Fecal Microbiota Transplantation Reduces Susceptibility to Epithelial Injury and Modulates Tryptophan Metabolism of Microbial Community in a Piglet Model

Background and Aims: Fecal microbiota transplantation [FMT] has shown promise as a treatment for inflammatory bowel disease [IBD]. Using a piglet model, our previous study indicated that exogenous fecal microbiota can enhance gastrointestinal health through enhancing intestinal barrier. However, specific connections between FMT-induced microbial changes and modulation of intestinal barrier still remain to be fully illustrated. Here, we aimed to determine the potential role of metabolic function of gut microbiota in the beneficial effects of FMT. Methods: The influence of FMT on the maintenance of intestinal homeostasis was assessed by early-life gut microbiota intervention on newborn piglets and subsequent lipopolysaccharide [LPS] challenge. Analysis of the gut microbiome and metabolome was carried out by 16S rRNA sequencing and multiple mass spectrometry platforms. Results: FMT modulated the diversity and composition of colonic microbiota and reduced the susceptibility to LPS-induced destruction of epithelial integrity and severe inflammatory response. Metabolomic analysis revealed functional changes of the gut metabolome along with significant increase of typical microbiota-derived tryptophan catabolite indole-3-acetic acid in the colonic lumen. Further, metagenomics prediction analysis based on 16S rRNA sequencing also demonstrated that FMT modulated the metabolic functions of gut microbiota associated with tryptophan metabolism and intestinal homeostasis, which coincided with Downloaded from https://academic.oup.com/ecco-jcc/advance-article-abstract/doi/10.1093/ecco-jcc/jjy103/5053909 by University of Durham user on 16 July 2018 Ac ce pt ed M an us cr ipt Manuscript Doi: 10.1093/ecco-jcc/jjy103 up-regulation of cytokine interleukin-22 and enhanced activation of aryl hydrocarbon receptor in the recipient colon. Conclusions: Our data reveal a regulatory effect of FMT on tryptophan metabolism of gut microbiota in the recipient colon, which may play a potential role in the maintenance of intestinal barrier.

[1]  M. Mclaughlin,et al.  Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells , 2018, Nature Communications.

[2]  D. Misceo,et al.  Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy , 2018, Nature Genetics.

[3]  Shijie Geng,et al.  Exogenous Fecal Microbiota Transplantation from Local Adult Pigs to Crossbred Newborn Piglets , 2018, Front. Microbiol..

[4]  F. Gomes,et al.  Transforming Growth Factor β1/SMAD Signaling Pathway Activation Protects the Intestinal Epithelium from Clostridium difficile Toxin A-Induced Damage , 2017, Infection and Immunity.

[5]  J. Sperry,et al.  Mushroom-Derived Indole Alkaloids. , 2017, Journal of natural products.

[6]  K. Shankar,et al.  Formula diet driven microbiota shifts tryptophan metabolism from serotonin to tryptamine in neonatal porcine colon , 2017, Microbiome.

[7]  S. Ghosh,et al.  Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System. , 2017, Cell metabolism.

[8]  M. Kamm,et al.  Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial , 2017, The Lancet.

[9]  E. Elinav,et al.  Microbiome-Modulated Metabolites at the Interface of Host Immunity , 2017, The Journal of Immunology.

[10]  M. Hepworth,et al.  Functional and phenotypic heterogeneity of group 3 innate lymphoid cells , 2017, Immunology.

[11]  A. Khoruts,et al.  Understanding the mechanisms of faecal microbiota transplantation , 2016, Nature Reviews Gastroenterology &Hepatology.

[12]  Hua Mao,et al.  Fecal Microbiota Transplantation for Ulcerative Colitis: A Systematic Review and Meta-Analysis , 2016, PloS one.

[13]  B. Marsland.  Regulating inflammation with microbial metabolites , 2016, Nature Medicine.

[14]  Yizhen Wang,et al.  High therapeutic efficacy of Cathelicidin-WA against postweaning diarrhea via inhibiting inflammation and enhancing epithelial barrier in the intestine , 2016, Scientific Reports.

[15]  R. Xavier,et al.  CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands , 2016, Nature Medicine.

[16]  M. Liao,et al.  Beneficial Effects of Fecal Microbiota Transplantation on Ulcerative Colitis in Mice , 2016, Digestive Diseases and Sciences.

[17]  R. Jenq,et al.  Interleukin-22 Promotes Intestinal Stem Cell-Mediated Epithelial Regeneration , 2015, Nature.

[18]  P. Thacker,et al.  Dietary Sodium Butyrate Decreases Postweaning Diarrhea by Modulating Intestinal Permeability and Changing the Bacterial Communities in Weaned Piglets. , 2015, The Journal of nutrition.

[19]  A. Rezaei,et al.  Metabolites of Dietary Protein and Peptides by Intestinal Microbes and their Impacts on Gut. , 2015, Current protein & peptide science.

[20]  F. Shanahan,et al.  Manipulation of the microbiota for treatment of IBS and IBD-challenges and controversies. , 2014, Gastroenterology.

[21]  A. Kostic,et al.  The microbiome in inflammatory bowel disease: current status and the future ahead. , 2014, Gastroenterology.

[22]  Bo Li,et al.  Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection , 2014, Nature Communications.

[23]  H. Yi,et al.  Changes in gut microbial populations, intestinal morphology, expression of tight junction proteins, and cytokine production between two pig breeds after challenge with Escherichia coli K88: a comparative study. , 2013, Journal of animal science.

[24]  A. De Luca,et al.  Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. , 2013, Immunity.

[25]  T. Yoshimoto,et al.  Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases , 2013, Clinical & developmental immunology.

[26]  Xudong Xu,et al.  Indole-3-Acetic Acid Production by Endophytic Streptomyces sp. En-1 Isolated from Medicinal Plants , 2013, Current Microbiology.

[27]  L. Stronati,et al.  Characterization of adherent‐invasive Escherichia coli isolated from pediatric patients with inflammatory bowel disease , 2012, Inflammatory bowel diseases.

[28]  Liang Zhou,et al.  The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. , 2012, Immunity.

[29]  C. Garlanda,et al.  AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch , 2011, Nature Immunology.

[30]  A. Rizzo,et al.  Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. , 2011, Gastroenterology.

[31]  T. Yoshimoto,et al.  Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor , 2010, Proceedings of the National Academy of Sciences.

[32]  I. Penttila.  Milk-derived transforming growth factor-beta and the infant immune response. , 2010, The Journal of pediatrics.

[33]  S. Hogan,et al.  Intestinal barrier function: molecular regulation and disease pathogenesis. , 2009, The Journal of allergy and clinical immunology.

[34]  Guoyao Wu,et al.  l-Glutamine or l-alanyl-l-glutamine prevents oxidant- or endotoxin-induced death of neonatal enterocytes , 2009, Amino Acids.

[35]  X. Hua,et al.  Inter-species transplantation of gut microbiota from human to pigs , 2007, The ISME Journal.

[36]  R. Mrsny,et al.  Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. , 2005, The Journal of clinical investigation.

[37]  J. Mei,et al.  Transient changes of transforming growth factor-β expression in the small intestine of the pig in association with weaning , 2005, British Journal of Nutrition.

[38]  A. Keshavarzian,et al.  Intestinal barrier: An interface between health and disease , 2003, Journal of gastroenterology and hepatology.

[39]  R. Smeets,et al.  Transforming Growth Factor-β2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling , 2002, British Journal of Cancer.

[40]  B. Halkier,et al.  Cytochrome P450 CYP79B2 from Arabidopsis Catalyzes the Conversion of Tryptophan to Indole-3-acetaldoxime, a Precursor of Indole Glucosinolates and Indole-3-acetic Acid* , 2000, The Journal of Biological Chemistry.

[41]  S. Ben‐Sasson,et al.  Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation , 1992, The Journal of cell biology.

[42]  D. Artis,et al.  Functional biology of the IL-22-IL-22R pathway in regulating immunity and inflammation at barrier surfaces. , 2010, Advances in immunology.

[43]  Jay K Kolls,et al.  The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation , 2022 .

[44]  Thomas D. Schmittgen,et al.  Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2 2 DD C T Method , 2022 .