria, plays a vital role in overall wellness. However, the delicate balance of this intricate system is being compromised by the widespread presence of environmental toxins. The intricate connection between contaminants in the environment and human well-being has garnered significant attention in recent times. Although many environmental pollutants and their toxicity have been identified and studied in laboratory settings and animal models, there is insufficient data concerning their relevance to human physiology. Consequently, research on the toxicity of environmental toxins in GM has gained prominence in recent years. Various factors, such as air pollution, chemicals, heavy metals, and pesticides, have a detrimental impact on the composition and functioning of the GM. This comprehensive review aims to comprehend the toxic effects of numerous environmental pollutants, including antibiotics, endocrine-disrupting chemicals, heavy metals, and pesticides, on GM by examining recent research findings. The current analysis concludes that different types of environmental toxins can lead to GM dysbiosis and have various potential adverse effects on the well-being of animals. We investigate the alterations to the GM composition induced by contaminants and their impact on overall well-being, providing a fresh perspective on research related to pollutant exposure.
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Affiliation(s)
- Gautam Bhardwaj
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar sector-3, M-B Road, New Delhi 110017, India
| | - Yassine Riadi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh 247341, India; Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand 831001, India
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Rajiv Kumar Tonk
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar sector-3, M-B Road, New Delhi 110017, India.
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589 Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341 Sakaka, Aljouf, Saudi Arabia
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Lakshmi Thangavelu
- Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Shakir Saleem
- Department of Public Health. College of Health Sciences, Saudi Electronic University, Riyadh, Saudi Arabia.
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Nguyen KM, Wright EK. Vancomycin and Ustekinumab Combination Therapy in Acute Ulcerative Colitis. ACG Case Rep J 2024; 11:e01302. [PMID: 38469431 PMCID: PMC10927326 DOI: 10.14309/crj.0000000000001302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 01/31/2024] [Indexed: 03/13/2024] Open
Abstract
The role of antibiotics in the treatment of ulcerative colitis is limited. We present a case of a 25-year-old woman who presented with a flare of ulcerative colitis after an episode of infectious gastroenteritis on a background of known primary sclerosing cholangitis. After the flare, she experienced persistent abdominal pain and diarrhea associated with elevated fecal calprotectin and deep rectosigmoid ulcerations on endoscopy. After unsuccessful trials of vedolizumab, infliximab, and tofacitinib, the patient was commenced on ustekinumab, tacrolimus, and oral vancomycin. Tacrolimus was ceased successfully, but while on maintenance ustekinumab therapy, 2 attempts to cease vancomycin resulted in symptom recurrence and rising fecal calprotectin that improved with vancomycin recommencement. To date, the patient has been on vancomycin continuously for 18 months and remains clinically well with colonoscopy demonstrating inactive colitis. This case highlights how vancomycin may be beneficial in the management of treatment-refractory ulcerative colitis as an adjunct to biologic therapy.
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Affiliation(s)
- Khue M. Nguyen
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Australia
| | - Emily K. Wright
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Australia
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
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Ye Y, Tong HYK, Chong WH, Li Z, Tam PKH, Baptista-Hon DT, Monteiro O. A systematic review and meta-analysis of the effects of long-term antibiotic use on cognitive outcomes. Sci Rep 2024; 14:4026. [PMID: 38369574 PMCID: PMC10874946 DOI: 10.1038/s41598-024-54553-4] [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: 11/10/2023] [Accepted: 02/14/2024] [Indexed: 02/20/2024] Open
Abstract
Antibiotics are indispensable to infection management. However, use of antibiotics can cause gut microbiota dysbiosis, which has been linked to cognitive impairment by disrupting communication between the gut microbiota and the brain. We conducted a systematic review and meta-analysis on the effects of long-term antibiotic use on cognitive outcomes. We have searched PubMed, Web of Science, Embase, Cochrane Library and Scopus for English publications before March 2023 following the PRISMA guidelines. Screening, data extraction, and quality assessment were performed in duplicate. 960 articles were screened and 16 studies which evaluated the effect of any antibiotic compared to no antibiotics or placebo were included. Case-reports, in vitro and animal studies were excluded. We found that antibiotic use was associated with worse cognitive outcomes with a pooled effect estimate of - 0.11 (95% CI - 0.15, - 0.07, Z = 5.45; P < 0.00001). Subgroup analyses performed on adult vs pediatric patients showed a similar association of antibiotic on cognition in both subgroups. Antibiotic treatment was not associated with worse cognition on subjects with existing cognitive impairment. On the other hand, antibiotic treatment on subjects with no prior cognitive impairment was associated with worse cognitive performance later in life. This calls for future well-designed and well-powered studies to investigate the impact of antibiotics on cognitive performance.
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Affiliation(s)
- Yongqin Ye
- Faculty of Medicine, Medical Sciences Division, Macau University of Science and Technology, Avenida da Harmonia, Praia Park, Coloane, 999078, Macao SAR, China
| | | | - Wai Hong Chong
- Faculty of Medicine, Medical Sciences Division, Macau University of Science and Technology, Avenida da Harmonia, Praia Park, Coloane, 999078, Macao SAR, China
| | - Zhiqian Li
- Faculty of Medicine, Medical Sciences Division, Macau University of Science and Technology, Avenida da Harmonia, Praia Park, Coloane, 999078, Macao SAR, China
| | - Paul Kwong Hang Tam
- Faculty of Medicine, Medical Sciences Division, Macau University of Science and Technology, Avenida da Harmonia, Praia Park, Coloane, 999078, Macao SAR, China
| | - Daniel T Baptista-Hon
- Faculty of Medicine, Medical Sciences Division, Macau University of Science and Technology, Avenida da Harmonia, Praia Park, Coloane, 999078, Macao SAR, China
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, UK
| | - Olivia Monteiro
- Faculty of Medicine, Medical Sciences Division, Macau University of Science and Technology, Avenida da Harmonia, Praia Park, Coloane, 999078, Macao SAR, China.
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Kellogg TD, Ceglia S, Mortzfeld BM, Zeamer AL, Foley SE, Ward DV, Bhattarai SK, McCormick BA, Reboldi A, Bucci V. Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during Clostridioides difficile infection in the large intestine. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.29.574039. [PMID: 38352546 PMCID: PMC10862725 DOI: 10.1101/2024.01.29.574039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/22/2024]
Abstract
Metabolic byproducts of the intestinal microbiota are crucial in maintaining host immune tone and shaping inter-species ecological dynamics. Among these metabolites, succinate is a driver of tuft cell (TC) differentiation and consequent type 2 immunity-dependent protection against invading parasites in the small intestine. Succinate is also a growth enhancer of the nosocomial pathogen Clostridioides difficile in the large intestine. To date, no research has shown the role of succinate in modulating TC dynamics in the large intestine, or the relevance of this immune pathway to C. difficile pathophysiology. Here we reveal the existence of a three-way circuit between commensal microbes, C. difficile and host epithelial cells which centers around succinate. Through selective microbiota depletion experiments we demonstrate higher levels of type 2 cytokines leading to expansion of TCs in the colon. We then demonstrate the causal role of the microbiome in modulating colonic TC abundance and subsequent type 2 cytokine induction using rational supplementation experiments with fecal transplants and microbial consortia of succinate-producing bacteria. We show that administration of a succinate-deficient Bacteroides thetaiotaomicron knockout (Δfrd) significantly reduces the enhanced type 2 immunity in mono-colonized mice. Finally, we demonstrate that mice prophylactically administered with the consortium of succinate-producing bacteria show reduced C. difficile-induced morbidity and mortality compared to mice administered with heat-killed bacteria or the vehicle. This effect is reduced in a partial tuft cell knockout mouse, Pou2f3+/-, and nullified in the tuft cell knockout mouse, Pou2f3-/-, confirming that the observed protection occurs via the TC pathway. Succinate is an intermediary metabolite of the production of short-chain fatty acids, and its concentration often increases during dysbiosis. The first barrier to enteric pathogens alike is the intestinal epithelial barrier, and host maintenance and strengthening of barrier integrity is vital to homeostasis. Considering our data, we propose that activation of TC by the microbiota-produced succinate in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by intestinal pathogens.
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Affiliation(s)
- Tasia D. Kellogg
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
| | - Simona Ceglia
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
- Department of Pathology, UMass Chan Medical School, Worcester, MA, USA
| | - Benedikt M. Mortzfeld
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
| | - Abigail L. Zeamer
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
| | - Sage E. Foley
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA
- Current address: Transformational and Translational Immunology Discovery Department, AbbVie, Cambridge, MA, USA
| | - Doyle V. Ward
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
| | - Shakti K. Bhattarai
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
| | - Beth A. McCormick
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
| | - Andrea Reboldi
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
- Department of Pathology, UMass Chan Medical School, Worcester, MA, USA
| | - Vanni Bucci
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA
- Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA
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Jo J, Hu C, Begum K, Wang W, Le TM, Agyapong S, Hanson BM, Ayele H, Lancaster C, Jahangir Alam M, Gonzales-Luna AJ, Garey KW. Fecal Pharmacokinetics and Gut Microbiome Effects of Oral Omadacycline Versus Vancomycin in Healthy Volunteers. J Infect Dis 2024; 229:273-281. [PMID: 38051631 PMCID: PMC10786255 DOI: 10.1093/infdis/jiad537] [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: 09/07/2023] [Revised: 11/21/2023] [Accepted: 11/30/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults. METHODS This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations were assessed, and microbiome changes were compared. RESULTS Sixteen healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years were enrolled; 62.5% were male, and participants' mean body mass index was 23.5 (SD, 4.0) kg/m2. Omadacycline was well tolerated with no safety signal differences between the 2 antibiotics. A rapid initial increase in fecal concentrations of omadacycline was observed compared to vancomycin, with maximum concentrations achieved within 48 hours. A significant difference in alpha diversity was observed following therapy in both the omadacycline and vancomycin groups (P < .05). Bacterial abundance and beta diversity analysis showed differing microbiome changes in subjects who received omadacycline versus vancomycin. CONCLUSIONS Subjects given omadacycline had high fecal concentrations with a distinct microbiome profile compared to vancomycin. CLINICAL TRIALS REGISTRATION NCT06030219.
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Affiliation(s)
- Jinhee Jo
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Chenlin Hu
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Khurshida Begum
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Weiqun Wang
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Thanh M Le
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Samantha Agyapong
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Blake M Hanson
- UTHealth Houston School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas
| | - Hossaena Ayele
- UTHealth Houston School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas
| | - Chris Lancaster
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - M Jahangir Alam
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Anne J Gonzales-Luna
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Kevin W Garey
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
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31
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Spari D, Zwicky SN, Yilmaz B, Salm L, Candinas D, Beldi G. Intestinal dysbiosis as an intraoperative predictor of septic complications: evidence from human surgical cohorts and preclinical models of peritoneal sepsis. Sci Rep 2023; 13:22921. [PMID: 38129468 PMCID: PMC10739899 DOI: 10.1038/s41598-023-49034-z] [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: 03/07/2023] [Accepted: 12/03/2023] [Indexed: 12/23/2023] Open
Abstract
Major surgery exposes the intestinal microbiota to inflammatory and antibiotic stressors, which alter the microbiota composition of the intestinal lumen and fecal contents. However, it is not sufficiently understood, if such dysbiosis develops already during surgery and if alterations in microbiota may be the cause of surgical complications. End-of-surgery composition of the microbiota in the rectum was assessed in 41 patients undergoing either rectal or duodenopancreatic resection and was compared to baseline before surgery using 16S-rRNA sequencing. A subset of patients developed severe dysbiosis at the end of surgery, which was characterized by an overgrowth of the Proteobacteria phylum that includes the facultative pathogen E. coli. To test if dysbiosis impacts on surgical outcomes, dysbiosis was modeled in mice by a single oral administration of vancomycin prior to cecal ligation and puncture. Dysbiosis was associated with impaired post-surgical survival, dysregulation of the host's immune response, elevated bacterial virulence and reduced bacterial metabolism of carbon sources. In conclusion, dysbiosis can be detected already at the end of surgery in a fraction of patients undergoing major surgery. Modelling surgery-associated dysbiosis in mice using single-shot administration of vancomycin induced dysbiosis and resulted in elevated mortality.
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Affiliation(s)
- Daniel Spari
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland
| | - Simone N Zwicky
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland
| | - Bahtiyar Yilmaz
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland
| | - Lilian Salm
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland
| | - Daniel Candinas
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland
| | - Guido Beldi
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland.
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Lin L, Zhang K, Xiong Q, Zhang J, Cai B, Huang Z, Yang B, Wei B, Chen J, Niu Q. Gut microbiota in pre-clinical rheumatoid arthritis: From pathogenesis to preventing progression. J Autoimmun 2023; 141:103001. [PMID: 36931952 DOI: 10.1016/j.jaut.2023.103001] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 12/30/2022] [Accepted: 01/31/2023] [Indexed: 03/17/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive polyarthritis that leads to cartilage and bone damage. Pre-clinical RA is a prolonged state before clinical arthritis and RA develop, in which autoantibodies (antibodies against citrullinated proteins, rheumatoid factors) can be present due to the breakdown of immunologic self-tolerance. As early treatment initiation before the onset of polyarthritis may achieve sustained remission, optimize clinical outcomes, and even prevent RA progression, the pre-clinical RA stage is showing the prospect to be the window of opportunity for RA treatment. Growing evidence has shown the role of the gut microbiota in inducing systemic inflammation and polyarthritis via multiple mechanisms, which may involve molecular mimicry, impaired intestinal barrier function, gut microbiota-derived metabolites mediated immune regulation, modulation of the gut microbiota's effect on immune cells, intestinal epithelial cells autophagy, and the interaction between the microbiome and human leukocyte antigen alleles as well as microRNAs. Since gut microbiota alterations in pre-clinical RA have been reported, potential therapies for modifying the gut microbiota in pre-clinical RA, including natural products, antibiotic therapy, fecal microbiota transplantation, probiotics, microRNAs therapy, vitamin D supplementation, autophagy inducer-based treatment, prebiotics, and diet, holds great promise for the successful treatment and even prevention of RA via altering ongoing inflammation. In this review, we summarized current studies that include pathogenesis of gut microbiota in RA progression and promising therapeutic strategies to provide novel ideas for the management of pre-clinical RA and possibly preventing arthritis progression.
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Affiliation(s)
- Liyan Lin
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Keyi Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Qiao Xiong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Infection Control, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Junlong Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Bei Cai
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhuochun Huang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Yang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Wei
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
| | - Qian Niu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
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Fishbein SRS, Mahmud B, Dantas G. Antibiotic perturbations to the gut microbiome. Nat Rev Microbiol 2023; 21:772-788. [PMID: 37491458 DOI: 10.1038/s41579-023-00933-y] [Citation(s) in RCA: 127] [Impact Index Per Article: 63.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2023] [Indexed: 07/27/2023]
Abstract
Antibiotic-mediated perturbation of the gut microbiome is associated with numerous infectious and autoimmune diseases of the gastrointestinal tract. Yet, as the gut microbiome is a complex ecological network of microorganisms, the effects of antibiotics can be highly variable. With the advent of multi-omic approaches for systems-level profiling of microbial communities, we are beginning to identify microbiome-intrinsic and microbiome-extrinsic factors that affect microbiome dynamics during antibiotic exposure and subsequent recovery. In this Review, we discuss factors that influence restructuring of the gut microbiome on antibiotic exposure. We present an overview of the currently complex picture of treatment-induced changes to the microbial community and highlight essential considerations for future investigations of antibiotic-specific outcomes. Finally, we provide a synopsis of available strategies to minimize antibiotic-induced damage or to restore the pretreatment architectures of the gut microbial community.
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Affiliation(s)
- Skye R S Fishbein
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Bejan Mahmud
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Gautam Dantas
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
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34
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Koneru S, Thiruvadi V, Ramesh M. Gut microbiome and its clinical implications: exploring the key players in human health. Curr Opin Infect Dis 2023; 36:353-359. [PMID: 37593952 DOI: 10.1097/qco.0000000000000958] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/19/2023]
Abstract
PURPOSE OF REVIEW The human gut harbors a diverse community of microorganisms known as the gut microbiota. Extensive research in recent years has shed light on the profound influence of the gut microbiome on human health and disease. This review aims to explore the role of the gut microbiome in various clinical conditions and highlight the emerging therapeutic potential of targeting the gut microbiota for disease management. RECENT FINDINGS Knowledge of the influence of gut microbiota on human physiology led to the development of various therapeutic possibilities such as fecal microbiota transplant (FMT), phage therapy, prebiotics, and probiotics. Recently, the U.S. FDA approved two FMT products for the treatment of recurrent Clostridioides difficile infection with ongoing research for the treatment of various disease conditions. SUMMARY Advancement in the knowledge of the association between gut microbiota and various disease processes has paved the way for novel therapeutics.
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Affiliation(s)
- Sindhuja Koneru
- Division of Infectious Diseases, Henry Ford Hospital, Detroit, Michigan, USA
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35
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Mc Loughlin J, Hinchion J. The gut microbiome and cardiac surgery an unusual symphony. Perfusion 2023; 38:1330-1339. [PMID: 35466814 DOI: 10.1177/02676591221097219] [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: 01/19/2023]
Abstract
The relationship between the gut microbiome and various organ systems has gained interest throughout the scientific community in recent times. The understanding of these complex relationships has greatly improved with clinical benefits now being seen. Cardiopulmonary bypass (CPB) is a form of extracorporeal circulation that provides circulatory and respiratory support during cardiac surgery. This physiological support facilitates a still and bloodless field facilitating operations on the heart to be performed. Through various mechanisms CPB results in a systemic inflammatory response syndrome (SIRS). This response can vary from mild hypotension to multiple organ failure. It remains difficult to predict the degree to which a patient will experience SIRS post-operatively. The relationship between the composition of the gut microbiome and inflammatory processes associated with disease has been seen across several fields including gastroenterology, neurology, psychiatry and cardiology. To date, minimal research has been undertaken to examine the impact the gut microbiome has on outcomes following cardiac surgery. This review paper explores the pathophysiology behind the SIRS response associated with CPB for cardiac surgery and the hypothesis that a correlation exists between a patients gut microbiome composition and the degree of inflammatory response experienced following cardiac surgery.
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Affiliation(s)
- Joseph Mc Loughlin
- Department of Cardiothoracic Surgery, Cork University Hospital, Cork, Ireland
| | - J Hinchion
- Department of Cardiothoracic Surgery, Cork University Hospital, Cork, Ireland
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36
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Adade E, Tawiah PO, Roos C, Chuma IS, Lubinza CC, Mfinanga SGM, Knauf S, Sylverken AA. Antimicrobial susceptibility profile of oral and rectal microbiota of non-human primate species in Ghana: A threat to human health. Vet Med Sci 2023; 10:e1271. [PMID: 37733757 PMCID: PMC10804077 DOI: 10.1002/vms3.1271] [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: 04/03/2023] [Revised: 08/14/2023] [Accepted: 08/18/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND The potential for the transfer of zoonotic diseases, including bacteria between human and non-human primates (NHPs), is expected to rise. It is posited that NHPs that live in close contact with humans serve as sentinels and reservoirs for antibiotic-resistant bacteria. OBJECTIVES The objective was to characterize the oral and rectal bacteria in Ghanaian NHPs and profile the antimicrobial susceptibility of the isolated bacteria. METHODS Oral and rectal swabs were obtained from 40 immobilized wild and captive NHPs from 7 locations in Ghana. Standard bacteriological procedures were used in the isolation, preliminary identification, automated characterization and antimicrobial susceptibility test (AST) of bacteria using the Vitek 2 Compact system. RESULTS Gram-negative bacteria dominated isolates from the rectal swabs (n = 76, 85.4%), whereas Gram-positive bacteria were more common in the oral swabs (n = 41, 82%). Staphylococcus haemolyticus (n = 7, 14%) was the most occurring bacterial species isolated from the oral swabs, whereas Escherichia coli (n = 32, 36%) dominated bacteria isolates from rectal swabs. Enterobacter spp. had the highest (39%) average phenotypic resistance to antimicrobials that were used for AST, whereas a trend of high resistance was recorded against norfloxacin, Ampicillin and Tetracycline in Gram-negative bacteria. Similarly, among Gram-positive bacteria, Staphylococcus spp. had the highest (25%) average phenotypic resistance to antimicrobials used for AST, and a trend of high resistance was recorded against penicillin G and oxacillin. CONCLUSIONS This study has established that apparently healthy NHPs that live in anthropized environments in Ghana harbour zoonotic and antimicrobial resistant bacteria.
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Affiliation(s)
- Eugene Adade
- Department of Theoretical and Applied BiologyKwame Nkrumah University of Science and TechnologyKumasiGhana
- Kumasi Centre for Collaborative Research in Tropical MedicineKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Patrick Ofori Tawiah
- Department of Theoretical and Applied BiologyKwame Nkrumah University of Science and TechnologyKumasiGhana
- Kumasi Centre for Collaborative Research in Tropical MedicineKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Christian Roos
- Gene Bank of Primates and Primate Genetics LaboratoryGerman Primate CenterLeibniz Institute for Primate ResearchGöttingenGermany
| | | | - Clara Clavery Lubinza
- National Institute for Medical ResearchMuhimbili Medical Research CentreDar es SalaamTanzania
| | | | - Sascha Knauf
- Institute of International Animal Health/One HealthFriedrich‐Loeffler‐InstitutFederal Institute for Animal HealthGreifswald – Insel RiemsGermany
| | - Augustina Angelina Sylverken
- Department of Theoretical and Applied BiologyKwame Nkrumah University of Science and TechnologyKumasiGhana
- Kumasi Centre for Collaborative Research in Tropical MedicineKwame Nkrumah University of Science and TechnologyKumasiGhana
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37
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Button JE, Cosetta CM, Reens AL, Brooker SL, Rowan-Nash AD, Lavin RC, Saur R, Zheng S, Autran CA, Lee ML, Sun AK, Alousi AM, Peterson CB, Koh AY, Rechtman DJ, Jenq RR, McKenzie GJ. Precision modulation of dysbiotic adult microbiomes with a human-milk-derived synbiotic reshapes gut microbial composition and metabolites. Cell Host Microbe 2023; 31:1523-1538.e10. [PMID: 37657443 DOI: 10.1016/j.chom.2023.08.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 06/13/2023] [Accepted: 08/07/2023] [Indexed: 09/03/2023]
Abstract
Manipulation of the gut microbiome using live biotherapeutic products shows promise for clinical applications but remains challenging to achieve. Here, we induced dysbiosis in 56 healthy volunteers using antibiotics to test a synbiotic comprising the infant gut microbe, Bifidobacterium longum subspecies infantis (B. infantis), and human milk oligosaccharides (HMOs). B. infantis engrafted in 76% of subjects in an HMO-dependent manner, reaching a relative abundance of up to 81%. Changes in microbiome composition and gut metabolites reflect altered recovery of engrafted subjects compared with controls. Engraftment associates with increases in lactate-consuming Veillonella, faster acetate recovery, and changes in indolelactate and p-cresol sulfate, metabolites that impact host inflammatory status. Furthermore, Veillonella co-cultured in vitro and in vivo with B. infantis and HMO converts lactate produced by B. infantis to propionate, an important mediator of host physiology. These results suggest that the synbiotic reproducibly and predictably modulates recovery of a dysbiotic microbiome.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Martin L Lee
- Prolacta Bioscience, Duarte, CA 91010, USA; Department of Biostatistics, University of California Los Angeles, Fielding School of Public Health, Los Angeles, CA 90095, USA
| | - Adam K Sun
- Prolacta Bioscience, Duarte, CA 91010, USA
| | - Amin M Alousi
- Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Christine B Peterson
- Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Andrew Y Koh
- Department of Pediatrics, Division of Hematology/Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | | | - Robert R Jenq
- Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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38
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Fitzmaurice MG, Hohlfelder B, Srinivas P, Rudoni M, Brizendine KD, Budev M. Implementation of routine Clostridioides difficile infection (CDI) primary prophylaxis in lung transplant recipients. Clin Transplant 2023; 37:e15079. [PMID: 37477286 DOI: 10.1111/ctr.15079] [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: 01/24/2023] [Revised: 07/09/2023] [Accepted: 07/11/2023] [Indexed: 07/22/2023]
Abstract
Lung transplant recipients are at an increased risk for Clostridioides difficile infection (CDI), and those who develop CDI post-transplant can have worsened outcomes including graft failure and death. We sought to describe the efficacy and safety of primary CDI prophylaxis with oral vancomycin among 86 adult lung transplant recipients. Overall, we observed a 9.3% (8/86) incidence of CDI among patients receiving prophylaxis, with the majority of infections occurring a median of 25 days after completion of prophylaxis. Furthermore, we observed a 4.7% incidence of VRE infection/colonization. Opportunities exist to optimize the duration of CDI prophylaxis to balance the benefits and risks in lung transplant recipients.
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Affiliation(s)
- Mary Grace Fitzmaurice
- Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Pharmacy and Transplant Institute, Henry Ford Health, Detroit, MI, USA
| | | | | | - Michael Rudoni
- Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kyle D Brizendine
- Department of Infectious Diseases, Cleveland Clinic, Cleveland, Ohio, USA
| | - Marie Budev
- Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic, Cleveland, Ohio, USA
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39
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Ziegler MJ, Flores EJ, Epps M, Hopkins K, Glaser L, Mull NK, Pegues DA. Clostridioides difficile dynamic electronic order panel, an effective automated intervention to reduce inappropriate inpatient ordering. Infect Control Hosp Epidemiol 2023; 44:1294-1299. [PMID: 36927512 PMCID: PMC10750561 DOI: 10.1017/ice.2022.254] [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] [Indexed: 03/18/2023]
Abstract
BACKGROUND Ordering Clostridioides difficile diagnostics without appropriate clinical indications can result in inappropriate antibiotic prescribing and misdiagnosis of hospital onset C. difficile infection. Manual processes such as provider review of order appropriateness may detract from other infection control or antibiotic stewardship activities. METHODS We developed an evidence-based clinical algorithm that defined appropriateness criteria for testing for C. difficile infection. We then implemented an electronic medical record-based order-entry tool that utilized discrete branches within the clinical algorithm including history of prior C. difficile test results, laxative or stool-softener administration, and documentation of unformed bowel movements. Testing guidance was then dynamically displayed with supporting patient data. We compared the rate of completed C. difficile tests after implementation of this intervention at 5 hospitals to a historic baseline in which a best-practice advisory was used. RESULTS Using mixed-effects Poisson regression, we found that the intervention was associated with a reduction in the incidence rate of both C. difficile ordering (incidence rate ratio [IRR], 0.74; 95% confidence interval [CI], 0.63-0.88; P = .001) and C. difficile-positive tests (IRR, 0.83; 95% CI, 0.76-0.91; P < .001). On segmented regression analysis, we identified a sustained reduction in orders over time among academic hospitals and a new reduction in orders over time among community hospitals. CONCLUSIONS An evidence-based dynamic order panel, integrated within the electronic medical record, was associated with a reduction in both C. difficile ordering and positive tests in comparison to a best practice advisory, although the impact varied between academic and community facilities.
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Affiliation(s)
- Matthew J Ziegler
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Healthcare Epidemiology, Infection Prevention and Control, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Emilia J Flores
- Center for Evidence-based Practice, University of Pennsylvania Health System, Philadelphia, Pennsylvania, Pennsylvania
| | - Mika Epps
- Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kathleen Hopkins
- Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Laurel Glaser
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nikhil K Mull
- Center for Evidence-based Practice, University of Pennsylvania Health System, Philadelphia, Pennsylvania, Pennsylvania
- Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - David A Pegues
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Healthcare Epidemiology, Infection Prevention and Control, University of Pennsylvania, Philadelphia, Pennsylvania
- Division of General Internal Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Conlon ASC, Chopra Z, Cahalan S, Cinti S, Rao K. Effects of procalcitonin on antimicrobial treatment decisions in patients with coronavirus disease 2019 (COVID-19). Infect Control Hosp Epidemiol 2023; 44:1314-1320. [PMID: 36330692 DOI: 10.1017/ice.2022.262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVE To describe the natural course of procalcitonin (PCT) in patients with coronavirus disease 2019 (COVID-19) and the correlation between PCT and antimicrobial prescribing to provide insight into best practices for PCT data utilization in antimicrobial stewardship in this population. DESIGN Single-center, retrospective, observational study. SETTING Michigan Medicine. PATIENTS Inpatients aged ≥18 years hospitalized March 1, 2020, through October 31, 2021, who were positive for severe acute respiratory coronavirus virus 2 (SARS-CoV-2), with ≥1 PCT measurement. Exclusion criteria included antibiotics for nonpulmonary bacterial infection on admission, treatment with azithromycin only for chronic obstructive pulmonary disease (COPD) exacerbation, and pre-existing diagnosis of cystic fibrosis with positive respiratory cultures. METHODS A structured query was used to extract data. For patients started on antibiotics, bacterial pneumonia (bPNA) was determined through chart review. Multivariable models were used to assess associations of PCT level and bPNA with antimicrobial use. RESULTS Of 793 patients, 224 (28.2%) were initiated on antibiotics: 33 (14.7%) had proven or probable bPNA, 125 (55.8%) had possible bPNA, and 66 (29.5%) had no bPNA. Patients had a mean of 4.1 (SD, ±5.2) PCT measurements if receiving antibiotics versus a mean of 2.0 (SD, ±2.6) if not. Initial PCT level was highest for those with proven/probable bPNA and was associated with antibiotic initiation (odds ratio 95% confidence interval [CI], 1.17-1.30). Initial PCT (rate ratio [RR] 95% CI, 1.01-1.08), change in PCT over time (RR 95% CI, 1.01-1.05), and bPNA group (RR 95% CI, 1.23-1.84) were associated with antibiotic duration. CONCLUSIONS PCT trends are associated with the decision to initiate antibiotics and duration of treatment, independent of bPNA status and comorbidities. Prospective studies are needed to determine whether PCT level can be used to safely make decisions regarding antibiotic treatment for COVID-19.
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Affiliation(s)
| | - Zoey Chopra
- University of Michigan Medical School, Ann Arbor, Michigan
| | | | - Sandro Cinti
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Krishna Rao
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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Dela Cruz M, Lin H, Han J, Adler E, Boissiere J, Khalid M, Sidebottom A, Sundararajan A, Lehmann C, Moran A, Odenwald M, Stutz M, Kim G, Pinney S, Jeevanandam V, Alegre ML, Pamer E, Nguyen AB. Reduced immunomodulatory metabolite concentrations in peri-transplant fecal samples from heart allograft recipients. FRONTIERS IN TRANSPLANTATION 2023; 2:1182534. [PMID: 38993864 PMCID: PMC11235359 DOI: 10.3389/frtra.2023.1182534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 06/30/2023] [Indexed: 07/13/2024]
Abstract
Background Emerging evidence is revealing the impact of the gut microbiome on hematopoietic and solid organ transplantation. Prior studies postulate that this influence is mediated by bioactive metabolites produced by gut-dwelling commensal bacteria. However, gut microbial metabolite production has not previously been measured among heart transplant (HT) recipients. Methods In order to investigate the potential influence of the gut microbiome and its metabolites on HT, we analyzed the composition and metabolite production of the fecal microbiome among 48 HT recipients at the time of HT. Results Compared to 20 healthy donors, HT recipients have significantly reduced alpha, i.e. within-sample, microbiota diversity, with significantly lower abundances of key anaerobic commensal bacteria and higher abundances of potentially pathogenic taxa that have been correlated with adverse outcomes in other forms of transplantation. HT recipients have a wide range of microbiota-derived fecal metabolite concentrations, with significantly reduced levels of immune modulatory metabolites such as short chain fatty acids and secondary bile acids compared to healthy donors. These differences were likely due to disease severity and prior antibiotic exposures but were not explained by other demographic or clinical factors. Conclusions Key potentially immune modulatory gut microbial metabolites are quantifiable and significantly reduced among HT recipients compared to healthy donors. Further study is needed to understand whether this wide range of gut microbial dysbiosis and metabolite alterations impact clinical outcomes and if they can be used as predictive biomarkers or manipulated to improve transplant outcomes.
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Affiliation(s)
- Mark Dela Cruz
- Department of Medicine, Section of Cardiology, University of Chicago Medicine, Chicago, IL, United States
| | - Huaiying Lin
- Duchossois Family Institute, University of Chicago, Chicago, IL, United States
| | - Jiho Han
- Department of Medicine, Section of Cardiology, University of Chicago Medicine, Chicago, IL, United States
| | - Emerald Adler
- Duchossois Family Institute, University of Chicago, Chicago, IL, United States
| | - Jaye Boissiere
- Duchossois Family Institute, University of Chicago, Chicago, IL, United States
| | - Maryam Khalid
- Duchossois Family Institute, University of Chicago, Chicago, IL, United States
| | - Ashley Sidebottom
- Duchossois Family Institute, University of Chicago, Chicago, IL, United States
| | - Anitha Sundararajan
- Duchossois Family Institute, University of Chicago, Chicago, IL, United States
| | - Christopher Lehmann
- Department of Medicine, Section of Infectious Diseases, University of Chicago Medicine, Chicago, IL, United States
| | - Angelica Moran
- Department of Pathology, University of Chicago Medicine, Chicago, IL, United States
| | - Matthew Odenwald
- Department of Medicine, Section of Gastroenterology, University of Chicago Medicine, Chicago, IL, United States
| | - Matthew Stutz
- Department of Medicine, Section of Pulmonary and Critical Care, University of Chicago Medicine, Chicago, IL, United States
| | - Gene Kim
- Department of Medicine, Section of Cardiology, University of Chicago Medicine, Chicago, IL, United States
| | - Sean Pinney
- Department of Medicine, Section of Cardiology, University of Chicago Medicine, Chicago, IL, United States
| | - Valluvan Jeevanandam
- Department of Surgery, Section of Cardiac Surgery, University of Chicago Medicine, Chicago, IL, United States
| | - Maria-Luisa Alegre
- Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL, United States
| | - Eric Pamer
- Duchossois Family Institute, University of Chicago, Chicago, IL, United States
| | - Ann B. Nguyen
- Department of Medicine, Section of Cardiology, University of Chicago Medicine, Chicago, IL, United States
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Shahin M, Ji B, Dixit PD. EMBED: Essential MicroBiomE Dynamics, a dimensionality reduction approach for longitudinal microbiome studies. NPJ Syst Biol Appl 2023; 9:26. [PMID: 37339950 PMCID: PMC10282069 DOI: 10.1038/s41540-023-00285-6] [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: 02/03/2023] [Accepted: 05/23/2023] [Indexed: 06/22/2023] Open
Abstract
Dimensionality reduction offers unique insights into high-dimensional microbiome dynamics by leveraging collective abundance fluctuations of multiple bacteria driven by similar ecological perturbations. However, methods providing lower-dimensional representations of microbiome dynamics both at the community and individual taxa levels are not currently available. To that end, we present EMBED: Essential MicroBiomE Dynamics, a probabilistic nonlinear tensor factorization approach. Like normal mode analysis in structural biophysics, EMBED infers ecological normal modes (ECNs), which represent the unique orthogonal modes capturing the collective behavior of microbial communities. Using multiple real and synthetic datasets, we show that a very small number of ECNs can accurately approximate microbiome dynamics. Inferred ECNs reflect specific ecological behaviors, providing natural templates along which the dynamics of individual bacteria may be partitioned. Moreover, the multi-subject treatment in EMBED systematically identifies subject-specific and universal abundance dynamics that are not detected by traditional approaches. Collectively, these results highlight the utility of EMBED as a versatile dimensionality reduction tool for studies of microbiome dynamics.
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Affiliation(s)
- Mayar Shahin
- Department of Physics, University of Florida, Gainesville, FL, 32611, USA.
| | - Brian Ji
- Physician-Scientist Training Pathway, Department of Medicine, UCSD, San Diego, CA, 92103, USA
| | - Purushottam D Dixit
- Department of Physics, University of Florida, Gainesville, FL, 32611, USA.
- Genetics Institute, University of Florida, Gainesville, FL, 32611, USA.
- Department of Chemical Engineering, University of Florida, Gainesville, FL, 32611, USA.
- Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
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He Y, Xu M, Lu S, Zou W, Wang Y, Fakhar-E-Alam Kulyar M, Iqbal M, Li K. Seaweed polysaccharides treatment alleviates injury of inflammatory responses and gut barrier in LPS-induced mice. Microb Pathog 2023; 180:106159. [PMID: 37201636 DOI: 10.1016/j.micpath.2023.106159] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 05/20/2023]
Abstract
Gastrointestinal (GI) disease is a common digestive tract disease effects health of millions of human globally each year, thus the role of intestinal microflora had been emphasized. Seaweed polysaccharides featured a wide range of pharmacological activities, such as antioxidant activity and pharmacological action, but whether they can alleviate the dysbiosis of gut microbial ecology caused by lipopolysaccharide (LPS) exposure has not been well conducted. In this study, we investigated the effects of different concentration of seaweed polysaccharides on LPS-induced intestinal disorder by using microscope and 16S rRNA high-throughput sequencing. Histopathological results indicated that the intestinal structure in the LPS-induced group was damaged. Furthermore, LPS exposure not only reduced the intestinal microbial diversity in mice but also induced momentous transformation in its composition, including a significantly increased in some pathogenic bacteria (Helicobacter, Citrobacter and Mucispirillum) and decreased in several beneficial bacteria (Firmicutes, Lactobacillus, Akkermansia and Parabacteroides). Nonetheless, seaweed polysaccharide administration could recover the gut microbial dysbiosis and the loss of gut microbial diversity induced by LPS exposure. In summary, seaweed polysaccharides were effective against LPS-induced intestinal damage in mice via the modulation of intestinal microecology.
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Affiliation(s)
- Yuanyuan He
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, PR China
| | - Mengen Xu
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, PR China
| | - Sijia Lu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Wen Zou
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Yaping Wang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, PR China
| | | | - Mudassar Iqbal
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, PR China; University College of Veterinary & Animal Sciences, Islamia University of Bahawalpur, 61100, Pakistan
| | - Kun Li
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China.
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Hasan N, Yang H. Evaluation of microbial and vancomycin treatments in ulcerative colitis in murine models. PLoS One 2023; 18:e0285613. [PMID: 37167242 PMCID: PMC10174502 DOI: 10.1371/journal.pone.0285613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/26/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Despite the number of available therapies for ulcerative colitis (UC), severe side effects and high cost has limited their clinical application. Thus, finding new alternative strategies with minimal side effects is inevitable. Therefore, this study aimed to compare the effectiveness of different therapeutic approaches in DSS-induced colitis. METHODS Firstly, we designed oral bio-therapeutic products, Live Bacterial Products (LBP), which include a mixture of fecal bacteria strains isolated from healthy mice and prepared by microencapsulation and freeze-dried techniques. Then we investigated the efficiency of 7 days of freeze-dried FMT, LBP, and vancomycin treatments in DSS-induced colitis. Secondly, we compared the effect of 15 days of microbial therapies (freeze-dried powder of FMT and LBP microcapsules) and seven days of oral vancomycin on the severity of colitis in mice. Furthermore, the levels of IL-1β and TNF-α were measured in serum by ELISA, and the fecal microbiota diversity was analyzed by high-throughput sequencing for all mice groups. RESULTS After seven days of treatments, our results indicated that oral vancomycin reduced the severity of DSS-induced colitis in mice, where weight gain and a decrease in IL-1 β and TNF-α levels were observed in the vancomycin group compared with other treatment groups. While after two weeks of treatment, the LBP microcapsules were able to reduce the severity of colitis. And at the end of the treatment period, weight gain and a decrease in the DAI scores and the levels of IL-1β and TNF-α were noted in the LBP treatment group compared to other treatment groups. By high-throughput sequencing of the 16S rRNA gene, our results showed that while the microcapsules LBP treatment increased the fecal microbial diversity, after vancomycin therapy, most of the fecal microbiota genera and operational taxonomic units (OTUs) were depleted. CONCLUSION Our results concluded that treatment duration and preparation methods affect the microbial therapies' efficiency in UC. Furthermore, this study highlighted the negative consequences of oral vancomycin administration on gut health that should be known before using this medication.
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Affiliation(s)
- Nihal Hasan
- Department of Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, People’s Republic of China
- Faculty of Health Science, Al-Baath University, Homs, Syria
| | - Hongyi Yang
- Department of Microbiology, Northeast Forestry University, Harbin, Heilongjiang, People’s Republic of China
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Rakuša E, Fink A, Tamgüney G, Heneka MT, Doblhammer G. Sporadic Use of Antibiotics in Older Adults and the Risk of Dementia: A Nested Case-Control Study Based on German Health Claims Data. J Alzheimers Dis 2023:JAD221153. [PMID: 37182873 DOI: 10.3233/jad-221153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
BACKGROUND Antibiotics for systemic use may increase the risk of neurodegeneration, yet antibiotic therapy may be able to halt or mitigate an episode of neurodegenerative decline. OBJECTIVE To investigate the association of sporadic use of antibiotics and subsequent dementia risk (including Alzheimer's disease). METHODS We used data from the largest public health insurance fund in Germany, the Allgemeine Ortskrankenkasse (AOK). Each of the 35,072 dementia cases aged 60 years and older with a new dementia diagnosis during the observation period from 2006 to 2018 was matched with two control-patients by age, sex, and time since 2006. We ran conditional logistic regression models for dementia risk in terms of odds ratios (OR) as a function of antibiotic use for the entire antibiotic group and for each antibiotic subgroup. We controlled for comorbidities, need for long-term care, hospitalizations, and nursing home placement. RESULTS Antibiotic use was positively associated with dementia (OR = 1.18, 95% confidence interval (95% CI):1.14-1.22), which became negative after adjustment for comorbidities, at least one diagnosis of bacterial infection or disease, and covariates (OR = 0.93, 95% CI:0.90-0.96). Subgroups of antibiotics were also negatively associated with dementia after controlling for covariates: tetracyclines (OR = 0.94, 95% CI:0.90-0.98), beta-lactam antibacterials, penicillins (OR = 0.93, 95% CI:0.90-0.97), other beta-lactam antibacterials (OR = 0.92, 95% CI:0.88-0.95), macrolides, lincosamides, and streptogramins (OR = 0.88, 95% CI:0.85-0.92), and quinolone antibacterials (OR = 0.96, 95% CI:0.92-0.99). CONCLUSION Our results suggest that there was a decreased likelihood of dementia for preceding antibiotic use. The benefits of antibiotics in reducing inflammation and thus the risk of dementia need to be carefully weighed against the increase in antibiotic resistance.
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Affiliation(s)
- Elena Rakuša
- German Center for Neurodegenerative Diseases, Demographic Studies, Bonn, Germany
| | - Anne Fink
- German Center for Neurodegenerative Diseases, Demographic Studies, Bonn, Germany
| | - Gültekin Tamgüney
- Institut für Biologische Informationsprozesse, Strukturbiochemie (IBI-7), Forschungszentrum Jülich GmbH, Jülich, Germany
- Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Michael T Heneka
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
| | - Gabriele Doblhammer
- German Center for Neurodegenerative Diseases, Demographic Studies, Bonn, Germany
- University Rostock, Institute for Sociology and Demography, Rostock, Germany
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Bublitz A, Brauer M, Wagner S, Hofer W, Müsken M, Deschner F, Lesker TR, Neumann-Schaal M, Paul LS, Nübel U, Bartel J, Kany AM, Zühlke D, Bernecker S, Jansen R, Sievers S, Riedel K, Herrmann J, Müller R, Fuchs TM, Strowig T. The natural product chlorotonil A preserves colonization resistance and prevents relapsing Clostridioides difficile infection. Cell Host Microbe 2023; 31:734-750.e8. [PMID: 37098342 DOI: 10.1016/j.chom.2023.04.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 02/24/2023] [Accepted: 04/03/2023] [Indexed: 04/27/2023]
Abstract
Clostridioides difficile infections (CDIs) remain a healthcare problem due to high rates of relapsing/recurrent CDIs (rCDIs). Breakdown of colonization resistance promoted by broad-spectrum antibiotics and the persistence of spores contribute to rCDI. Here, we demonstrate antimicrobial activity of the natural product class of chlorotonils against C. difficile. In contrast to vancomycin, chlorotonil A (ChA) efficiently inhibits disease and prevents rCDI in mice. Notably, ChA affects the murine and porcine microbiota to a lesser extent than vancomycin, largely preserving microbiota composition and minimally impacting the intestinal metabolome. Correspondingly, ChA treatment does not break colonization resistance against C. difficile and is linked to faster recovery of the microbiota after CDI. Additionally, ChA accumulates in the spore and inhibits outgrowth of C. difficile spores, thus potentially contributing to lower rates of rCDI. We conclude that chlorotonils have unique antimicrobial properties targeting critical steps in the infection cycle of C. difficile.
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Affiliation(s)
- Arne Bublitz
- Department of Microbial Immune Regulation, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Madita Brauer
- Institute of Microbiology, Department of Microbial Physiology and Molecular Biology, University of Greifswald, Greifswald, Germany; Institute of Marine Biotechnology e.V., Greifswald, Germany
| | - Stefanie Wagner
- Friedrich-Loeffler-Institut, Institute of Molecular Pathogenesis, Jena, Germany
| | - Walter Hofer
- Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany; Department of Pharmacy, Saarland University, Saarbrücken, Germany
| | - Mathias Müsken
- Central Facility for Microscopy, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
| | - Felix Deschner
- Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany; Department of Pharmacy, Saarland University, Saarbrücken, Germany
| | - Till R Lesker
- Department of Microbial Immune Regulation, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Meina Neumann-Schaal
- Bacterial Metabolomics, Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany; Braunschweig Integrated Center of Systems Biology (BRICS), Technical University, Braunschweig, Germany
| | - Lena-Sophie Paul
- Friedrich-Loeffler-Institut, Institute of Molecular Pathogenesis, Jena, Germany
| | - Ulrich Nübel
- Braunschweig Integrated Center of Systems Biology (BRICS), Technical University, Braunschweig, Germany; Microbial Genome Research, Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Jürgen Bartel
- Institute of Microbiology, Department of Microbial Proteomics, University of Greifswald, Greifswald, Germany
| | - Andreas M Kany
- Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany; Department of Pharmacy, Saarland University, Saarbrücken, Germany
| | - Daniela Zühlke
- Institute of Microbiology, Department of Microbial Physiology and Molecular Biology, University of Greifswald, Greifswald, Germany
| | - Steffen Bernecker
- Department of Microbial Drugs, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
| | - Rolf Jansen
- Department of Microbial Drugs, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
| | - Susanne Sievers
- Institute of Microbiology, Department of Microbial Physiology and Molecular Biology, University of Greifswald, Greifswald, Germany
| | - Katharina Riedel
- Institute of Microbiology, Department of Microbial Physiology and Molecular Biology, University of Greifswald, Greifswald, Germany; Institute of Marine Biotechnology e.V., Greifswald, Germany
| | - Jennifer Herrmann
- Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany; Department of Pharmacy, Saarland University, Saarbrücken, Germany
| | - Rolf Müller
- Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany; Department of Pharmacy, Saarland University, Saarbrücken, Germany
| | - Thilo M Fuchs
- Friedrich-Loeffler-Institut, Institute of Molecular Pathogenesis, Jena, Germany.
| | - Till Strowig
- Department of Microbial Immune Regulation, Helmholtz Center for Infection Research, Braunschweig, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany; Centre for Individualised Infection Medicine (CiiM), Hannover, Germany.
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Watson AR, Füssel J, Veseli I, DeLongchamp JZ, Silva M, Trigodet F, Lolans K, Shaiber A, Fogarty E, Runde JM, Quince C, Yu MK, Söylev A, Morrison HG, Lee STM, Kao D, Rubin DT, Jabri B, Louie T, Eren AM. Metabolic independence drives gut microbial colonization and resilience in health and disease. Genome Biol 2023; 24:78. [PMID: 37069665 PMCID: PMC10108530 DOI: 10.1186/s13059-023-02924-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 04/07/2023] [Indexed: 04/19/2023] Open
Abstract
BACKGROUND Changes in microbial community composition as a function of human health and disease states have sparked remarkable interest in the human gut microbiome. However, establishing reproducible insights into the determinants of microbial succession in disease has been a formidable challenge. RESULTS Here we use fecal microbiota transplantation (FMT) as an in natura experimental model to investigate the association between metabolic independence and resilience in stressed gut environments. Our genome-resolved metagenomics survey suggests that FMT serves as an environmental filter that favors populations with higher metabolic independence, the genomes of which encode complete metabolic modules to synthesize critical metabolites, including amino acids, nucleotides, and vitamins. Interestingly, we observe higher completion of the same biosynthetic pathways in microbes enriched in IBD patients. CONCLUSIONS These observations suggest a general mechanism that underlies changes in diversity in perturbed gut environments and reveal taxon-independent markers of "dysbiosis" that may explain why widespread yet typically low-abundance members of healthy gut microbiomes can dominate under inflammatory conditions without any causal association with disease.
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Affiliation(s)
- Andrea R Watson
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
- Committee On Microbiology, The University of Chicago, Chicago, IL, 60637, USA
| | - Jessika Füssel
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
- Institute for Chemistry and Biology of the Marine Environment, University of Oldenburg, 26129, Oldenburg, Germany
| | - Iva Veseli
- Biophysical Sciences Program, The University of Chicago, Chicago, IL, 60637, USA
| | | | - Marisela Silva
- Department of Medicine, The University of Calgary, Calgary, AB, T2N 1N4, Canada
| | - Florian Trigodet
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Karen Lolans
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Alon Shaiber
- Biophysical Sciences Program, The University of Chicago, Chicago, IL, 60637, USA
| | - Emily Fogarty
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
- Committee On Microbiology, The University of Chicago, Chicago, IL, 60637, USA
| | - Joseph M Runde
- Department of Pediatrics, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
| | - Christopher Quince
- Organisms and Ecosystems, Earlham Institute, Norwich, Norwich, NR4 7UZ, UK
- Gut Microbes and Health, Quadram Institute, Norwich, NR4 7UQ, UK
| | - Michael K Yu
- Toyota Technological Institute at Chicago, Chicago, IL, 60637, USA
| | - Arda Söylev
- Department of Computer Engineering, Konya Food and Agriculture University, Konya, Turkey
| | - Hilary G Morrison
- Marine Biological Laboratory, Josephine Bay Paul Center, Woods Hole, Falmouth, MA, 02543, USA
| | - Sonny T M Lee
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Dina Kao
- Department of Medicine, University of Alberta, Edmonton, AB, T6G 2G3, Canada
| | - David T Rubin
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Bana Jabri
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Thomas Louie
- Department of Medicine, The University of Calgary, Calgary, AB, T2N 1N4, Canada
| | - A Murat Eren
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.
- Committee On Microbiology, The University of Chicago, Chicago, IL, 60637, USA.
- Institute for Chemistry and Biology of the Marine Environment, University of Oldenburg, 26129, Oldenburg, Germany.
- Marine Biological Laboratory, Josephine Bay Paul Center, Woods Hole, Falmouth, MA, 02543, USA.
- Helmholtz Institute for Functional Marine Biodiversity, 26129, Oldenburg, Germany.
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Xiang Q, Yan X, Lin X, Zheng H, Wang L, Wan J, Zhao W, Zhang W. Intestinal Microflora Altered by Vancomycin Exposure in Early Life Up-regulates Type 2 Innate Lymphocyte and Aggravates Airway Inflammation in Asthmatic Mice. Inflammation 2023; 46:509-521. [PMID: 36526899 DOI: 10.1007/s10753-022-01748-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 09/02/2022] [Accepted: 09/27/2022] [Indexed: 12/23/2022]
Abstract
Allergic asthma is a chronic inflammatory disease primarily mediated by Th2 immune mechanisms. Exposure to antibiotics during early life is associated with an increased risk of allergic asthma, although the exact mechanism is not fully understood. In this study, mice were randomly divided into a normal saline control group (NS group), an OVA-induced asthma group (OVA group), a vancomycin treatment control group (VAN.NS group), and a vancomycin treatment the OVA-induced asthma group (VAN.OVA group). The results showed that vancomycin altered dominant species in experimental mice. The phylum level histogram showed that Bacteroides abundance was increased, and Firmicutes abundance was decreased in the OVA group. Airway inflammation and airway hyperresponsiveness (AHR) were aggravated in the vancomycin-exposed group. Enzyme-linked immunosorbent assay (ELISA) showed that the serum levels of IL-5, IL-13, and IL-33 in the OVA group were higher than those in the NS group, especially in the VAN.OVA group. The expression of GATA binding protein-3(GATA3) and retinoid acid receptor-related orphan receptor alpha (RORa) increased in the OVA group, even more so in the VAN.OVA group. Group 2 innate lymphoid cells (ILC2s) in the lung detected by flow cytometry was increased in OVA mice more than those in control mice, with a more remarkable increase in the VAN.OVA. Our results demonstrated that vancomycin used in early life could alter the intestinal microecology of mice, which, in turn, aggravates airway inflammation and upregulate type 2 innate lymphocytes.
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Affiliation(s)
- Qiangwei Xiang
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Xueyuan West Road 109, Wenzhou, 325027, China
| | - Xiumei Yan
- Department of Pediatric Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Xixi Lin
- Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Hang Zheng
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Xueyuan West Road 109, Wenzhou, 325027, China
| | - Like Wang
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Xueyuan West Road 109, Wenzhou, 325027, China
| | - Jinyi Wan
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Xueyuan West Road 109, Wenzhou, 325027, China
| | - Wei Zhao
- The Second Clinical Medical College, Wenzhou Medical University, 270 West Xueyuan Road, Zhejiang Province, Wenzhou, 325027, China.
- Department of Allergy and Immunology for Clinical Operation, Department of Pediatrics, Virginia Commonwealth University, Richmond, VA, 23298, USA.
| | - Weixi Zhang
- Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Xueyuan West Road 109, Wenzhou, 325027, China.
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49
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Paz Del Socorro T, Tonneau M, Pasquier D, Chamaillard M. Short- and Long-term Repercussions of Vancomycin on Immune Surveillance and the Efficacy of Antitumor Treatments. Cancer J 2023; 29:98-101. [PMID: 36957980 DOI: 10.1097/ppo.0000000000000652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2023]
Abstract
ABSTRACT Although antibiotic is a major contributor to shifts in the intestinal flora that may persist for up to several months after cessation, it is now increasingly recognized that its prescription may differentially influence clinical outcome of different anticancer treatments. Intense clinical and basic research efforts aim then at gaining sufficient insights about how the cooperative action between the intestinal ecosystem and immune surveillance modulates the efficacy of anticancer treatments. In this review, we summarize multiple levels of knowledge between vancomycin exposure, the gut microbiota, and a meaningful therapeutic response. Furthermore, we discuss the mode of action of antibiotic therapy that is prescribed for prophylaxis of bacteremia and neutropenia and outline the opportunity for judiciously improving the efficacy of anticancer drugs.
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Affiliation(s)
| | - Marion Tonneau
- Academic Department of Radiation Oncology, Centre Oscar Lambret
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Hov JR, Karlsen TH. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2023; 20:135-154. [PMID: 36352157 DOI: 10.1038/s41575-022-00690-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) offers unique opportunities to explore the gut-liver axis owing to the close association between liver disease and colonic inflammation. It is well established that the gut microbiota in people with PSC differs from that of healthy individuals, but details of the microbial factors that demarcate PSC from inflammatory bowel disease (IBD) without PSC are poorly understood. In this Review, we aim to provide an overview of the latest literature on the gut microbiome in PSC and PSC with IBD, critically examining hypotheses on how microorganisms could contribute to the pathogenesis of PSC. A particular emphasis will be put on pathogenic features of the gut microbiota that might explain the occurrence of bile duct inflammation and liver disease in the context of IBD, and we postulate the potential existence of a specific yet unknown factor related to the gut-liver axis as causative in PSC. Available data are scrutinized in the perspective of therapeutic approaches related to the gut-liver axis.
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Affiliation(s)
- Johannes R Hov
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Tom H Karlsen
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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