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Martínez-Augustin O, Tena-Garitaonaindia M, Ceacero-Heras D, Jiménez-Ortas Á, Enguix-Huete JJ, Álvarez-Mercado AI, Ruiz-Henares G, Aranda CJ, Gámez-Belmonte R, Sánchez de Medina F. Macronutrients as Regulators of Intestinal Epithelial Permeability: Where Do We Stand? Compr Rev Food Sci Food Saf 2025; 24:e70178. [PMID: 40421830 DOI: 10.1111/1541-4337.70178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 03/23/2025] [Accepted: 04/04/2025] [Indexed: 05/28/2025]
Abstract
The intestinal barrier function (IBF) is essential for intestinal homeostasis. Its alterations have been linked to intestinal and systemic disease. Regulation of intestinal permeability is key in the maintenance of the IBF, in which the intestinal epithelium and tight junctions, the mucus layer, sIgA, and antimicrobial peptides are important factors. This review addresses the concept of IBF, focusing on permeability, and summarizes state-of-the-art information on how starvation and macronutrients regulate it. Novel mechanisms regulate intestinal permeability, like its induction by the normal process of nutrient absorption, the contribution of starvation-induced autophagy, or the stimulation of sIgA production by high-protein diets in a T-cell-independent fashion. In addition, observations evidence that starvation and protein restriction increase intestinal permeability, compromising mucin, antimicrobial peptides, and/or intestinal sIgA production. Regarding specific macronutrients, substantial evidence indicates that casein (compared to other protein sources), specific protein-derived peptides and glutamine reinforce IBF. Dietary carbohydrates regulate intestinal permeability in a structure- and composition-dependent fashion; fructose, glucose, and sucrose increase it, while nondigestible oligosaccharides (NDOs) decrease it. Among NDOs, human milk oligosaccharides (HMOs) stand as a promising tool. NODs effects are mediated by intestinal microbiota modulation, production of short-chain fatty acids, and direct interactions with intestinal cells. Finally, evidence supports avoiding high-fat diets for their detrimental effects on IBF. Most studies have been carried out in vitro or in animal models. More information is needed from clinical studies to substantiate beneficial effects and the use of macronutrients in the treatment and prevention of IBF-related diseases.
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Affiliation(s)
- Olga Martínez-Augustin
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Insituto de Nutrición y Tecnología de los alimentos José Mataix and Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Mireia Tena-Garitaonaindia
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Insituto de Nutrición y Tecnología de los alimentos José Mataix and Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Diego Ceacero-Heras
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Insituto de Nutrición y Tecnología de los alimentos José Mataix and Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Ángela Jiménez-Ortas
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Insituto de Nutrición y Tecnología de los alimentos José Mataix and Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Juan J Enguix-Huete
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Ana I Álvarez-Mercado
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Guillermo Ruiz-Henares
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Carlos J Aranda
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina- IBIMA Plataforma BIONAND, RICORS "Enfermedades inflamatorias", Málaga, Spain
| | - Reyes Gámez-Belmonte
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Fermín Sánchez de Medina
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
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Tonnele H, Chen D, Morillo F, Garcia-Calleja J, Chitre AS, Johnson BB, Sanches TM, Bonder MJ, Gonzalez A, Kosciolek T, George AM, Han W, Holl K, Horvath A, Ishiwari K, King CP, Lamparelli AC, Martin CD, Martinez AG, Netzley AH, Tripi JA, Wang T, Bosch E, Doris PA, Stegle O, Chen H, Flagel SB, Meyer PJ, Richards JB, Robinson TE, Woods LCS, Polesskaya O, Knight R, Palmer AA, Baud A. Novel insights into the genetic architecture and mechanisms of host/microbiome interactions from a multi-cohort analysis of outbred laboratory rats. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.20.644349. [PMID: 40166210 PMCID: PMC11957159 DOI: 10.1101/2025.03.20.644349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
The intestinal microbiome influences health and disease. Its composition is affected by host genetics and environmental exposures. Understanding host genetic effects is critical but challenging in humans, due to the difficulty of detecting, mapping and interpreting them. To address this, we analysed host genetic effects in four cohorts of outbred laboratory rats exposed to distinct but controlled environments. We found that polygenic host genetic effects were consistent across environments. We identified three replicated microbiome-associated loci. One involved a sialyltransferase gene and Paraprevotella and we found a similar association, between ST6GAL1 and Paraprevotella, in a human cohort. Given Paraprevotella's known immunity-potentiating functions, this suggests ST6GAL1's effects on IgA nephropathy and COVID-19 breakthrough infections may be mediated by Paraprevotella. Moreover, we found evidence of indirect genetic effects on microbiome phenotypes, which substantially increased their total genetic variance. Finally, we identified a novel mechanism whereby indirect genetic effects can contribute to "missing heritability".
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Affiliation(s)
- Helene Tonnele
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Denghui Chen
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Felipe Morillo
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Jorge Garcia-Calleja
- Institute of Evolutionary Biology (CSIC-UPF), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Apurva S Chitre
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Benjamin B Johnson
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | | | - Marc Jan Bonder
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Antonio Gonzalez
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Tomasz Kosciolek
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Anthony M George
- Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA8
| | - Wenyan Han
- Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Katie Holl
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Aidan Horvath
- Department of Psychology, University of Michigan, Ann Arbor, MI, USA
| | - Keita Ishiwari
- Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA8
- Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA
| | | | | | - Connor D Martin
- Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA8
- Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA
| | - Angel Garcia Martinez
- Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Alesa H Netzley
- Department of Psychology, University of Michigan, Ann Arbor, MI, USA
| | - Jordan A Tripi
- Department of Psychology, University at Buffalo, NY, USA
| | - Tengfei Wang
- Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Elena Bosch
- Institute of Evolutionary Biology (CSIC-UPF), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Peter A Doris
- Center for Human Genetics, Institute of Molecular Medicine, McGovern Medical School, University of Texas at Houston, TX, USA
| | - Oliver Stegle
- European Molecular Biology Laboratory, Heidelberg, Germany
| | - Hao Chen
- Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Shelly B. Flagel
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
| | - Paul J Meyer
- Department of Psychology, University at Buffalo, NY, USA
| | - Jerry B Richards
- Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA8
- Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA
| | - Terry E. Robinson
- Department of Psychology, University of Michigan, Ann Arbor, MI, USA
| | - Leah C Solberg Woods
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Oksana Polesskaya
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Rob Knight
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Department of Computer Science & Engineering, University of California San Diego, La Jolla, CA, USA
- Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
- Halıcıoğlu Data Science Institute, University of California San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, La Jolla, CA, San Diego, USA
| | - Abraham A Palmer
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
- Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
| | - Amelie Baud
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
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Fu K, Cui J, Li Y, Zhang Y, Wang Y, Wu J, Chen X, Xue F, Ren J, Dai J, Tang F. Escherichia coli phage ΦPNJ-9 adheres to mucus via a variant Hoc protein. J Virol 2025; 99:e0178924. [PMID: 39723818 PMCID: PMC11853027 DOI: 10.1128/jvi.01789-24] [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: 10/13/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Phages, as antagonists of bacteria, hold significant promise for combating drug-resistant bacterial infections. Their host specificity allows phages to target pathogenic bacteria without disrupting the gut microbiota, offering distinct advantages in the prevention and control of intestinal pathogens. The interaction between the phage and the gut plays a crucial role in the efficacy of phage-mediated bacterial killing. However, the mechanisms underlying these interactions remain poorly understood. In this study, we demonstrate that the clinically isolated T4-like phage, ΦPNJ-9, effectively adheres to the intestinal mucosa in vivo. This adhesion is mediated by the phage's Hoc protein, which interacts with MUC2 in the mucus. The Hoc protein of ΦPNJ-9 represents a variant, consisting of only three domains and lacking Domain 3, in contrast to phage T4. The key interacting sites on ΦPNJ-9 Hoc are amino acids S183, L184, and T185 within Domain 2. Displaying Domain 2 of ΦPNJ-9 Hoc on the surface of M13 phage significantly enhances its adhesion to the intestinal mucosa. Additionally, we identify fucose residues in MUC2 as the critical binding sites for the phage. Through this adhesion, the phage occupies the intestinal niche, thereby protecting the mucosal layer from pathogenic Escherichia coli infections. Our findings highlight the role of Hoc proteins in phage adhesion to intestinal mucus and the variation in binding sites, providing key insights for phage-based strategies aimed at preventing and controlling intestinal pathogens.IMPORTANCEThe rise in antibiotic-resistant pathogenic bacteria has sparked renewed interest in phage therapy as a promising alternative, particularly for targeting intestinal pathogens due to phage's host specificity. However, clinical applications have revealed that many phages are ineffective in eliminating bacteria within the gut, primarily due to the complex interactions between the phage and the gut environment. However, the mechanisms underlying these interactions remain poorly understood. Our previous study demonstrated that a T4-like phage adheres to the intestinal mucosa through the interaction between its Hoc protein and MUC2 in the mucus. Whether this model is widespread among T4-like phages remains unknown. Here, we characterize a variant Hoc protein from a T4-like phage, and identify new binding sites within this protein. Our findings suggest that the interaction between Hoc and MUC2 is likely common, but the critical binding sites vary depending on the specific phage.
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Affiliation(s)
- Kailai Fu
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Jiaqi Cui
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Yao Li
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Yuhan Zhang
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Yang Wang
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Jiaoling Wu
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Xinru Chen
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Feng Xue
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Jianluan Ren
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Jianjun Dai
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Fang Tang
- Key Laboratory of Animal Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
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Liu H, Huang R, Shen B, Huang C, Zhou Q, Xu J, Chen S, Lin X, Wang J, Zhao X, Guo Y, Ai X, Liu Y, Wang Y, Zhang W, Zhi F. Live Akkermansia muciniphila boosts dendritic cell retinoic acid synthesis to modulate IL-22 activity and mitigate colitis in mice. MICROBIOME 2024; 12:275. [PMID: 39734222 PMCID: PMC11684322 DOI: 10.1186/s40168-024-01995-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 12/02/2024] [Indexed: 12/31/2024]
Abstract
BACKGROUND The interplay between gut microbiota and immune responses is crucial in ulcerative colitis (UC). Though Akkermansia muciniphila (Akk) shows therapeutic potential, the mechanisms remain unclear. This study sought to investigate differences in therapeutic efficacy among different forms or strains of Akk and elucidate the underlying mechanisms. RESULTS Employing a dextran sulfate sodium (DSS)-induced colitis mouse model, we assessed Akk's impact on colitis using cellular cytokine analysis, immune phenotyping, proteomics, and biochemical methods. Our results suggest that treatment with live Akk effectively reduced colitis in the DSS-induced model, whereas heat-inactivated Akk did not yield the same results. Notably, Akk exhibited protective properties by promoting the secretion of IL-22 by Group 3 innate lymphoid cells (ILC3s), as evidenced by the absence of protection in IL-22 knockout mice. Additionally, Akk augmented the population of CD103+CD11b- dendritic cells (DCs) and enhanced their retinoic acid (RA) synthesis through the modulation of RALDH2, a crucial enzyme in RA metabolism. The depletion of RALDH2 in DCs diminished Akk's protective properties and impaired IL-22-mediated mucosal healing. Mechanistically, Akk activated RA production in DCs by enhancing the JAK2-STAT3 signaling pathway. Additionally, various strains of Akk may exhibit differing abilities to alleviate colitis, with the novel strain Am06 derived from breast milk showing consistent efficacy similar to the reference strain. CONCLUSIONS In summary, our findings indicate that certain strains of Akk may mitigate colitis through the promotion of RA synthesis and IL-22 secretion, underscoring the potential efficacy of Akk as a therapeutic intervention for the management of UC. Video Abstract.
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Affiliation(s)
- Hongbin Liu
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruo Huang
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Binhai Shen
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chongyang Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qian Zhou
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiahui Xu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shengbo Chen
- Department of Gastroenterology, Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
| | - Xinlong Lin
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jun Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinmei Zhao
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yandong Guo
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiuyun Ai
- Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yangyang Liu
- Guangzhou ZhiYi Biotechnology Co., Ltd, Guangzhou, China
| | - Ye Wang
- Guangzhou ZhiYi Biotechnology Co., Ltd, Guangzhou, China
| | - Wendi Zhang
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Fachao Zhi
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Wang Z, Ye R, Zhang S, Liu C, Chen K, Zhu K, Wang P, Wang F, Huang J. Amelioration of LPS-Induced Jejunum Injury and Mucus Barrier Damage in Mice by IgY Embedded in W/O/W Emulsion. Foods 2024; 13:4138. [PMID: 39767078 PMCID: PMC11675984 DOI: 10.3390/foods13244138] [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: 10/28/2024] [Revised: 12/12/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Chicken yolk immunoglobulin (IgY) is a natural immunologically active antibody extracted from egg yolk and can be used as a natural dietary supplement for the treatment of inflammation and damage to the intestines. In our study, IgY was embedded in a double emulsion (W/O/W; DE) to explore the therapeutic effect of the embedded IgY on Lipopolysaccharide (LPS)-induced jejunal injury in mice. The results showed that W/O/W-embedded IgY as a dietary supplement (IgY + DE) attenuated LPS-induced damage to mouse small intestinal structures and protected the integrity of the jejunal mucosal barrier. IgY + DE increased the amount of related transcription factors (Math1, Spdef, Elf3, and Klf4) and promoted thrush cell differentiation. IgY + DE ameliorated LPS-induced reduction in mucin quantity and markers. It promoted the expression of Muc1 and Muc2 and increased the mRNA expression levels of Muc1, Muc2, Muc3, Muc4, Muc13, and Agr2 (p < 0.05). IgY + DE increased the expression of several glycosyltransferases involved in mucin glycosylation. IgY + DE also neutralized the LPS attack on the expression of jejunal inflammatory factors IL-1β, IL-6, IL-4, and TNF-α. In conclusion, the IgY-embedded double emulsion can be used as a dietary supplement for immunotherapy to prevent LPS-induced jejunal injury in mice.
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Affiliation(s)
- Zhaohui Wang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Ruihua Ye
- College of Veterinary Medicine, China Agricultural University, Beijing 100083, China;
| | - Shidi Zhang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Chuanming Liu
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Ke Chen
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Kongdi Zhu
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Pengjie Wang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Fuqing Wang
- Tibet Tianhong Science and Technology Co., Ltd., Lasha 851414, China
| | - Jiaqiang Huang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
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Mach N. The forecasting power of the mucin-microbiome interplay in livestock respiratory diseases. Vet Q 2024; 44:1-18. [PMID: 38606662 PMCID: PMC11018052 DOI: 10.1080/01652176.2024.2340003] [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: 05/23/2023] [Accepted: 03/31/2024] [Indexed: 04/13/2024] Open
Abstract
Complex respiratory diseases are a significant challenge for the livestock industry worldwide. These diseases considerably impact animal health and welfare and cause severe economic losses. One of the first lines of pathogen defense combines the respiratory tract mucus, a highly viscous material primarily composed of mucins, and a thriving multi-kingdom microbial ecosystem. The microbiome-mucin interplay protects from unwanted substances and organisms, but its dysfunction may enable pathogenic infections and the onset of respiratory disease. Emerging evidence also shows that noncoding regulatory RNAs might modulate the structure and function of the microbiome-mucin relationship. This opinion paper unearths the current understanding of the triangular relationship between mucins, the microbiome, and noncoding RNAs in the context of respiratory infections in animals of veterinary interest. There is a need to look at these molecular underpinnings that dictate distinct health and disease outcomes to implement effective prevention, surveillance, and timely intervention strategies tailored to the different epidemiological contexts.
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Affiliation(s)
- Núria Mach
- IHAP, Université de Toulouse, INRAE, ENVT, Toulouse, France
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7
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Okumura R, Takeda K. The role of the mucosal barrier system in maintaining gut symbiosis to prevent intestinal inflammation. Semin Immunopathol 2024; 47:2. [PMID: 39589551 PMCID: PMC11599372 DOI: 10.1007/s00281-024-01026-5] [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: 10/10/2023] [Accepted: 09/29/2024] [Indexed: 11/27/2024]
Abstract
In the intestinal tract, where numerous intestinal bacteria reside, intestinal epithelial cells produce and release various antimicrobial molecules that form a complex barrier on the mucosal surface. These barrier molecules can be classified into two groups based on their functions: those that exhibit bactericidal activity through chemical reactions, such as antimicrobial peptides, and those that physically hinder bacterial invasion, like mucins, which lack bactericidal properties. In the small intestine, where Paneth cells specialize in producing antimicrobial peptides, the chemical barrier molecules primarily inhibit bacterial growth. In contrast, in the large intestine, where Paneth cells are absent, allowing bacterial growth, the primary defense mechanism is the physical barrier, mainly composed of mucus, which controls bacterial movement and prevents their invasion of intestinal tissues. The expression of these barrier molecules is regulated by metabolites produced by bacteria in the intestinal lumen and cytokines produced by immune cells in the lamina propria. This regulation establishes a defense mechanism that adapts to changes in the intestinal environment, such as alterations in gut microbial composition and the presence of pathogenic bacterial infections. Consequently, when the integrity of the gut mucosal barrier is compromised, commensal bacteria and pathogenic microorganisms from outside the body can invade intestinal tissues, leading to conditions such as intestinal inflammation, as observed in cases of inflammatory bowel disease.
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Affiliation(s)
- Ryu Okumura
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan
- Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Kiyoshi Takeda
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan.
- Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, 565-0871, Japan.
- Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, 565-0871, Japan.
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8
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Wang YN, Zhai XY, Wang Z, Gao CL, Mi SC, Tang WL, Fu XM, Li HB, Yue LF, Li PF, Xi SY. Jianpi-Huatan-Huoxue-Anshen formula ameliorates gastrointestinal inflammation and microecological imbalance in chemotherapy-treated mice transplanted with H22 hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:4209-4231. [DOI: 10.4251/wjgo.v16.i10.4209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 08/06/2024] [Accepted: 09/03/2024] [Indexed: 09/26/2024] Open
Abstract
BACKGROUND Jianpi-Huatan-Huoxue-Anshen formula [Tzu-Chi cancer-antagonizing & life-protecting II decoction (TCCL)] is a Chinese medical formula that has been clinically shown to reduce the gastrointestinal side effects of chemotherapy in cancer patients and improve their quality of life. However, its effect and mechanism on the intestinal microecology after chemotherapy are not yet clear.
AIM To discover the potential mechanisms of TCCL on gastrointestinal inflammation and microecological imbalance in chemotherapy-treated mice transplanted with hepatocellular carcinoma (HCC).
METHODS Ninety-six mice were inoculated subcutaneously with HCC cells. One week later, the mice received a large dose of 5-fluorouracil by intraperitoneal injection to establish a HCC chemotherapy model. Thirty-six mice were randomly selected before administration, and feces, ileal tissue, and ileal contents were collected from each mouse. The remaining mice were randomized into normal saline, continuous chemotherapy, Yangzheng Xiaoji capsules-treated, and three TCCL-treated groups. After treatment, feces, tumors, liver, spleen, thymus, stomach, jejunum, ileum, and colon tissues, and ileal contents were collected. Morphological changes, serum levels of IL-1β, IL-6, IL-8, IL-10, IL-22, TNF-α, and TGF-β, intestinal SIgA, and protein and mRNA expression of ZO-1, NF-κB, Occludin, MUC-2, Claudin-1, and IκB-α in colon tissues were documented. The effect of TCCL on the abundance and diversity of intestinal flora was analyzed using 16S rDNA sequencing.
RESULTS TCCL treatment improved thymus and spleen weight, thymus and spleen indexes, and body weight, decreased tumor volumes and tumor tissue cell density, and alleviated injury to gastric, ileal, and colonic mucosal tissues. Among proteins and genes associated with inflammation, IL-10, TGF-β, SIgA, ZO-1, MUC-2, and Occludin were upregulated, whereas NF-κB, IL-1β, IL-6, TNF-α, IL-22, IL-8, and IκB-α were downregulated. Additionally, TCCL increased the proportions of fecal Actinobacteria, AF12, Adlercreutzia, Clostridium, Coriobacteriaceae, and Paraprevotella in the intermediate stage of treatment, decreased the proportions of Mucipirillum, Odoribacter, RF32, YS2, and Rikenellaceae but increased the proportions of p_Deferribacteres and Lactobacillus at the end of treatment. Studies on ileal mucosal microbiota showed similar findings. Moreover, TCCL improved community richness, evenness, and the diversity of fecal and ileal mucosal flora.
CONCLUSION TCCL relieves pathological changes in tumor tissue and chemotherapy-induced gastrointestinal injury, potentially by reducing the release of pro-inflammatory factors to repair the gastrointestinal mucosa, enhancing intestinal barrier function, and maintaining gastrointestinal microecological balance. Hence, TCCL is a very effective adjuvant to chemotherapy.
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Affiliation(s)
- Ya-Nan Wang
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Xiang-Yang Zhai
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Zheng Wang
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Chun-Ling Gao
- Department of Radiotherapy, Chenggong Hospital of Xiamen University, PLA 73rd Army Hospital, Xiamen 361003, Fujian Province, China
| | - Sui-Cai Mi
- Department of Oncology, Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361015, Fujian Province, China
| | - Wen-Li Tang
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Xue-Min Fu
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Huai-Bang Li
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Li-Feng Yue
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Peng-Fei Li
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Sheng-Yan Xi
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
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9
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Raya Tonetti F, Eguileor A, Llorente C. Goblet cells: guardians of gut immunity and their role in gastrointestinal diseases. EGASTROENTEROLOGY 2024; 2:e100098. [PMID: 39524932 PMCID: PMC11542612 DOI: 10.1136/egastro-2024-100098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 08/08/2024] [Indexed: 11/16/2024]
Abstract
Goblet cells (GCs) are specialised guardians lining the intestine. They play a critical role in gut defence and immune regulation. GCs continuously secrete mucus creating a physical barrier to protect from pathogens while harbouring symbiotic gut bacteria adapted to live within the mucus. GCs also form specialised GC-associated passages in a dynamic and regulated manner to deliver luminal antigens to immune cells, promoting gut tolerance and preventing inflammation. The composition of gut bacteria directly influences GC function, highlighting the intricate interplay between these components of a healthy gut. Indeed, imbalances in the gut microbiome can disrupt GC function, contributing to various gastrointestinal diseases like colorectal cancer, inflammatory bowel disease, cystic fibrosis, pathogen infections and liver diseases. This review explores the interplay between GCs and the immune system. We delve into the underlying mechanisms by which GC dysfunction contributes to the development and progression of gastrointestinal diseases. Finally, we examine current and potential treatments that target GCs and represent promising avenues for further investigation.
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Affiliation(s)
- Fernanda Raya Tonetti
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, California, USA
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10
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Calvigioni M, Mazzantini D, Celandroni F, Vozzi G, Ghelardi E. Cultivating complexity: Advancements in establishing in vitro models for the mucus-adhering gut microbiota. Microb Biotechnol 2024; 17:e70036. [PMID: 39435730 PMCID: PMC11494453 DOI: 10.1111/1751-7915.70036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 10/02/2024] [Indexed: 10/23/2024] Open
Abstract
A healthy mucus is essential for maintaining intestinal homeostasis and overall well-being. In recent years, extensive research focused on understanding the intricate interactions between mucus and the gut microbiota. Mucus-adhering bacteria play crucial roles in preserving barrier integrity, epithelial permeability and mucus architecture, as well as in the colonization resistance against pathogens. Unravelling the significance of these microorganisms in human health and disease is challenging, primarily because most of the studies on the human gut microbiota rely on faecal samples, which do not fully represent the microecological complexity found in the intestinal mucosa. This review discusses novel strategies to specifically target and evaluate the mucosal microbiota, such as culturomics applied to mucosal biopsies or brushings, intestinal organoids and artificial in vitro models incorporating mucus.
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Affiliation(s)
- Marco Calvigioni
- Department of Translational Research and New Technologies in Medicine and SurgeryUniversity of PisaPisaItaly
| | - Diletta Mazzantini
- Department of Translational Research and New Technologies in Medicine and SurgeryUniversity of PisaPisaItaly
| | - Francesco Celandroni
- Department of Translational Research and New Technologies in Medicine and SurgeryUniversity of PisaPisaItaly
| | - Giovanni Vozzi
- Department of Information BioengineeringUniversity of PisaPisaItaly
- Research Center Enrico PiaggioUniversity of PisaPisaItaly
| | - Emilia Ghelardi
- Department of Translational Research and New Technologies in Medicine and SurgeryUniversity of PisaPisaItaly
- Research Center Nutraceuticals and Food for Health – NutrafoodUniversity of PisaPisaItaly
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11
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Zhang J, Huang Y, Li H, Xu P, Liu Q, Sun Y, Zhang Z, Wu T, Tang Q, Jia Q, Xia Y, Xu Y, Jing X, Li J, Mo L, Xie W, Qu A, He J, Li Y. B3galt5 functions as a PXR target gene and regulates obesity and insulin resistance by maintaining intestinal integrity. Nat Commun 2024; 15:5919. [PMID: 39004626 PMCID: PMC11247088 DOI: 10.1038/s41467-024-50198-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: 12/16/2023] [Accepted: 07/03/2024] [Indexed: 07/16/2024] Open
Abstract
Pregnane X receptor (PXR) has been reported to regulate glycolipid metabolism. The dysfunction of intestinal barrier contributes to metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. Here, we show that activation of PXR by tributyl citrate (TBC), an intestinal-selective PXR agonist, improves high fat diet (HFD)-induced obesity. The metabolic benefit of intestinal PXR activation is associated with upregulation of β-1,3 galactosyltransferase 5 (B3galt5). Our results reveal that B3galt5 mainly expresses in the intestine and is a direct PXR transcriptional target. B3galt5 knockout exacerbates HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. B3galt5 ablation impairs the O-glycosylation of mucin2, destabilizes the mucus layer, and increases intestinal permeability. Furthermore, B3galt5 deficiency abolishes the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggest the intestinal-selective PXR activation regulates B3galt5 expression and maintains metabolic homeostasis, making it a potential therapeutic strategy in obesity.
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Affiliation(s)
- Jinhang Zhang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ya Huang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Department of Pharmacy, GuiQian International General Hospital, Guiyang, China
| | - Hong Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Qinhui Liu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yang Sun
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming, Yunnan Province, China
| | - Zijing Zhang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tong Wu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qin Tang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qingyi Jia
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yan Xia
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ying Xu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiandan Jing
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiahui Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Mo
- Center of Gerontology and Geriatrics, West China Hospital of Sichuan University, Chengdu, China
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, P.R. China
| | - Jinhan He
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yanping Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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12
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de Ram C, van der Lugt B, Elzinga J, Geerlings S, Steegenga WT, Belzer C, Schols HA. Revealing Glycosylation Patterns in In Vitro-Produced Mucus Exposed to Pasteurized Mucus-Associated Intestinal Microbes by MALDI-TOF-MS and PGC-LC-MS/MS. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:15345-15356. [PMID: 38932522 PMCID: PMC11247495 DOI: 10.1021/acs.jafc.4c01401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 05/28/2024] [Accepted: 06/16/2024] [Indexed: 06/28/2024]
Abstract
The human intestinal mucus layer protects against pathogenic microorganisms and harmful substances, whereas it also provides an important colonization niche for mutualistic microbes. The main functional components of mucus are heavily glycosylated proteins, called mucins. Mucins can be cleaved and utilized by intestinal microbes. The mechanisms between intestinal microbes and the regulation of mucin glycosylation are still poorly understood. In this study, in vitro mucus was produced by HT29-MTX-E12 cells under Semi-Wet interface with Mechanical Stimulation. Cells were exposed to pasteurized nonpathogenic bacteria Akkermansia muciniphila, Ruminococcus gnavus, and Bacteroides fragilis to evaluate influence on glycosylation patterns. Following an optimized protocol, O- and N-glycans were efficiently and reproducibly released, identified, and semiquantified using MALDI-TOF-MS and PGC-LC-MS/MS. Exposure of cells to bacteria demonstrated increased diversity of sialylated O-glycans and increased abundance of high mannose N-glycans in in vitro produced mucus. Furthermore, changes in glycan ratios were observed. It is speculated that bacterial components interact with the enzymatic processes in glycan production and that pasteurized bacteria influence glycosyltransferases or genes involved. These results highlight the influence of pasteurized bacteria on glycosylation patterns, stress the intrinsic relationship between glycosylation and microbiota, and show the potential of using in vitro produced mucus to study glycosylation behavior.
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Affiliation(s)
- Carol de Ram
- Laboratory
of Food Chemistry, Wageningen University
& Research, Bornse Weilanden 9, 6708 WG Wageningen, The Netherlands
| | - Benthe van der Lugt
- Human
Nutrition and Health, Wageningen University
& Research, Stippeneng
4, 6708 WE Wageningen, The Netherlands
| | - Janneke Elzinga
- Laboratory
of Microbiology, Wageningen University &
Research, Stippeneng
4, 6708 WE Wageningen, The Netherlands
| | - Sharon Geerlings
- Laboratory
of Microbiology, Wageningen University &
Research, Stippeneng
4, 6708 WE Wageningen, The Netherlands
| | - Wilma T. Steegenga
- Human
Nutrition and Health, Wageningen University
& Research, Stippeneng
4, 6708 WE Wageningen, The Netherlands
| | - Clara Belzer
- Laboratory
of Microbiology, Wageningen University &
Research, Stippeneng
4, 6708 WE Wageningen, The Netherlands
| | - Henk A. Schols
- Laboratory
of Food Chemistry, Wageningen University
& Research, Bornse Weilanden 9, 6708 WG Wageningen, The Netherlands
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13
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Bai D, Zhao J, Wang R, Du J, Zhou C, Gu C, Wang Y, Zhang L, Zhao Y, Lu N. Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier. Acta Pharm Sin B 2024; 14:1677-1692. [PMID: 38572095 PMCID: PMC10985029 DOI: 10.1016/j.apsb.2023.12.015] [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: 10/03/2023] [Revised: 12/06/2023] [Accepted: 12/25/2023] [Indexed: 04/05/2024] Open
Abstract
Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment, significantly curtailing the efficacy of these treatments and, in some cases, resulting in fatal consequences. Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis, the paucity of effective treatments for such damage is evident. In our study, we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells, thereby fortifying the integrity of the intestinal mucus barrier. This enhanced barrier function serves to resist microbial invasion and subsequently reduces the inflammatory response. Importantly, this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs. Mechanistically, E. copr up-regulates the expression of AUF1, leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells. An especially significant finding is that E. copr activates the AhR pathway, thereby promoting the expression of AUF1. In summary, our results strongly indicate that E. copr enhances the intestinal mucus barrier, effectively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUF1 pathway, consequently enhancing Muc2 mRNA stability.
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Affiliation(s)
- Dongsheng Bai
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jiawei Zhao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Runde Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jiaying Du
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Chen Zhou
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Chunyang Gu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yuxiang Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Lulu Zhang
- Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Yue Zhao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Na Lu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
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14
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Saldova R, Thomsson KA, Wilkinson H, Chatterjee M, Singh AK, Karlsson NG, Knaus UG. Characterization of intestinal O-glycome in reactive oxygen species deficiency. PLoS One 2024; 19:e0297292. [PMID: 38483964 PMCID: PMC10939276 DOI: 10.1371/journal.pone.0297292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/02/2024] [Indexed: 03/17/2024] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation resulting from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Reactive oxygen species (ROS) generated by NADPH oxidases (NOX) provide antimicrobial defense, redox signaling and gut barrier maintenance. NADPH oxidase mutations have been identified in IBD patients, and mucus layer disruption, a critical aspect in IBD pathogenesis, was connected to NOX inactivation. To gain insight into ROS-dependent modification of epithelial glycosylation the colonic and ileal mucin O-glycome of mice with genetic NOX inactivation (Cyba mutant) was analyzed. O-glycans were released from purified murine mucins and analyzed by hydrophilic interaction ultra-performance liquid chromatography in combination with exoglycosidase digestion and mass spectrometry. We identified five novel glycans in ileum and found minor changes in O-glycans in the colon and ileum of Cyba mutant mice. Changes included an increase in glycans with terminal HexNAc and in core 2 glycans with Fuc-Gal- on C3 branch, and a decrease in core 3 glycans in the colon, while the ileum showed increased sialylation and a decrease in sulfated glycans. Our data suggest that NADPH oxidase activity alters the intestinal mucin O-glycans that may contribute to intestinal dysbiosis and chronic inflammation.
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Affiliation(s)
- Radka Saldova
- National Institute for Bioprocessing, NIBRT GlycoScience Group, Research and Training, Blackrock, Dublin, Ireland
- CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland, Galway, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Kristina A. Thomsson
- Proteomics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hayden Wilkinson
- National Institute for Bioprocessing, NIBRT GlycoScience Group, Research and Training, Blackrock, Dublin, Ireland
- CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland, Galway, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | | | - Ashish K. Singh
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Niclas G. Karlsson
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Faculty of Health Science, Department of Life Science and Health, Oslo Metropolitan University, Oslo, Norway
| | - Ulla G. Knaus
- School of Medicine, University College Dublin, Dublin, Ireland
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15
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Fekete E, Allain T, Sosnowski O, Anderson S, Lewis IA, Buret AG. Giardia spp.-induced microbiota dysbiosis disrupts intestinal mucin glycosylation. Gut Microbes 2024; 16:2412676. [PMID: 39412866 PMCID: PMC11485787 DOI: 10.1080/19490976.2024.2412676] [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: 03/18/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/18/2024] Open
Abstract
Infection with the protozoan parasite Giardia duodenalis (syn. intestinalis, lamblia) has been associated with intestinal mucus disruptions and microbiota dysbiosis. The mechanisms remain incompletely understood. Mucus consists primarily of densely glycosylated mucin glycoproteins. Mucin O-glycans influence mucus barrier properties and mucin-microbe interactions and are frequently altered during disease. In this study, we observed time-dependent and regiospecific alterations to intestinal mucin glycosylation patterns and the expression of mucin-associated glycosyltransferase genes during Giardia infection. Glycosylation alterations were observed in Giardia-infected mice in the upper small intestine, the site of parasite colonization, and in the distal colon, where active trophozoites were absent. Alterations occurred as early as day 2 post-infection and persisted in mice after parasite clearance. We also observed small intestinal goblet cell hyperplasia and thinning of the distal colon mucus barrier during early infection, and microbiota alterations and altered production of cecal SCFAs. Giardia-induced alterations to mucin glycosylation were at least in part dependent on microbiota dysbiosis, as transplantation of a dysbiotic mucosal microbiota collected from Giardia-infected mice recapitulated some alterations. This study describes a novel mechanism by which Giardia alters intestinal mucin glycosylation, and implicates the small intestinal microbiota in regulation of mucin glycosylation patterns throughout the gastrointestinal tract.
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Affiliation(s)
- Elena Fekete
- Department of Biological Sciences, University of Calgary, Calgary, Canada
- Host-Parasite Interaction Network, University of Calgary, Calgary, Canada
- Inflammation Research Network, University of Calgary, Calgary, Canada
| | - Thibault Allain
- Department of Biological Sciences, University of Calgary, Calgary, Canada
- Host-Parasite Interaction Network, University of Calgary, Calgary, Canada
- Inflammation Research Network, University of Calgary, Calgary, Canada
| | - Olivia Sosnowski
- Department of Biological Sciences, University of Calgary, Calgary, Canada
- Host-Parasite Interaction Network, University of Calgary, Calgary, Canada
- Inflammation Research Network, University of Calgary, Calgary, Canada
| | - Stephanie Anderson
- Department of Biological Sciences, University of Calgary, Calgary, Canada
- Host-Parasite Interaction Network, University of Calgary, Calgary, Canada
- Inflammation Research Network, University of Calgary, Calgary, Canada
| | - Ian A. Lewis
- Department of Biological Sciences, University of Calgary, Calgary, Canada
| | - Andre G. Buret
- Department of Biological Sciences, University of Calgary, Calgary, Canada
- Host-Parasite Interaction Network, University of Calgary, Calgary, Canada
- Inflammation Research Network, University of Calgary, Calgary, Canada
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16
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Flores JN, Lubin JB, Silverman MA. The case for microbial intervention at weaning. Gut Microbes 2024; 16:2414798. [PMID: 39468827 PMCID: PMC11540084 DOI: 10.1080/19490976.2024.2414798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 10/30/2024] Open
Abstract
Weaning, the transition from a milk-based diet to solid food, coincides with the most significant shift in gut microbiome composition in the lifetime of most mammals. Notably, this period also marks a "window of opportunity" where key components of the immune system develop, and host-microbe interactions shape long-term immune homeostasis thereby influencing the risk of autoimmune and inflammatory diseases. This review provides a comprehensive analysis of the changes in nutrition, microbiota, and host physiology that occur during weaning. We explore how these weaning-associated processes differ across species, lifestyles, and regions of the intestine. Using prinicples of microbial ecology, we propose that the weaning transition is an optimal period for microbiome-targeted therapeutic interventions. Additionally, we suggest that replicating features of the weaning microbiome in adults could promote the successful engraftment of probiotics. Finally, we highlight key research areas that could deepen our understanding of the complex relationships between diet, commensal microbes, and the host, informing the development of more effective microbial therapies.
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Affiliation(s)
- Julia N. Flores
- Division of Infectious Disease, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jean-Bernard Lubin
- Division of Infectious Disease, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Michael A. Silverman
- Division of Infectious Disease, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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17
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Krigul KL, Feeney RH, Wongkuna S, Aasmets O, Holmberg SM, Andreson R, Puértolas-Balint F, Pantiukh K, Sootak L, Org T, Tenson T, Org E, Schroeder BO. A history of repeated antibiotic usage leads to microbiota-dependent mucus defects. Gut Microbes 2024; 16:2377570. [PMID: 39034613 PMCID: PMC11529412 DOI: 10.1080/19490976.2024.2377570] [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: 03/03/2024] [Accepted: 07/03/2024] [Indexed: 07/23/2024] Open
Abstract
Recent evidence indicates that repeated antibiotic usage lowers microbial diversity and ultimately changes the gut microbiota community. However, the physiological effects of repeated - but not recent - antibiotic usage on microbiota-mediated mucosal barrier function are largely unknown. By selecting human individuals from the deeply phenotyped Estonian Microbiome Cohort (EstMB), we here utilized human-to-mouse fecal microbiota transplantation to explore long-term impacts of repeated antibiotic use on intestinal mucus function. While a healthy mucus layer protects the intestinal epithelium against infection and inflammation, using ex vivo mucus function analyses of viable colonic tissue explants, we show that microbiota from humans with a history of repeated antibiotic use causes reduced mucus growth rate and increased mucus penetrability compared to healthy controls in the transplanted mice. Moreover, shotgun metagenomic sequencing identified a significantly altered microbiota composition in the antibiotic-shaped microbial community, with known mucus-utilizing bacteria, including Akkermansia muciniphila and Bacteroides fragilis, dominating in the gut. The altered microbiota composition was further characterized by a distinct metabolite profile, which may be caused by differential mucus degradation capacity. Consequently, our proof-of-concept study suggests that long-term antibiotic use in humans can result in an altered microbial community that has reduced capacity to maintain proper mucus function in the gut.
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Affiliation(s)
- Kertu Liis Krigul
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Rachel H. Feeney
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
| | - Supapit Wongkuna
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
| | - Oliver Aasmets
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Sandra M. Holmberg
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
| | - Reidar Andreson
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
- Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Fabiola Puértolas-Balint
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
| | - Kateryna Pantiukh
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Linda Sootak
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
- Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Tõnis Org
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
- Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Tanel Tenson
- Institute of Technology, University of Tartu, Tartu, Estonia
| | - Elin Org
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Bjoern O. Schroeder
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
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18
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Zhao T, Zhang Y, Nan L, Zhu Q, Wang S, Xie Y, Dong X, Cao C, Lin X, Lu Y, Liu Y, Huang L, Gong G, Wang Z. Impact of structurally diverse polysaccharides on colonic mucin O-glycosylation and gut microbiota. NPJ Biofilms Microbiomes 2023; 9:97. [PMID: 38081891 PMCID: PMC10713555 DOI: 10.1038/s41522-023-00468-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Understanding how dietary polysaccharides affect mucin O-glycosylation and gut microbiota could provide various nutrition-based treatments. Here, the O-glycan profile of the colonic mucosa and gut microbiome were investigated in C57BL/6J mice fed six structurally diverse dietary polysaccharides and a mixture of six fibers. Dietary polysaccharides increased total O-glycans, mainly by stimulating neutral glycans. Highly branched arabinogalactan promoted terminally fucosylated core 1 O-glycans; whereas linear polysaccharides, including pectin, konjac glucomannan, inulin, and the fiber mixture, favored terminally di-fucosylated O-glycans. The last three polysaccharides also lowered the level of sulfated O-glycans and sialylated mono-fucosylated O-glycans. Varied monosaccharide composition in mixed polysaccharides had a synergistic beneficial effect, boosting fucosylated neutral glycans, decreasing acidic glycans, and stimulating microbial richness and diversity. Dietary polysaccharides containing arabinose and sulfate groups enhanced the relative abundances of Akkermansia and Muribaculaceae, respectively. The present comparison reveals the relationship between dietary polysaccharide structure, mucin O-glycan composition, and intestinal microorganisms.
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Affiliation(s)
- Tong Zhao
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Yue Zhang
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Linhua Nan
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Qing Zhu
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Shukai Wang
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Yutao Xie
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Xinling Dong
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Cui Cao
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Xiaoliang Lin
- Infinitus (China) Company Ltd, Guangzhou, 510000, Guangdong, China
| | - Yu Lu
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Yuxia Liu
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Linjuan Huang
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Guiping Gong
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China.
| | - Zhongfu Wang
- Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an, 710069, China.
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19
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Clark A, Mach N. The gut mucin-microbiota interactions: a missing key to optimizing endurance performance. Front Physiol 2023; 14:1284423. [PMID: 38074323 PMCID: PMC10703311 DOI: 10.3389/fphys.2023.1284423] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 10/27/2023] [Indexed: 01/22/2025] Open
Abstract
Endurance athletes offer unique physiology and metabolism compared to sedentary individuals. Athletes training at high intensities for prolonged periods are at risk for gastrointestinal disturbances. An important factor in endurance performance is the integrity and function of the gut barrier, which primarily depends on heavily O-glycosylated mucins. Emerging evidence shows a complex bidirectional dialogue between glycans on mucins and gut microorganisms. This review emphasizes the importance of the crosstalk between the gut microbiome and host mucus mucins and some of the mechanisms underlying this symbiosis. The contribution of mucin glycans to the composition and functionality of the gut microbiome is discussed, as well as the persuasive impact of the gut microbiome on mucin composition, thickness, and immune and metabolic functions. Lastly, we propose natural and synthetic glycans supplements to improve intestinal mucus production and barrier function, offering new opportunities to enhance endurance athletes' performance and gut health.
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Affiliation(s)
- Allison Clark
- Universitat Oberta de Catalunya, Universitat de Catalunya, Barcelona, Spain
| | - Núria Mach
- Interactions hôtes-agents pathogènes, Université de Toulouse, Institut national de recherche pour l’agriculture, l’alimentation et l’environnement, École nationale vétérinaire de Toulouse, Toulouse, France
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20
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Yang WH, Aziz PV, Heithoff DM, Kim Y, Ko JY, Cho JW, Mahan MJ, Sperandio M, Marth JD. Innate mechanism of mucosal barrier erosion in the pathogenesis of acquired colitis. iScience 2023; 26:107883. [PMID: 37752945 PMCID: PMC10518488 DOI: 10.1016/j.isci.2023.107883] [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: 01/26/2023] [Revised: 08/16/2023] [Accepted: 09/07/2023] [Indexed: 09/28/2023] Open
Abstract
The colonic mucosal barrier protects against infection, inflammation, and tissue ulceration. Composed primarily of Mucin-2, proteolytic erosion of this barrier is an invariant feature of colitis; however, the molecular mechanisms are not well understood. We have applied a recurrent food poisoning model of acquired inflammatory bowel disease using Salmonella enterica Typhimurium to investigate mucosal barrier erosion. Our findings reveal an innate Toll-like receptor 4-dependent mechanism activated by previous infection that induces Neu3 neuraminidase among colonic epithelial cells concurrent with increased Cathepsin-G protease secretion by Paneth cells. These anatomically separated host responses merge with the desialylation of nascent colonic Mucin-2 by Neu3 rendering the mucosal barrier susceptible to increased proteolytic breakdown by Cathepsin-G. Depletion of Cathepsin-G or Neu3 function using pharmacological inhibitors or genetic-null alleles protected against Mucin-2 proteolysis and barrier erosion and reduced the frequency and severity of colitis, revealing approaches to preserve and potentially restore the mucosal barrier.
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Affiliation(s)
- Won Ho Yang
- Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center; La Jolla, CA 92037, USA
- Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Peter V. Aziz
- Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center; La Jolla, CA 92037, USA
| | - Douglas M. Heithoff
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Yeolhoe Kim
- Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Jeong Yeon Ko
- Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Jin Won Cho
- Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Michael J. Mahan
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Markus Sperandio
- Walter Brendel Center for Experimental Medicine, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilians University, Munich, Germany
| | - Jamey D. Marth
- Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center; La Jolla, CA 92037, USA
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21
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Yang Q, Lyu S, Xu M, Li S, Du Z, Liu X, Shang X, Yu Z, Liu J, Zhang T. Potential Benefits of Egg White Proteins and Their Derived Peptides in the Regulation of the Intestinal Barrier and Gut Microbiota: A Comprehensive Review. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:13168-13180. [PMID: 37639307 DOI: 10.1021/acs.jafc.3c03230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
Impaired intestinal barrier function can impede the digestion and absorption of nutrients and cause a range of metabolic disorders, which are the main causes of intestinal disease. Evidence suggests that proper dietary protein intake can prevent and alleviate intestinal diseases. Egg white protein (EWP) has received considerable attention, because of its high protein digestibility and rich amino acid composition. Furthermore, bioactive peptides may have an increased repair effect due to their high degradation efficiency in the gut. In this study, we aimed to review the effects of EWP and its bioactive peptides on intestinal structural repair. The potential modulation mechanisms by which EWP and their peptides regulate the gut microbiota and intestinal barrier can be summarized as follows: (1) restoring the structure of the intestinal barrier to its intact form, (2) enhancing the intestinal immune system and alleviating the inflammatory response and oxidative damage, and (3) increasing the relative abundance of beneficial bacteria and metabolites. Further in-depth analysis of the coregulation of multiple signaling pathways by EWP is required, and the combined effects of these multiple mechanisms requires further evaluation in experimental models. Human trials can be considered to understand new directions for development.
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Affiliation(s)
- Qi Yang
- Jilin Provincial Key Laboratory of Nutrition and Functional Food, Jilin University, 130062 Changchun, China
- College of Food Science and Engineering, Jilin University, 130062 Changchun, China
| | - Siwen Lyu
- Jilin Provincial Key Laboratory of Nutrition and Functional Food, Jilin University, 130062 Changchun, China
- College of Food Science and Engineering, Jilin University, 130062 Changchun, China
| | - Menglei Xu
- Jilin Provincial Key Laboratory of Nutrition and Functional Food, Jilin University, 130062 Changchun, China
- College of Food Science and Engineering, Jilin University, 130062 Changchun, China
| | - Shengrao Li
- Jilin Provincial Key Laboratory of Nutrition and Functional Food, Jilin University, 130062 Changchun, China
- College of Food Science and Engineering, Jilin University, 130062 Changchun, China
| | - Zhiyang Du
- Jilin Provincial Key Laboratory of Nutrition and Functional Food, Jilin University, 130062 Changchun, China
- College of Food Science and Engineering, Jilin University, 130062 Changchun, China
| | - Xuanting Liu
- Jilin Provincial Key Laboratory of Nutrition and Functional Food, Jilin University, 130062 Changchun, China
- College of Food Science and Engineering, Jilin University, 130062 Changchun, China
| | - Xiaomin Shang
- Jilin Provincial Key Laboratory of Nutrition and Functional Food, Jilin University, 130062 Changchun, China
- College of Food Science and Engineering, Jilin University, 130062 Changchun, China
| | - Zhipeng Yu
- School of Food Science and Engineering, Hainan University, 570228 Haikou, China
| | - Jingbo Liu
- Jilin Provincial Key Laboratory of Nutrition and Functional Food, Jilin University, 130062 Changchun, China
- College of Food Science and Engineering, Jilin University, 130062 Changchun, China
| | - Ting Zhang
- Jilin Provincial Key Laboratory of Nutrition and Functional Food, Jilin University, 130062 Changchun, China
- College of Food Science and Engineering, Jilin University, 130062 Changchun, China
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22
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Moran ET, Bedford MR. Endogenous mucin conveyed to the mucosa with microbes can assure lumen fermentation and large intestinal security-swine versus fowl. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2023; 14:403-410. [PMID: 37635931 PMCID: PMC10457508 DOI: 10.1016/j.aninu.2023.06.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 06/15/2023] [Accepted: 06/18/2023] [Indexed: 08/29/2023]
Abstract
Endogenous protein leaving the ileum largely consists of accrued mucins from the upper gastrointestinal tract (GIT) that had resisted digestion. The amounts released rely on their mucosal generation during enteral feeding which vary with age as well as diet. These digestion resistant proteins of endogenous origin continue to be unavailable in the large intestine, whereas those of dietary origin provide amino acids that largely support the existing microbial population while denying limited amounts for absorption. Other mucins pre-exist within the large intestine as two layers at the lumen surface. A loose layer harboring a diverse microbial population is superimposed on the unstirred water layer (USWL) which simultaneously acts as an obstacle to microbes at the loose layer while performing as a molecular sieve for nutrients. The USWL is formed through interplay between enterocyte and goblet cells; however, the basis for presence of the loose layer is elusive. Large intestinal fermentation predominates within the colon of swine, whereas fowl employ their ceca. Motility within the colon of swine segregates fine materials into haustrae out-pocketings that parallel their placement within the ceca of fowl. Viscous mucins from small intestinal endogenous losses may envelop microbes within the large intestinal lumen to present successive adherents on the USWL that assemble its loose layer. The loose layer continually functions as a microbial reservoir in support of lumen fermentation. Microbial catabolism of mucin within the loose layer is known to be slow, but its proximity to the enterocyte is of advantage to enterocyte absorption with by-product amino acids fostering the USWL.
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Affiliation(s)
- Edwin T. Moran
- Poultry Science Department, Auburn University, AL 36849-5416, USA
| | - Michael R. Bedford
- AB Vista, Woodstock Court, Blenheim Road, Marlborough Road, Wiltshire, SN8 4NA, UK
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23
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Yamaguchi M, Yamamoto K. Mucin glycans and their degradation by gut microbiota. Glycoconj J 2023; 40:493-512. [PMID: 37318672 DOI: 10.1007/s10719-023-10124-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 03/13/2023] [Accepted: 05/22/2023] [Indexed: 06/16/2023]
Abstract
The human intestinal tract is inhabited by a tremendous number of microorganisms, which are collectively termed "the gut microbiota". The intestinal epithelium is covered with a dense layer of mucus that prevents penetration of the gut microbiota into underlying tissues of the host. Recent studies have shown that the maturation and function of the mucus layer are strongly influenced by the gut microbiota, and alteration in the structure and function of the gut microbiota is implicated in several diseases. Because the intestinal mucus layer is at a crucial interface between microbes and their host, its breakdown leads to gut bacterial invasion that can eventually cause inflammation and infection. The mucus is composed of mucin, which is rich in glycans, and the various structures of the complex carbohydrates of mucins can select for distinct mucosa-associated bacteria that are able to bind mucin glycans, and sometimes degrade them as a nutrient source. Mucin glycans are diverse molecules, and thus mucin glycan degradation is a complex process that requires a broad range of glycan-degrading enzymes. Because of the increased recognition of the role of mucus-associated microbes in human health, how commensal bacteria degrade and use host mucin glycans has become of increased interest. This review provides an overview of the relationships between the mucin glycan of the host and gut commensal bacteria, with a focus on mucin degradation.
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Affiliation(s)
- Masanori Yamaguchi
- Department of Organic Bio Chemistry, Faculty of Education, Wakayama University, 930, Sakaedani, Wakayama, 640-8510, Japan.
| | - Kenji Yamamoto
- Center for Innovative and Joint Research, Wakayama University, 930, Sakaedani, Wakayama, 640-8510, Japan
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24
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Feng S, Zhang C, Chen S, He R, Chao G, Zhang S. TLR5 Signaling in the Regulation of Intestinal Mucosal Immunity. J Inflamm Res 2023; 16:2491-2501. [PMID: 37337514 PMCID: PMC10276996 DOI: 10.2147/jir.s407521] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/23/2023] [Indexed: 06/21/2023] Open
Abstract
Toll-like receptor 5 (TLR5) is a pattern recognition receptor that specifically recognizes flagellin and consequently plays a crucial role in the control of intestinal homeostasis by activating innate and adaptive immune responses. TLR5 overexpression, on the other hand, might disrupt the intestinal mucosal barrier, which serves as the first line of defense against harmful microbes. The intestine symbiotic bacteria, mucous layer, intestinal epithelial cells (IECs), adherens junctions (such as tight junctions and peripheral membrane proteins), the intestinal mucosal immune system, and cytokines make up the intestinal mucosal barrier. Impaired barrier function has been linked to intestinal illnesses such as inflammatory bowel disease (IBD). IBD is a persistent non-specific inflammatory illness of the digestive system with an unknown cause. It is now thought to be linked to infection, environment, genes, immune system, and the gut microbiota. The significance of immunological dysfunction in IBD has received more attention in recent years. The purpose of this paper is to explore TLR5's position in the intestinal mucosal barrier and its relevance to IBD.
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Affiliation(s)
- Shuyan Feng
- Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Chi Zhang
- Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Shanshan Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, People’s Republic of China
| | - Ruonan He
- Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Guanqun Chao
- Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, 310018, People’s Republic of China
| | - Shuo Zhang
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, People’s Republic of China
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25
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Gorman H, Moreau F, Dufour A, Chadee K. IgGFc-binding protein and MUC2 mucin produced by colonic goblet-like cells spatially interact non-covalently and regulate wound healing. Front Immunol 2023; 14:1211336. [PMID: 37359538 PMCID: PMC10285406 DOI: 10.3389/fimmu.2023.1211336] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 05/30/2023] [Indexed: 06/28/2023] Open
Abstract
The colonic mucus bilayer is the first line of innate host defense that at the same time houses and nourishes the commensal microbiota. The major components of mucus secreted by goblet cells are MUC2 mucin and the mucus-associated protein, FCGBP (IgGFc-binding protein). In this study, we determine if FCGBP and MUC2 mucin were biosynthesized and interacted together to spatially enhance the structural integrity of secreted mucus and its role in epithelial barrier function. MUC2 and FCGBP were coordinately regulated temporally in goblet-like cells and in response to a mucus secretagogue but not in CRISPR-Cas9 gene-edited MUC2 KO cells. Whereas ~85% of MUC2 was colocalized with FCGBP in mucin granules, ~50% of FCGBP was diffusely distributed in the cytoplasm of goblet-like cells. STRING-db v11 analysis of the mucin granule proteome revealed no protein-protein interaction between MUC2 and FCGBP. However, FCGBP interacted with other mucus-associated proteins. FCGBP and MUC2 interacted via N-linked glycans and were non-covalently bound in secreted mucus with cleaved low molecular weight FCGBP fragments. In MUC2 KO, cytoplasmic FCGBP was significantly increased and diffusely distributed in wounded cells that healed by enhanced proliferation and migration within 2 days, whereas, in WT cells, MUC2 and FCGBP were highly polarized at the wound margin which impeded wound closure by 6 days. In DSS colitis, restitution and healed lesions in Muc2+/+ but not Muc2-/- littermates, were accompanied by a rapid increase in Fcgbp mRNA and delayed protein expression at 12- and 15-days post DSS, implicating a potential novel endogenous protective role for FCGBP in wound healing to maintain epithelial barrier function.
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Affiliation(s)
- Hayley Gorman
- Department of Microbiology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
- Department of Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - France Moreau
- Department of Microbiology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
- Department of Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Antoine Dufour
- Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
- Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
| | - Kris Chadee
- Department of Microbiology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
- Department of Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
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26
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Kumar V, Kumar V, Kondepudi KK, Chopra K, Bishnoi M. Capsazepine-Induced Altered Colonic Mucosal Health Limits Isomalto-oligosaccharide Action in High-Fat Diet-Fed C57BL/6J Mice. ACS Pharmacol Transl Sci 2023; 6:600-613. [PMID: 37082749 PMCID: PMC10111622 DOI: 10.1021/acsptsci.2c00243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Indexed: 04/05/2023]
Abstract
The present study sought to understand the effects of a combination of altered colonic mucosal health (intrarectal capsazepine administration) and high-fat diet (HFD) administration in mice. Furthermore, we also studied whether this combination prevents protective actions of dietary prebiotic, isomaltooligosaccharides. We studied the alterations in intestinal permeability, histological and transcriptional changes, short-chain fatty acid (SCFA) concentrations, and gut microbial abundance. Capsazepine (CPZ) was administered rectally twice a day along with HFD feeding. Following confirmation of CPZ action (loss of TRPA1 and TRPV1-associated nocifensive behavior), the intrarectal dose of CPZ was reduced to once in 2 days up to 8 weeks. Simultaneous intrarectal administration of CPZ exacerbated the HFD (8 weeks feeding)-induced damage to mucosal lining, intestinal permeability, tight junction protein expression, SCFA levels, and gut bacterial abundances. This higher degree of mucosal damage and pathological alteration in colonic mucosa prevented the previously reported protective actions of isomaltooligosaccharides as a prebiotic in HFD-fed mice. Overall, we present evidence that colonic precondition (gut permeability and mucosal lining) is an important factor in determination of HFD-induced changes in the colon, and success of diet-associated interventions (dietary fibers, pre/probiotics, etc.) is dependent on it.
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Affiliation(s)
- Vibhu Kumar
- TR(i)P
for Health Laboratory, Centre for Excellence in Functional Foods,
Department of Food and Nutritional Biotechnology, National Agri-Food Biotechnology Institute (NABI), Knowledge City-Sector 81, SAS Nagar, Punjab 140306, India
- University
Institute of Pharmaceutical Sciences, Panjab
University, Chandigarh 160014, India
| | - Vijay Kumar
- TR(i)P
for Health Laboratory, Centre for Excellence in Functional Foods,
Department of Food and Nutritional Biotechnology, National Agri-Food Biotechnology Institute (NABI), Knowledge City-Sector 81, SAS Nagar, Punjab 140306, India
- Department
of Biotechnology, Panjab University, Sector-25, Chandigarh 160014, India
| | - Kanthi Kiran Kondepudi
- TR(i)P
for Health Laboratory, Centre for Excellence in Functional Foods,
Department of Food and Nutritional Biotechnology, National Agri-Food Biotechnology Institute (NABI), Knowledge City-Sector 81, SAS Nagar, Punjab 140306, India
| | - Kanwaljit Chopra
- University
Institute of Pharmaceutical Sciences, Panjab
University, Chandigarh 160014, India
| | - Mahendra Bishnoi
- TR(i)P
for Health Laboratory, Centre for Excellence in Functional Foods,
Department of Food and Nutritional Biotechnology, National Agri-Food Biotechnology Institute (NABI), Knowledge City-Sector 81, SAS Nagar, Punjab 140306, India
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Shuoker B, Pichler MJ, Jin C, Sakanaka H, Wu H, Gascueña AM, Liu J, Nielsen TS, Holgersson J, Nordberg Karlsson E, Juge N, Meier S, Morth JP, Karlsson NG, Abou Hachem M. Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria. Nat Commun 2023; 14:1833. [PMID: 37005422 PMCID: PMC10067855 DOI: 10.1038/s41467-023-37533-6] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 03/21/2023] [Indexed: 04/04/2023] Open
Abstract
The mucolytic human gut microbiota specialist Akkermansia muciniphila is proposed to boost mucin-secretion by the host, thereby being a key player in mucus turnover. Mucin glycan utilization requires the removal of protective caps, notably fucose and sialic acid, but the enzymatic details of this process remain largely unknown. Here, we describe the specificities of ten A. muciniphila glycoside hydrolases, which collectively remove all known sialyl and fucosyl mucin caps including those on double-sulfated epitopes. Structural analyses revealed an unprecedented fucosidase modular arrangement and explained the sialyl T-antigen specificity of a sialidase of a previously unknown family. Cell-attached sialidases and fucosidases displayed mucin-binding and their inhibition abolished growth of A. muciniphila on mucin. Remarkably, neither the sialic acid nor fucose contributed to A. muciniphila growth, but instead promoted butyrate production by co-cultured Clostridia. This study brings unprecedented mechanistic insight into the initiation of mucin O-glycan degradation by A. muciniphila and nutrient sharing between mucus-associated bacteria.
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Affiliation(s)
- Bashar Shuoker
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, 2800, Denmark
- Biotechnology, Department of Chemistry, Lund University, Lund, Sweden
| | - Michael J Pichler
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, 2800, Denmark
| | - Chunsheng Jin
- Proteomics Core Facility at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hiroka Sakanaka
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, 2800, Denmark
| | - Haiyang Wu
- Quadram Institute Bioscience, Norwich, UK
| | | | - Jining Liu
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Tine Sofie Nielsen
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, 2800, Denmark
| | - Jan Holgersson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | | | - Sebastian Meier
- Department of Chemistry, Technical University of Denmark, Kgs Lyngby, Denmark
| | - Jens Preben Morth
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, 2800, Denmark.
| | - Niclas G Karlsson
- Proteomics Core Facility at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maher Abou Hachem
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, 2800, Denmark.
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28
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Interaction between gut microbiota and sex hormones and their relation to sexual dimorphism in metabolic diseases. Biol Sex Differ 2023; 14:4. [PMID: 36750874 PMCID: PMC9903633 DOI: 10.1186/s13293-023-00490-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/30/2023] [Indexed: 02/09/2023] Open
Abstract
Metabolic diseases, such as obesity, metabolic syndrome (MetS) and type 2 diabetes (T2D), are now a widespread pandemic in the developed world. These pathologies show sex differences in their development and prevalence, and sex steroids, mainly estrogen and testosterone, are thought to play a prominent role in this sexual dimorphism. The influence of sex hormones on these pathologies is not only reflected in differences between men and women, but also between women themselves, depending on the hormonal changes associated with the menopause. The observed sex differences in gut microbiota composition have led to multiple studies highlighting the interaction between steroid hormones and the gut microbiota and its influence on metabolic diseases, ultimately pointing to a new therapy for these diseases based on the manipulation of the gut microbiota. This review aims to shed light on the role of sexual hormones in sex differences in the development and prevalence of metabolic diseases, focusing on obesity, MetS and T2D. We focus also the interaction between sex hormones and the gut microbiota, and in particular the role of microbiota in aspects such as gut barrier integrity, inflammatory status, and the gut-brain axis, given the relevance of these factors in the development of metabolic diseases.
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29
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Lin SJH, Helm ET, Gabler NK, Burrough ER. Acute infection with Brachyspira hyodysenteriae affects mucin expression, glycosylation, and fecal MUC5AC. Front Cell Infect Microbiol 2023; 12:1042815. [PMID: 36683692 PMCID: PMC9852840 DOI: 10.3389/fcimb.2022.1042815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/28/2022] [Indexed: 01/08/2023] Open
Abstract
Introduction Infection with strongly β-hemolytic strains of Brachyspira hyodysenteriae leads to swine dysentery (SD), a production-limiting disease that causes mucohemorrhagic diarrhea and typhlocolitis in pigs. This pathogen has strong chemotactic activity toward mucin, and infected pigs often have a disorganized mucus layer and marked de novo expression of MUC5AC, which is not constitutively expressed in the colon. It has been shown that fucose is chemoattractant for B. hyodysenteriae, and a highly fermentable fiber diet can mitigate and delay the onset of SD. Methods We used lectins targeting sialic acids in α-2,6 or α-2,3 linkages, N-acetylglucosamine (GlcNAc), α-linked L-fucose, and an immunohistochemical stain targeting N-glycolylneuraminic acid (NeuGc) to investigate the local expression of these mucin glycans in colonic tissues of pigs with acute SD. We used a commercial enzyme-linked immunosorbent assay (ELISA) to quantify fecal MUC5AC in infected pigs and assess its potential as a diagnostic monitoring tool and RNA in situ hybridization to detect IL-17A in the colonic mucosa. Results Colonic mucin glycosylation during SD has an overall increase in fucose, a spatially different distribution of GlcNAc with more expression within the crypt lumens of the upper colonic mucosa, and decreased expression or a decreased trend of sialic acids in α-2,6 or α-2,3 linkages, and NeuGc compared to the controls. The degree of increased fucosylation was less in the colonic mucosa of pigs with SD and fed the highly fermentable fiber diet. There was a significant increase in MUC5AC in fecal and colonic samples of pigs with SD at the endpoint compared to the controls, but the predictive value for disease progression was limited. Discussion Fucosylation and the impact of dietary fiber may play important roles in the pathogenesis of SD. The lack of predictive value for fecal MUC5AC quantification by ELISA is possibly due to the presence of other non-colonic sources of MUC5AC in the feces. The moderate correlation between IL-17A, neutrophils and MUC5AC confirms its immunoregulatory and mucin stimulatory role. Our study characterizes local alteration of mucin glycosylation in the colonic mucosa of pigs with SD after B. hyodysenteriae infection and may provide insight into host-pathogen interaction.
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Affiliation(s)
- Susanne Je-Han Lin
- Department of Veterinary Pathology, Iowa State University, Ames, IA, United States
| | - Emma T Helm
- Department of Animal Science, Iowa State University, Ames, IA, United States
| | - Nicholas K Gabler
- Department of Animal Science, Iowa State University, Ames, IA, United States
| | - Eric R Burrough
- Department of Veterinary Diagnostic and Production Animal Medicine, Iowa State University, Ames, IA, United States
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30
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Raev S, Amimo J, Saif L, Vlasova A. Intestinal mucin-type O-glycans: the major players in the host-bacteria-rotavirus interactions. Gut Microbes 2023; 15:2197833. [PMID: 37020288 PMCID: PMC10078158 DOI: 10.1080/19490976.2023.2197833] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 03/28/2023] [Indexed: 04/07/2023] Open
Abstract
Rotavirus (RV) causes severe diarrhea in young children and animals worldwide. Several glycans terminating in sialic acids (SAs) and histo-blood group antigens (HBGAs) on intestinal epithelial cell (IEC) surface have been recognized to act as attachment sites for RV. IECs are protected by the double layer of mucus of which O-glycans (including HBGAs and SAs) are a major organic component. Luminal mucins, as well as bacterial glycans, can act as decoy molecules removing RV particles from the gut. The composition of the intestinal mucus is regulated by complex O-glycan-specific interactions among the gut microbiota, RV and the host. In this review, we highlight O-glycan-mediated interactions within the intestinal lumen prior to RV attachment to IECs. A better understanding of the role of mucus is essential for the development of alternative therapeutic tools including the use of pre- and probiotics to control RV infection.
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Affiliation(s)
- S.A. Raev
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, USA
| | - J.O. Amimo
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, USA
- Department of Animal Production, Faculty of Veterinary Medicine, University of Nairobi, Nairobi, Kenya
| | - L.J. Saif
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, USA
| | - A.N. Vlasova
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, USA
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31
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Abstract
Sucrose, the primary circulating sugar in plants, contains equal amounts of fructose and glucose. The latter is the predominant circulating sugar in animals and thus the primary fuel source for various tissue and cell types in the body. Chronic excessive energy intake has, however, emerged as a major driver of obesity and associated pathologies including nonalcoholic fatty liver diseases (NAFLD) and the more severe nonalcoholic steatohepatitis (NASH). Consumption of a high-caloric, western-style diet induces gut dysbiosis and inflammation resulting in leaky gut. Translocation of gut-derived bacterial content promotes hepatic inflammation and ER stress, and when either or both of these are combined with steatosis, it can cause NASH. Here, we review the metabolic links between diet-induced changes in the gut and NASH. Furthermore, therapeutic interventions for the treatment of obesity and liver metabolic diseases are also discussed with a focus on restoring the gut-liver axis.
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32
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Paone P, Suriano F, Jian C, Korpela K, Delzenne NM, Van Hul M, Salonen A, Cani PD. Prebiotic oligofructose protects against high-fat diet-induced obesity by changing the gut microbiota, intestinal mucus production, glycosylation and secretion. Gut Microbes 2022; 14:2152307. [PMID: 36448728 PMCID: PMC9715274 DOI: 10.1080/19490976.2022.2152307] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Obesity is a major risk factor for the development of type 2 diabetes and cardiovascular diseases, and gut microbiota plays a key role in influencing the host energy homeostasis. Moreover, obese mice have a different gut microbiota composition, associated with an alteration of the intestinal mucus layer, which represents the interface between the bacteria and the host. We previously demonstrated that prebiotic treatment with oligofructose (FOS) counteracted the effects of diet-induced obesity, together with changes in the gut microbiota composition, but it is not known if the intestinal mucus layer could be involved. In this study, we found that, in addition to preventing high-fat diet (HFD) induced obesity in mice, the treatment with FOS increased the expression of numerous genes involved in mucus production, glycosylation and secretion, the expression of both secreted and transmembrane mucins, and the differentiation and number of goblet cells. These results were associated with significant changes in the gut microbiota composition, with FOS significantly increasing the relative and absolute abundance of the bacterial genera Odoribacter, Akkermansia, two unknown Muribaculaceae and an unknown Ruminococcaceae. Interestingly, all these bacterial genera had a negative association with metabolic parameters and a positive association with markers of the mucus layer. Our study shows that FOS treatment is able to prevent HFD-induced metabolic disorders, at least in part, by acting on all the processes of the mucus production. These data suggest that targeting the mucus and the gut microbiota by using prebiotics could help to prevent or mitigate obesity and related disorders.
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Affiliation(s)
- Paola Paone
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium,Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO Department, WEL Research Institute, Wavre, Belgium
| | - Francesco Suriano
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium,Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO Department, WEL Research Institute, Wavre, Belgium
| | - Ching Jian
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Katri Korpela
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Nathalie M. Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Matthias Van Hul
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium,Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO Department, WEL Research Institute, Wavre, Belgium
| | - Anne Salonen
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Patrice D. Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium,Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO Department, WEL Research Institute, Wavre, Belgium,CONTACT Patrice D. Cani Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
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Suriano F, Nyström EEL, Sergi D, Gustafsson JK. Diet, microbiota, and the mucus layer: The guardians of our health. Front Immunol 2022; 13:953196. [PMID: 36177011 PMCID: PMC9513540 DOI: 10.3389/fimmu.2022.953196] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/19/2022] [Indexed: 12/12/2022] Open
Abstract
The intestinal tract is an ecosystem in which the resident microbiota lives in symbiosis with its host. This symbiotic relationship is key to maintaining overall health, with dietary habits of the host representing one of the main external factors shaping the microbiome-host relationship. Diets high in fiber and low in fat and sugars, as opposed to Western and high-fat diets, have been shown to have a beneficial effect on intestinal health by promoting the growth of beneficial bacteria, improve mucus barrier function and immune tolerance, while inhibiting pro-inflammatory responses and their downstream effects. On the contrary, diets low in fiber and high in fat and sugars have been associated with alterations in microbiota composition/functionality and the subsequent development of chronic diseases such as food allergies, inflammatory bowel disease, and metabolic disease. In this review, we provided an updated overview of the current understanding of the connection between diet, microbiota, and health, with a special focus on the role of Western and high-fat diets in shaping intestinal homeostasis by modulating the gut microbiota.
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Affiliation(s)
- Francesco Suriano
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Elisabeth E. L. Nyström
- Unit for Degradomics of the Protease Web, Institute of Biochemistry, Kiel University, Kiel, Germany
| | - Domenico Sergi
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Jenny K. Gustafsson
- Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
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34
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Yin Y, Cai J, Zhou L, Xing L, Zhang W. Dietary oxidized beef protein alters gut microbiota and induces colonic inflammatory damage in C57BL/6 mice. Front Nutr 2022; 9:980204. [PMID: 36118776 PMCID: PMC9478438 DOI: 10.3389/fnut.2022.980204] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/16/2022] [Indexed: 11/22/2022] Open
Abstract
This study aimed to investigate the effect of oxidized beef protein on colon health. C57BL/6 mice were fed diets containing in vitro oxidized beef protein (carbonyl content 5.83/9.02 nmol/mg protein) or normal beef protein (control group, carbonyl content 2.27 nmol/mg protein) for 10 weeks. Histological observations showed that oxidized beef protein diet induced notable inflammatory cell infiltrations in colon. The analysis of high-throughput sequencing indicated oxidized beef protein largely altered the composition of gut microbiota (GM) by increasing proinflammatory bacteria (Desulfovibrio, Bacteroides, Enterorhabdus) while reducing beneficial bacteria (Lactobacillus, Akkermansia). In addition, oxidized beef protein remarkably increased protein fermentation in the colon, which was evidenced by the elevated i-butyrate, i-valerate, and ammonia levels in feces. Furthermore, consuming oxidized beef protein destroyed colon barrier functions by decreasing tight junction proteins expression. These changes in colonic ecosystem activated the proinflammatory pathway of lipopolysaccharide/toll-like receptor-4/nuclear factor kappa B (LPS/TLR-4/NF-κB), eventually leading to colonic inflammatory damage in mice. Taken together, these results imply that consuming oxidized beef protein detrimentally regulates GM and impairs colon health.
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35
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Xia B, Zhong R, Wu W, Luo C, Meng Q, Gao Q, Zhao Y, Chen L, Zhang S, Zhao X, Zhang H. Mucin O-glycan-microbiota axis orchestrates gut homeostasis in a diarrheal pig model. MICROBIOME 2022; 10:139. [PMID: 36045454 PMCID: PMC9429786 DOI: 10.1186/s40168-022-01326-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 07/13/2022] [Indexed: 05/03/2023]
Abstract
BACKGROUND Post-weaning diarrhea in piglets reduces growth performance and increases mortality, thereby causing serious economic losses. The intestinal epithelial cells and microbiota reciprocally regulate each other in order to maintain intestinal homeostasis and control inflammation. However, a relative paucity of research has been focused on the host-derived regulatory network that controls mucin O-glycans and thereby changes gut microbiota during diarrhea in infancy. At the development stage just after birth, the ontogeny of intestinal epithelium, immune system, and gut microbiota appear similar in piglets and human infants. Here, we investigated the changes of mucin O-glycans associated with gut microbiota using a diarrheal post-weaned piglet model. RESULTS We found that diarrhea disrupted the colonic mucus layer and caused aberrant mucin O-glycans, including reduced acidic glycans and truncated glycans, leading to an impaired gut microenvironment. Subsequently, the onset of diarrhea, changes in microbiota and bacterial translocation, resulting in compromised epithelial barrier integrity, enhanced susceptibility to inflammation, and mild growth faltering. Furthermore, we found the activation of NLRP3 inflammasome complexes in the diarrheal piglets when compared to the healthy counterparts, triggered the release of proinflammatory cytokines IL-1β and IL-18, and diminished autophagosome formation, specifically the defective conversion of LC3A/B I into LC3A/B II and the accumulation of p62. Additionally, selective blocking of the autophagy pathway by 3-MA led to the reduction in goblet cell-specific gene transcript levels in vitro. CONCLUSIONS We observed that diarrheal piglets exhibited colonic microbiota dysbiosis and mucosal barrier dysfunction. Our data demonstrated that diarrhea resulted in the activation of inflammasomes and autophagy restriction along with aberrant mucin O-glycans including reduced acidic glycans and truncated glycans. The results suggested the mucin O-glycans-microbiota axis is likely associated with diarrheal pathogenesis. Our study provides novel insights into the pathophysiology of early-weaning-induced diarrheal disease in piglets and potentially understanding of disease mechanisms of diarrhea for human infants. Understanding the molecular pathology and pathogenesis of diarrhea is a prerequisite for the development of novel and effective therapies. Our data suggest that facilitating O-glycan elongation, modifying the microbiota, and developing specific inhibitors to some key inflammasomes could be the options for therapy of diarrhea including human infants. Video abstract.
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Affiliation(s)
- Bing Xia
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, 102206 China
| | - Ruqing Zhong
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Weida Wu
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Chengzeng Luo
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Qingshi Meng
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Qingtao Gao
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Yong Zhao
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Liang Chen
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Sheng Zhang
- Institute of Biotechnology, Cornell University, Ithaca, NY 14853 USA
| | - Xin Zhao
- Department of Animal Science, McGill University, Montreal, Quebec H9X3V9 Canada
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China
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36
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Loktionov A. Colon mucus in colorectal neoplasia and beyond. World J Gastroenterol 2022; 28:4475-4492. [PMID: 36157924 PMCID: PMC9476883 DOI: 10.3748/wjg.v28.i32.4475] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/23/2022] [Accepted: 08/06/2022] [Indexed: 02/06/2023] Open
Abstract
Little was known about mammalian colon mucus (CM) until the beginning of the 21st century. Since that time considerable progress has been made in basic research addressing CM structure and functions. Human CM is formed by two distinct layers composed of gel-forming glycosylated mucins that are permanently secreted by goblet cells of the colonic epithelium. The inner layer is dense and impenetrable for bacteria, whereas the loose outer layer provides a habitat for abundant commensal microbiota. Mucus barrier integrity is essential for preventing bacterial contact with the mucosal epithelium and maintaining homeostasis in the gut, but it can be impaired by a variety of factors, including CM-damaging switch of commensal bacteria to mucin glycan consumption due to dietary fiber deficiency. It is proven that impairments in CM structure and function can lead to colonic barrier deterioration that opens direct bacterial access to the epithelium. Bacteria-induced damage dysregulates epithelial proliferation and causes mucosal inflammatory responses that may expand to the loosened CM and eventually result in severe disorders, including colitis and neoplastic growth. Recently described formation of bacterial biofilms within the inner CM layer was shown to be associated with both inflammation and cancer. Although obvious gaps in our knowledge of human CM remain, its importance for the pathogenesis of major colorectal diseases, comprising inflammatory bowel disease and colorectal cancer, is already recognized. Continuing progress in CM exploration is likely to result in the development of a range of new useful clinical applications addressing colorectal disease diagnosis, prevention and therapy.
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37
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Transcriptional Profiling of the Small Intestine and the Colon Reveals Modulation of Gut Infection with Citrobacter rodentium According to the Vitamin A Status. Nutrients 2022; 14:nu14081563. [PMID: 35458125 PMCID: PMC9026425 DOI: 10.3390/nu14081563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/01/2022] [Accepted: 04/04/2022] [Indexed: 12/10/2022] Open
Abstract
Vitamin A (VA) deficiency and diarrheal diseases are both serious public health issues worldwide. VA deficiency is associated with impaired intestinal barrier function and increased risk of mucosal infection-related mortality. The bioactive form of VA, retinoic acid, is a well-known regulator of mucosal integrity. Using Citrobacter rodentium-infected mice as a model for diarrheal diseases in humans, previous studies showed that VA-deficient (VAD) mice failed to clear C. rodentium as compared to their VA-sufficient (VAS) counterparts. However, the distinct intestinal gene responses that are dependent on the host’s VA status still need to be discovered. The mRNAs extracted from the small intestine (SI) and the colon were sequenced and analyzed on three levels: differential gene expression, enrichment, and co-expression. C. rodentium infection interacted differentially with VA status to alter colon gene expression. Novel functional categories downregulated by this pathogen were identified, highlighted by genes related to the metabolism of VA, vitamin D, and ion transport, including improper upregulation of Cl− secretion and disrupted HCO3− metabolism. Our results suggest that derangement of micronutrient metabolism and ion transport, together with the compromised immune responses in VAD hosts, may be responsible for the higher mortality to C. rodentium under conditions of inadequate VA.
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Bergstrom K, Xia L. The barrier and beyond: Roles of intestinal mucus and mucin-type O-glycosylation in resistance and tolerance defense strategies guiding host-microbe symbiosis. Gut Microbes 2022; 14:2052699. [PMID: 35380912 PMCID: PMC8986245 DOI: 10.1080/19490976.2022.2052699] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Over the past two decades, our appreciation of the gut mucus has moved from a static lubricant to a dynamic and essential component of the gut ecosystem that not only mediates the interface between host tissues and vast microbiota, but regulates how this ecosystem functions to promote mutualistic symbioses and protect from microbe-driven diseases. By delving into the complex chemistry and biology of the mucus, combined with innovative in vivo and ex vivo approaches, recent studies have revealed novel insights into the formation and function of the mucus system, the O-glycans that make up this system, and how they mediate two major host-defense strategies - resistance and tolerance - to reduce damage caused by indigenous microbes and opportunistic pathogens. This current review summarizes these findings by highlighting the emerging roles of mucus and mucin-type O-glycans in influencing host and microbial physiology with an emphasis on host defense strategies against bacteria in the gastrointestinal tract.
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Affiliation(s)
- Kirk Bergstrom
- Department of Biology, University of British Columbia, Okanagan Campus, 3333 University Way, Kelowna, British ColumbiaV1V 1V7, Canada,Kirk Bergstrom Department of Biology, University of British Columbia, 3333 University Way, Kelowna, B.C. Canada
| | - Lijun Xia
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, OK, Oklahoma73104, USA,Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, OK, Oklahoma73104, USA,CONTACT Lijun Xia Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, OK, Oklahoma73104, USA
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39
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Lin L, Li Y, Zhou G, Wang Y, Li L, Han J, Chen M, He Y, Zhang S. Multi-Omics Analysis of Western-style Diet Increased Susceptibility to Experimental Colitis in Mice. J Inflamm Res 2022; 15:2523-2537. [PMID: 35479832 PMCID: PMC9037890 DOI: 10.2147/jir.s361039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/08/2022] [Indexed: 11/23/2022] Open
Abstract
Background Western-style diet (WSD) is associated with inflammatory bowel disease (IBD) prevalence. However, the impact of WSD on IBD development and its underlying mechanism remain unclear. Transcriptomics and metabolomics could be beneficial for identifying key factors in WSD-related experimental IBD susceptibility. However, no such study has been conducted yet. We aimed to analyze the implications of WSD for experimental colitis susceptibility in mice and its underlying mechanism using these high-throughput technologies. Methods We fed experimental mice a WSD and a control diet from weaning. After 9 weeks, the mice were treated with 2,4,6 trinitrobenzene sulfonic acid to induce colitis, and the control group was treated with 50% ethanol (commonly used IBD animal model). Genome-wide microarray and liquid chromatography-tandem mass spectrometry were used to identify the differential transcripts and metabolites of experimental colitis with and without pre-illness WSD. Results WSD induced more severe inflammation in experimental colitis than the control diet. We found 2540 up-regulated genes and 2737 down-regulated genes in experimental colitis with WSD compared with those for the control diet. In addition, levels of 41 colonic tissue metabolites and 56 serum metabolites showed significant differences. Integrating transcriptomic and metabolomic data, we found major co-expression networks through which WSD promoted experimental IBD susceptibility, including enzymes of biotransformation, glycan synthesis and metabolism, steroid hormone metabolites. Conclusion Pre-illness WSD increased experimental colitis susceptibility. Our results could provide important evidences for the potential mechanisms and assist dietary recommendations to better manage IBD.
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Affiliation(s)
- Lihui Lin
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Ying Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Division of Gastroenterology, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Gaoshi Zhou
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Ying Wang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Li Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Jing Han
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Minhu Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Yao He
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Correspondence: Shenghong Zhang; Yao He, Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China, Email ;
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Yao Y, Kim G, Shafer S, Chen Z, Kubo S, Ji Y, Luo J, Yang W, Perner SP, Kanellopoulou C, Park AY, Jiang P, Li J, Baris S, Aydiner EK, Ertem D, Mulder DJ, Warner N, Griffiths AM, Topf-Olivestone C, Kori M, Werner L, Ouahed J, Field M, Liu C, Schwarz B, Bosio CM, Ganesan S, Song J, Urlaub H, Oellerich T, Malaker SA, Zheng L, Bertozzi CR, Zhang Y, Matthews H, Montgomery W, Shih HY, Jiang J, Jones M, Baras A, Shuldiner A, Gonzaga-Jauregui C, Snapper SB, Muise AM, Shouval DS, Ozen A, Pan KT, Wu C, Lenardo MJ. Mucus sialylation determines intestinal host-commensal homeostasis. Cell 2022; 185:1172-1188.e28. [PMID: 35303419 PMCID: PMC9088855 DOI: 10.1016/j.cell.2022.02.013] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 12/18/2021] [Accepted: 02/09/2022] [Indexed: 02/07/2023]
Abstract
Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.
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Affiliation(s)
- Yikun Yao
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA
| | - Girak Kim
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Samantha Shafer
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA
| | - Zuojia Chen
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Satoshi Kubo
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yanlong Ji
- Hematology/Oncology, Department of Medicine II, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany; Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany
| | - Jialie Luo
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Weiming Yang
- Section on Biological Chemistry, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD 20892, USA
| | - Sebastian P Perner
- Hematology/Oncology, Department of Medicine II, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany
| | - Chrysi Kanellopoulou
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ann Y Park
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ping Jiang
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jian Li
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Safa Baris
- Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University, 34722 Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Marmara University, 34722 Istanbul, Turkey
| | - Elif Karakoc Aydiner
- Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University, 34722 Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Marmara University, 34722 Istanbul, Turkey
| | - Deniz Ertem
- Marmara University School of Medicine, Division of Pediatric Gastroenterology Hepatology and Nutrition, 34854 Istanbul, Turkey
| | - Daniel J Mulder
- Departments of Pediatrics, Medicine, and Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Neil Warner
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Anne M Griffiths
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Chani Topf-Olivestone
- Pediatric Gastroenterology, Kaplan Medical Center, Pasternak St., POB 1, Rehovot 76100, Israel
| | - Michal Kori
- Pediatric Gastroenterology, Kaplan Medical Center, Pasternak St., POB 1, Rehovot 76100, Israel
| | - Lael Werner
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel
| | - Jodie Ouahed
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA
| | - Michael Field
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA
| | - Chengyu Liu
- Transgenic Core Facility, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA
| | - Benjamin Schwarz
- Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Catharine M Bosio
- Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Sundar Ganesan
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jian Song
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD 20892, USA
| | - Henning Urlaub
- Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany; Institute of Clinical Chemistry, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Thomas Oellerich
- Hematology/Oncology, Department of Medicine II, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany; German Cancer Consortium/German Cancer Research Center, 69120 Heidelberg, Germany
| | - Stacy A Malaker
- Yale University, Department of Chemistry, New Haven, CT 06511, USA
| | - Lixin Zheng
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA
| | - Carolyn R Bertozzi
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA
| | - Yu Zhang
- Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA
| | - Helen Matthews
- Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA
| | - Will Montgomery
- Neuro-Immune Regulome Unit, National Eye Institute, NIH, Bethesda, MD 20892, USA
| | - Han-Yu Shih
- Neuro-Immune Regulome Unit, National Eye Institute, NIH, Bethesda, MD 20892, USA
| | - Jiansheng Jiang
- Molecular Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA
| | - Marcus Jones
- Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Aris Baras
- Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Alan Shuldiner
- Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
| | - Claudia Gonzaga-Jauregui
- Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA; International Laboratory for Human Genome Research, Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Querétaro 04510, Mexico
| | - Scott B Snapper
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA
| | - Aleixo M Muise
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, IMS, and Biochemistry, University of Toronto, Toronto, ON M5G 1X8, Canada
| | - Dror S Shouval
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel
| | - Ahmet Ozen
- The Isil Berat Barlan Center for Translational Medicine, Marmara University, 34722 Istanbul, Turkey; Marmara University School of Medicine, Division of Pediatric Gastroenterology Hepatology and Nutrition, 34854 Istanbul, Turkey
| | - Kuan-Ting Pan
- Hematology/Oncology, Department of Medicine II, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany
| | - Chuan Wu
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
| | - Michael J Lenardo
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
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Coletto E, Latousakis D, Pontifex MG, Crost EH, Vaux L, Perez Santamarina E, Goldson A, Brion A, Hajihosseini MK, Vauzour D, Savva GM, Juge N. The role of the mucin-glycan foraging Ruminococcus gnavus in the communication between the gut and the brain. Gut Microbes 2022; 14:2073784. [PMID: 35579971 PMCID: PMC9122312 DOI: 10.1080/19490976.2022.2073784] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Ruminococcus gnavus is a prevalent member of the human gut microbiota, which is over-represented in inflammatory bowel disease and neurological disorders. We previously showed that the ability of R. gnavus to forage on mucins is strain-dependent and associated with sialic acid metabolism. Here, we showed that mice monocolonized with R. gnavus ATCC 29149 (Rg-mice) display changes in major sialic acid derivatives in their cecum content, blood, and brain, which is accompanied by a significant decrease in the percentage of sialylated residues in intestinal mucins relative to germ-free (GF) mice. Changes in metabolites associated with brain function such as tryptamine, indolacetate, and trimethylamine N-oxide were also detected in the cecal content of Rg-mice when compared to GF mice. Next, we investigated the effect of R. gnavus monocolonization on hippocampus cell proliferation and behavior. We observed a significant decrease of PSA-NCAM immunoreactive granule cells in the dentate gyrus (DG) of Rg-mice as compared to GF mice and recruitment of phagocytic microglia in the vicinity. Behavioral assessments suggested an improvement of the spatial working memory in Rg-mice but no change in other cognitive functions. These results were also supported by a significant upregulation of genes involved in proliferation and neuroplasticity. Collectively, these data provide first insights into how R. gnavus metabolites may influence brain regulation and function through modulation of granule cell development and synaptic plasticity in the adult hippocampus. This work has implications for further understanding the mechanisms underpinning the role of R. gnavus in neurological disorders.
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Affiliation(s)
- Erika Coletto
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK
| | - Dimitrios Latousakis
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK
| | - Matthew G Pontifex
- Norwich Medical School, Biomedical Research Centre, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
| | - Emmanuelle H Crost
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK
| | - Laura Vaux
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK
| | - Estella Perez Santamarina
- Norwich Medical School, Biomedical Research Centre, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
| | - Andrew Goldson
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK
| | - Arlaine Brion
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK
| | - Mohammad K Hajihosseini
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
| | - David Vauzour
- Norwich Medical School, Biomedical Research Centre, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
| | - George M Savva
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK
| | - Nathalie Juge
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK
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Brazil JC, Parkos CA. Finding the sweet spot: glycosylation mediated regulation of intestinal inflammation. Mucosal Immunol 2022; 15:211-222. [PMID: 34782709 PMCID: PMC8591159 DOI: 10.1038/s41385-021-00466-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 10/11/2021] [Accepted: 10/14/2021] [Indexed: 02/04/2023]
Abstract
Glycans are essential cellular components that facilitate a range of critical functions important for tissue development and mucosal homeostasis. Furthermore, specific alterations in glycosylation represent important diagnostic hallmarks of cancer that contribute to tumor cell dissociation, invasion, and metastasis. However, much less is known about how glycosylation contributes to the pathobiology of inflammatory mucosal diseases. Here we will review how epithelial and immune cell glycosylation regulates gut homeostasis and how inflammation-driven changes in glycosylation contribute to intestinal pathobiology.
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Affiliation(s)
- Jennifer C. Brazil
- grid.214458.e0000000086837370Department of Pathology, University of Michigan, Ann Arbor, MI 48109 USA
| | - Charles A. Parkos
- grid.214458.e0000000086837370Department of Pathology, University of Michigan, Ann Arbor, MI 48109 USA
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Lapaquette P, Bizeau JB, Acar N, Bringer MA. Reciprocal interactions between gut microbiota and autophagy. World J Gastroenterol 2021; 27:8283-8301. [PMID: 35068870 PMCID: PMC8717019 DOI: 10.3748/wjg.v27.i48.8283] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/09/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
A symbiotic relationship has set up between the gut microbiota and its host in the course of evolution, forming an interkingdom consortium. The gut offers a favorable ecological niche for microbial communities, with the whole body and external factors (e.g., diet or medications) contributing to modulating this microenvironment. Reciprocally, the gut microbiota is important for maintaining health by acting not only on the gut mucosa but also on other organs. However, failure in one or another of these two partners can lead to the breakdown in their symbiotic equilibrium and contribute to disease onset and/or progression. Several microbial and host processes are devoted to facing up the stress that could alter the symbiosis, ensuring the resilience of the ecosystem. Among these processes, autophagy is a host catabolic process integrating a wide range of stress in order to maintain cell survival and homeostasis. This cytoprotective mechanism, which is ubiquitous and operates at basal level in all tissues, can be rapidly down- or up-regulated at the transcriptional, post-transcriptional, or post-translational levels, to respond to various stress conditions. Because of its sensitivity to all, metabolic-, immune-, and microbial-derived stimuli, autophagy is at the crossroad of the dialogue between changes occurring in the gut microbiota and the host responses. In this review, we first delineate the modulation of host autophagy by the gut microbiota locally in the gut and in peripheral organs. Then, we describe the autophagy-related mechanisms affecting the gut microbiota. We conclude this review with the current challenges and an outlook toward the future interventions aiming at modulating host autophagy by targeting the gut microbiota.
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Affiliation(s)
- Pierre Lapaquette
- UMR PAM A 02.102, University Bourgogne Franche-Comté, Agrosup Dijon, Dijon 21000, France
| | - Jean-Baptiste Bizeau
- Eye and Nutrition Research Group, Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon 21000, France
| | - Niyazi Acar
- Eye and Nutrition Research Group, Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon 21000, France
| | - Marie-Agnès Bringer
- Eye and Nutrition Research Group, Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon 21000, France
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Abstract
The enzyme polypeptide N-acetylgalactosaminyltransferase like 6, encoded by the GALANTL6 gene, plays a role in the gut microbiome regarding regulation of short-chain fatty acids and their anti-inflammatory and resynthesis functions. It was hypothesized that the T allele of the GALNTL6 rs558129 polymorphism could have a positive effect on anaerobic metabolism. Thus, this study was performed to investigate the association between GALNTL6 rs558129 polymorphism and athletic performance in swimmers. A total of 147 Polish short distance (SDS) and 49 long distance swimmers (LDS) of national or international competitive levels and 379 controls were genotyped using the real-time polymerase chain reaction (real-time PCR). We found that the carriers of the T allele (CT+TT) had a 1.56 times higher chance of being SDS (odds ratio (OR): 95%CI 1.06-2.29) than the CC homozygotes. The T allele was overrepresented in the SDS compared with controls (33.7% vs. 25.7%, p = 0.025, OR 1.40, 95% CI 1.04-1.87), but no statistically significant differences were found for LDS. This study provides evidence for an association between the GALNTL6 rs558129 polymorphism and short distance swimming athlete status. Although more replication studies are needed, the preliminary data suggest an opportunity to use the analysis of GALNTL6 polymorphism along with other variants of candidate genes and standard phenotypic assessment in power-oriented sports selection.
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Sun J, Xue P, Liu J, Huang L, Lin G, Ran K, Yang J, Lu C, Zhao YZ, Xu HL. Self-Cross-Linked Hydrogel of Cysteamine-Grafted γ-Polyglutamic Acid Stabilized Tripeptide KPV for Alleviating TNBS-Induced Ulcerative Colitis in Rats. ACS Biomater Sci Eng 2021; 7:4859-4869. [PMID: 34547895 DOI: 10.1021/acsbiomaterials.1c00792] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
KPV (Lys-Pro-Val), which is a tripeptide derived from α-MSH (α-melanocyte-stimulating hormone), has an anti-inflammatory effect on colitis. However, KPV solution is very unstable when rectally administered, compromising its therapeutic efficacy. Herein, cysteamine-grafted γ-polyglutamic acid (SH-PGA) was synthesized by conjugating cysteamine with the carboxyl groups of γ-PGA. The synthesized SH-PGA has the thiol grafting amount of 4.5 ± 0.3 mmol/g. Without the use of the cross-linker, the SH-PGA hydrogel with 4% of the polymer was formed by self-cross-linking of thiol groups. Moreover, the formation of the SH-PGA hydrogel was not affected by KPV. The KPV/SH-PGA hydrogel presented higher elastic modulus (G') than the corresponding viscous modulus (G″) at 0.01-10 Hz, exhibiting good mechanical stability. The KPV/SH-PGA hydrogel presented a shear-thinning behavior, which was helpful for rectal administration. Only 30% of KPV was released from the KPV/SH-PGA hydrogel within 20 min, followed by a sustained-release behavior. Importantly, the stability of KPV in the SH-PGA hydrogel was obviously enhanced, which was presented by detecting its anti-inflammatory activity and promoting cell migration potential after 2 h of exposure to 37 °C. The enhanced therapeutic effect of the KPV/SH-PGA hydrogel on colitis was confirmed on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ulcerative colitis rats. The colitis symptoms including body weight loss and the disease activity index score were obviously attenuated by rectally administering the KPV/SH-PGA hydrogel. Besides, the KPV/SH-PGA hydrogel treatment prevented the colon shortening of TNBS-infused rats and decreased the colonic myeloperoxidase level. The morphology of the colon including the epithelial barrier, crypt, and intact goblet cells was recovered after KPV/SH-PGA hydrogel treatment. Besides, the KPV/SH-PGA hydrogel decreased the expression of proinflammatory cytokines such as tumor necrosis factor α and interleukin 6. Collectively, the KPV/SH-PGA hydrogel may provide a promising strategy for the treatment of ulcerative colitis.
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Affiliation(s)
- Jie Sun
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Pengpeng Xue
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Jiayi Liu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Lantian Huang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Gaolong Lin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Kunjie Ran
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Jiaojiao Yang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Cuitao Lu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Ying-Zheng Zhao
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - He-Lin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
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Ebrahim HA, Elsherbini DMA. Renovation of Intestinal Barrier by Polydatin in Experimentally Induced Ulcerative Colitis: Comparative Ultrastructural Study with L-Carnosine. Cells Tissues Organs 2021; 210:275-292. [PMID: 34461611 DOI: 10.1159/000516191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 03/26/2021] [Indexed: 11/19/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with intestinal epithelial barrier impairment. Polydatin (PD), a natural product isolated from Polygonum cuspidatum, is known to have an anti-inflammatory, antioxidant, and antiapoptotic effect. We attempted to compare the protective impact of PD pretreatment on alterations to the intestinal epithelial barrier and the colonic wall's ultrastructure accompanying ulcerative colitis to other conventional drugs in practice, primarily L-carnosine, which has not been addressed before. The rats were divided into 5 groups; 3 of them were treated with sulphasalazine (500 mg/kg), L-carnosine (30 mg/kg), and PD (45 mg/kg). All groups were administered their respective drugs 3 days before the UC was induced by acetic acid intra-rectally, and the treatment was continued until the 11th day. The disease activity index (DAI) was estimated, and a macroscopic scoring was established for the harvested colonic tissue. The tissues were extracted and processed for hematoxylin and eosin staining, caspase-3 immunohistochemical staining, electron microscopy, and biochemical analysis evaluating proinflammatory markers (IL-1β, TNF-α, and IL-6), myeloperoxidase (MPO), oxidative stress, and lipid peroxidation. Histopathological examination of colonic tissue showed that PD pretreatment effectively restored mucosal epithelial cells, intercellular tight junctions, goblet cells, and maintained the intestinal epithelial and endothelial barriers. PD suppressed MPO, proinflammatory markers, and malondialdehyde but enhanced superoxide dismutase and glutathione levels. It also hampered apoptosis, as evidenced by a reduction in caspase-3 expression. PD showed a significantly better response in preserving the intestinal epithelial barrier against acetic acid-induced colitis as compared to sulphasalazine and L-carnosine. These findings demonstrate the therapeutic role of PD for patients with UC.
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Affiliation(s)
- Hasnaa Ali Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.,Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Kostopoulos I, Aalvink S, Kovatcheva-Datchary P, Nijsse B, Bäckhed F, Knol J, de Vos WM, Belzer C. A Continuous Battle for Host-Derived Glycans Between a Mucus Specialist and a Glycan Generalist in vitro and in vivo. Front Microbiol 2021; 12:632454. [PMID: 34248864 PMCID: PMC8264420 DOI: 10.3389/fmicb.2021.632454] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 05/18/2021] [Indexed: 01/14/2023] Open
Abstract
The human gastrointestinal tract is colonized by a diverse microbial community, which plays a crucial role in human health. In the gut, a protective mucus layer that consists of glycan structures separates the bacteria from the host epithelial cells. These host-derived glycans are utilized by bacteria that have adapted to this specific compound in the gastrointestinal tract. Our study investigated the close interaction between two distinct gut microbiota members known to use mucus glycans, the generalist Bacteroides thetaiotaomicron and the specialist Akkermansia muciniphila in vitro and in vivo. The in vitro study, in which mucin was the only nutrient source, indicated that B. thetaiotaomicron significantly upregulated genes coding for Glycoside Hydrolases (GHs) and mucin degradation activity when cultured in the presence of A. muciniphila. Furthermore, B. thetaiotaomicron significantly upregulated the expression of a gene encoding for membrane attack complex/perforin (MACPF) domain in co-culture. The transcriptome analysis also indicated that A. muciniphila was less affected by the environmental changes and was able to sustain its abundance in the presence of B. thetaiotaomicron while increasing the expression of LPS core biosynthesis activity encoding genes (O-antigen ligase, Lipid A and Glycosyl transferases) as well as ABC transporters. Using germ-free mice colonized with B. thetaiotaomicron and/or A. muciniphila, we observed a more general glycan degrading profile in B. thetaiotaomicron while the expression profile of A. muciniphila was not significantly affected when colonizing together, indicating that two different nutritional niches were established in mice gut. Thus, our results indicate that a mucin degrading generalist adapts to its changing environment, depending on available carbohydrates while a mucin degrading specialist adapts by coping with competing microorganism through upregulation of defense related genes.
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Affiliation(s)
| | - Steven Aalvink
- Laboratory of Microbiology, Wageningen University, Wageningen, Netherlands
| | - Petia Kovatcheva-Datchary
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Bart Nijsse
- Laboratory of Systems and Synthetic Biology, Wageningen University, Wageningen, Netherlands
| | - Fredrik Bäckhed
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Jan Knol
- Laboratory of Microbiology, Wageningen University, Wageningen, Netherlands.,Danone Nutricia Research, Utrecht, Netherlands
| | - Willem M de Vos
- Laboratory of Microbiology, Wageningen University, Wageningen, Netherlands.,Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Clara Belzer
- Laboratory of Microbiology, Wageningen University, Wageningen, Netherlands
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Lili Q, Xiaohui L, Haiguang M, Jinbo W. Clostridium butyricum Induces the Production and Glycosylation of Mucins in HT-29 Cells. Front Cell Infect Microbiol 2021; 11:668766. [PMID: 34222040 PMCID: PMC8248542 DOI: 10.3389/fcimb.2021.668766] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 06/01/2021] [Indexed: 11/24/2022] Open
Abstract
C. butyricum is a common gut commensal bacterium, which has many positive functions in human intestine. In this study, we investigated the effects of monosaccharide and its derivatives on the adhesion of C. butyricum to the mucus of HT-29 cells. RNA interference was performed to assess the roles of MUC2 and glycan in the adhesion of C. butyricum to HT-29 cells. The effects of C. butyricum on the glycosylation of mucins were assayed with fluorescence microscope. The expression levels of mucins and glycotransferases were also determined. The results showed that C. butyricum could adhere to the mucins secreted by HT-29 cells. Several kinds of monosaccharides inhibited the adhesion of C. butyricum to HT-29 cells, which suggested that the mucus glycan was the attaching sites of this bacterium. Knockdown of MUC2, FUT2 or GALNT7 significantly decreased the numbers of the bacteria adhering to HT-29 cells. When colonizing on the surface of HT-29 cells, C. butyricum could increase the production of mucins, promote the expression of glycotransferase, and induce the glycosylation of mucins. These results demonstrated that the glycan of mucus played important roles in the adhesion of C. butyricum to HT-29 cells. This study indicates for the first time that C. butyricum possesses the ability to modulate the glycosylation profile of mucus secreted by HT-29 cells. These findings contribute to understanding the mechanism of interaction between colonic epithelial cells and commensal bacteria.
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Affiliation(s)
- Qi Lili
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
| | - Lu Xiaohui
- Research Department, Ningbo Biomart Lifetech Co.Ltd, Ningbo, China
| | - Mao Haiguang
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
| | - Wang Jinbo
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
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Liu AR, Yang SP, Zhang XL. Effects of interaction between mesenchymal stem cells and gut microbiota in treatment of inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2021; 29:312-318. [DOI: 10.11569/wcjd.v29.i6.312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Ai-Ru Liu
- Department of Gastroenterology, the Second Hospital of Hebei Medical University, Shijiazhuang 050035, Hebei Province, China
| | - Shao-Peng Yang
- Department of Gastroenterology, the Second Hospital of Hebei Medical University, Shijiazhuang 050035, Hebei Province, China
| | - Xiao-Lan Zhang
- Department of Gastroenterology, the Second Hospital of Hebei Medical University, Shijiazhuang 050035, Hebei Province, China
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Liu Y, Peng FX. Research progress on O-GlcNAcylation in the occurrence, development, and treatment of colorectal cancer. World J Gastrointest Surg 2021; 13:96-115. [PMID: 33643531 PMCID: PMC7898190 DOI: 10.4240/wjgs.v13.i2.96] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 12/21/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023] Open
Abstract
For a long time, colorectal cancer (CRC) has been ranked among the top cancer-related mortality rates, threatening human health. As a significant post-translational modification, O-GlcNAcylation plays an essential role in complex life activities. Related studies have found that the occurrence, development, and metastasis of CRC are all related to abnormal O-GlcNAcylation and participate in many critical biological processes, such as gene transcription, signal transduction, cell growth, and differentiation. Recently, nucleotide sugar analogs, tumor-specific carbohydrate vaccine, SIRT1 longevity gene, dendritic cells as targets, and NOTCH gene have become effective methods to induce antitumor therapy. Not long ago, checkpoint kinase 1 and checkpoint kinase 2 were used as therapeutic targets for CRC, but there are still many problems to be solved. With an in-depth study of protein chip, mass spectrometry, chromatography, and other technologies, O-GlcNAcylation research will accelerate rapidly, which may provide new ideas for the research and development of antitumor drugs and the discovery of new CRC diagnostic markers.
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Affiliation(s)
- Yao Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of North Sichuan Medical College, Mianyang 621000, Sichuan Province, China
- Department of Gastrointestinal Surgery, Sichuan Mianyang 404 Hospital, Mianyang 621000, Sichuan Province, China
| | - Fang-Xing Peng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of North Sichuan Medical College, Mianyang 621000, Sichuan Province, China
- Department of Gastrointestinal Surgery, Sichuan Mianyang 404 Hospital, Mianyang 621000, Sichuan Province, China
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