Precision editing of the gut microbiota ameliorates colitis

Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis, characterized by changes in gut microbial communities that include an expansion of facultative anaerobic bacteria of the Enterobacteriaceae family (phylum Proteobacteria). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum-cofactor-dependent microbial respiratory pathways that are operational only during episodes of inflammation. By contrast, we found that tungstate treatment caused minimal changes in the microbiota composition under homeostatic conditions. Notably, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in mouse models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the inflamed gut.

[1]  Ryan D. Hernandez,et al.  Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism , 2013, Science Translational Medicine.

[2]  V. Stewart,et al.  Identification and expression of genes narL and narX of the nar (nitrate reductase) locus in Escherichia coli K-12 , 1988, Journal of bacteriology.

[3]  B. Finlay,et al.  Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. , 2007, Cell host & microbe.

[4]  T. Bobik,et al.  The Alternative Electron Acceptor Tetrathionate Supports B12-Dependent Anaerobic Growth ofSalmonella enterica Serovar Typhimurium on Ethanolamine or 1,2-Propanediol , 2001, Journal of bacteriology.

[5]  Cara L. Wilhelm,et al.  Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-γ-dependent elimination of Paneth cells , 2012, Nature Immunology.

[6]  Philipp C. Münch,et al.  Genome-guided design of a defined mouse microbiota that 1 confers colonization resistance against Salmonella enterica 2 serovar Typhimurium 3 , 2018 .

[7]  G. Núñez,et al.  Regulated Virulence Controls the Ability of a Pathogen to Compete with the Gut Microbiota , 2012, Science.

[8]  Sanjai J. Parikh,et al.  Host-Derived Nitrate Boosts Growth of E. coli in the Inflamed Gut , 2013, Science.

[9]  R. Hay,et al.  Nuclear retention of IkappaBalpha protects it from signal-induced degradation and inhibits nuclear factor kappaB transcriptional activation. , 1999, The Journal of biological chemistry.

[10]  D. Theriaque,et al.  Intestinal microbial ecology in premature infants assessed with non-culture-based techniques. , 2010, The Journal of pediatrics.

[11]  D. Richardson,et al.  Properties of the periplasmic nitrate reductases from Paracoccus pantotrophus and Escherichia coli after growth in tungsten-supplemented media. , 2003, FEMS microbiology letters.

[12]  M. Stolte,et al.  Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine , 2004, Gut.

[13]  B. Decallonne,et al.  The use of real-time reverse transcriptase PCR for the quantification of cytokine gene expression. , 2003, Journal of biomolecular techniques : JBT.

[14]  S. Winter,et al.  The Vi‐capsule prevents Toll‐like receptor 4 recognition of Salmonella , 2008, Cellular microbiology.

[15]  Jill K Thompson,et al.  Nuclear Retention of IκBα Protects It from Signal-induced Degradation and Inhibits Nuclear Factor κB Transcriptional Activation* , 1999, The Journal of Biological Chemistry.

[16]  Pietro Liò,et al.  FisHiCal: an R package for iterative FISH-based calibration of Hi-C data , 2014, Bioinform..

[17]  J. Schölmerich,et al.  The role of the resident intestinal flora in acute and chronic dextran sulfate sodium‐induced colitis in mice , 2000, European journal of gastroenterology & hepatology.

[18]  N. Pace,et al.  Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases , 2007, Proceedings of the National Academy of Sciences.

[19]  E. Denou,et al.  The Role of Pathogenic Microbes and Commensal Bacteria in Irritable Bowel Syndrome , 2010, Digestive Diseases.

[20]  Wendy S. Garrett,et al.  Communicable Ulcerative Colitis Induced by T-bet Deficiency in the Innate Immune System , 2007, Cell.

[21]  Na-Ri Shin,et al.  Proteobacteria: microbial signature of dysbiosis in gut microbiota. , 2015, Trends in biotechnology.

[22]  P. Rutgeerts,et al.  Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection. , 1995, Gastroenterology.

[23]  D. Monack,et al.  Contribution of Flagellin Pattern Recognition to Intestinal Inflammation during Salmonella enterica Serotype Typhimurium Infection , 2009, Infection and Immunity.

[24]  R. Edwards,et al.  Microcins mediate competition among Enterobacteriaceae in the inflamed gut , 2016, Nature.

[25]  Richard A. Flavell,et al.  NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis , 2011, Cell.

[26]  W. Reindl,et al.  The Gut Microbiome in Inflammatory Bowel Diseases: Diagnostic and Therapeutic Implications , 2019, Visceral Medicine.

[27]  William A. Walters,et al.  QIIME allows analysis of high-throughput community sequencing data , 2010, Nature Methods.

[28]  S. Winter,et al.  The dynamics of gut‐associated microbial communities during inflammation , 2013, EMBO reports.

[29]  R. F. Wang,et al.  Construction of versatile low-copy-number vectors for cloning, sequencing and gene expression in Escherichia coli. , 1991, Gene.

[30]  C. Prantera,et al.  An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. , 1996, The American journal of gastroenterology.

[31]  A. Pühler,et al.  A Broad Host Range Mobilization System for In Vivo Genetic Engineering: Transposon Mutagenesis in Gram Negative Bacteria , 1983, Bio/Technology.

[32]  A. Torres,et al.  Escherichia coli isolated from a Crohn's disease patient adheres, invades, and induces inflammatory responses in polarized intestinal epithelial cells. , 2008, International journal of medical microbiology : IJMM.

[33]  Zhengwei Zhu,et al.  CD-HIT: accelerated for clustering the next-generation sequencing data , 2012, Bioinform..

[34]  R. Sartor,et al.  Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. , 2005, Gastroenterology.

[35]  Michael D. George,et al.  T Cells Help To Amplify Inflammatory Responses Induced by Salmonella enterica Serotype Typhimurium in the Intestinal Mucosa , 2008, Infection and Immunity.

[36]  J. Revillard,et al.  Immortalization of mouse intestinal epithelial cells by the SV40-large T gene. Phenotypic and immune characterization of the MODE-K cell line. , 1993, Journal of immunological methods.

[37]  J. Burgess,et al.  Improvement of phylum- and class-specific primers for real-time PCR quantification of bacterial taxa. , 2011, Journal of microbiological methods.

[38]  Adam Godzik,et al.  Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences , 2006, Bioinform..

[39]  J. Roth,et al.  Gut inflammation provides a respiratory electron acceptor for Salmonella , 2010, Nature.

[40]  G. Dougan,et al.  Salmonella enterica Serovar Typhimurium Exploits Inflammation to Compete with the Intestinal Microbiota , 2007, PLoS biology.

[41]  P. Srivastava,et al.  Multipartite Regulation of rctB, the Replication Initiator Gene of Vibrio cholerae Chromosome II , 2005, Journal of bacteriology.

[42]  S. Cherry,et al.  Microbial Respiration and Formate Oxidation as Metabolic Signatures of Inflammation-Associated Dysbiosis. , 2017, Cell host & microbe.

[43]  N. Salzman,et al.  Enteric Salmonellosis Disrupts the Microbial Ecology of the Murine Gastrointestinal Tract , 2007, Infection and Immunity.

[44]  Maria Karlsson,et al.  Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. , 2010, Cell host & microbe.

[45]  S. Winter,et al.  A Salmonella Virulence Factor Activates the NOD1/NOD2 Signaling Pathway , 2011, mBio.