Reprogrammed and transmissible intestinal microbiota confer diminished susceptibility to induced colitis in TMF
            <sup>−/−</sup>
            mice

Bel, Shai; Elkis, Yoav; Elifantz, Hila; Koren, Omry; Ben‐Hamo, Rotem; Lerer-Goldshtein, Tal; Rahimi, Roni; Horin, Shomron Ben; Nyska, Abraham; Shpungin, Sally; Nir, Uri

doi:10.1073/pnas.1319114111

Cited by 54 publications

(43 citation statements)

References 32 publications

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“…Moreover, this polymeric Muc2 dissociates almost completely after reduction by DTT or sulfide, supporting the hypothesis that S-S bond splitting by sulfide opens the mucus barrier. This hypothesis is supported further by the recent finding that increasing the number of S-S bonds in the Muc2 network increases the mucus barrier in mouse colon (25).…”

Section: Discussionsupporting

confidence: 63%

Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon

Ijssennagger

Belzer

Hooiveld

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

340

239

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Colorectal cancer risk is associated with diets high in red meat. Heme, the pigment of red meat, induces cytotoxicity of colonic contents and elicits epithelial damage and compensatory hyperproliferation, leading to hyperplasia. Here we explore the possible causal role of the gut microbiota in heme-induced hyperproliferation. To this end, mice were fed a purified control or heme diet (0.5 μmol/g heme) with or without broad-spectrum antibiotics for 14 d. Heme-induced hyperproliferation was shown to depend on the presence of the gut microbiota, because hyperproliferation was completely eliminated by antibiotics, although heme-induced luminal cytotoxicity was sustained in these mice. Colon mucosa transcriptomics revealed that antibiotics block heme-induced differential expression of oncogenes, tumor suppressors, and cell turnover genes, implying that antibiotic treatment prevented the hemedependent cytotoxic micelles to reach the epithelium. Our results indicate that this occurs because antibiotics reinforce the mucus barrier by eliminating sulfide-producing bacteria and mucin-degrading bacteria (e.g., Akkermansia). Sulfide potently reduces disulfide bonds and can drive mucin denaturation and microbial access to the mucus layer. This reduction results in formation of trisulfides that can be detected in vitro and in vivo. Therefore, trisulfides can serve as a novel marker of colonic mucolysis and thus as a proxy for mucus barrier reduction. In feces, antibiotics drastically decreased trisulfides but increased mucin polymers that can be lysed by sulfide. We conclude that the gut microbiota is required for hemeinduced epithelial hyperproliferation and hyperplasia because of the capacity to reduce mucus barrier function.colorectal cancer | red meat | mucus barrier | mucolysis | (tri)sulfides

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Section: Discussionsupporting

confidence: 63%

Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon

Ijssennagger

Belzer

Hooiveld

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

340

239

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“…In mice, interleukin-10 (IL-10) aids in preserving the mucus barrier in the intestine and alleviates colitis by preventing the misfolding of MUC2 and maintaining mucin production by GCs (42). Increased secretion of granular MUC2 by GCs in mice lacking the Tata element modulatory factor (TMF/ARA160) facilitates the growth of beneficial Lactobacillus species and uncultured members of the Ruminococcaceae and Roseburia, thereby endowing these mice with a transmissible reduced sensitivity to induced colitis (43). In the present study, administration of moderate-dose BLS mix increased the expression of MUC2 mRNA in the ileum, facilitating expansion of Lactobacillus populations and in turn enhancing the mucus barrier and activating the intestinal immune response to F4 ϩ ETEC challenge.…”

Section: Discussionmentioning

confidence: 99%

Oral Administration of a Select Mixture of Bacillus Probiotics Affects the Gut Microbiota and Goblet Cell Function following Escherichia coli Challenge in Newly Weaned Pigs of Genotype MUC4 That Are Supposed To Be Enterotoxigenic E. coli F4ab/ac Receptor Negative

Zhang

Zhu

Zhou

et al. 2017

Appl Environ Microbiol

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Structural disruption of the gut microbiota and impaired goblet cell function are collateral etiologic factors in enteric diseases. Low, moderate, or high doses of a Bacillus licheniformis-B. subtilis mixture (BLS mix) were orally administered to piglets of genotype MUC4 that are supposed to be F4-expressing enterotoxigenic Escherichia coli strain (F4 ϩ ETEC) F4ab/ac receptor negative (i.e., MUC4-resistant piglets) for 1 week before F4 ϩ ETEC challenge. The luminal contents were collected from the mucosa of the colon on day 8 after F4 ϩ ETEC challenge. The BLS mix attenuated E. coli-induced expansion of Bacteroides uniformis, Eubacterium eligens, Acetanaerobacterium, and Sporobacter populations. Clostridium and Turicibacter populations increased following F4 ϩ ETEC challenge in pigs pretreated with low-dose BLS mix. Lactobacillus gasseri and Lactobacillus salivarius populations increased after administration of BLS mix during E. coli infection. The beneficial effects of BLS mix were due in part to the expansion of certain Clostridium, Lactobacillus, and Turicibacter populations, with a corresponding increase in the number of goblet cells in the ileum via upregulated Atoh1 expression, in turn increasing MUC2 production and thus preserving the mucus barrier and enhancing host defenses against enteropathogenic bacteria. However, excessive BLS mix consumption may increase the risk for enteritis, partly through disruption of colonic microbial ecology, characterized by expansion of Proteobacteria and impaired goblet cell function in the ileum. Our findings suggest that oral administration of BLS mix reprograms the gut microbiota and enhances goblet cell function to ameliorate enteritis.IMPORTANCE The present study is important for improving our understanding of the protective role of probiotics against Escherichia coli infection in piglets. Structural disruption of the gut microbiota and impaired goblet cell function are collateral etiologic factors in enteric diseases. In this study, low, moderate, or high doses of a Bacillus licheniformis-B. subtilis mixture (BLS mix) were orally administered to MUC4-resistant piglets for 1 week before the F4-expressing ETEC strain (F4 ϩ ETEC) challenge. Our findings suggest that oral administration of BLS mix reprograms the gut microbiota and enhances goblet cell function to ameliorate enteritis. KEYWORDS

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“…Co-housing relies on passive transfer of GM and results in hybridization of microbiota from the two cohoused animals. Because of this, successful phenotype transfer provides strong support for a GM influence, but a lack of phenotype transfer does not necessarily eliminate a contribution of the GM to the phenotype 18, 101, 102 .…”

Section: Co-housing As a Means To Address Lack Of Reproducibilitymentioning

confidence: 99%

Microbiota and reproducibility of rodent models

2017

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The gut microbiota (GM) plays a critical role in human health and disease. Likewise, it is becoming increasingly evident that changes or disruptions to the GM can have significant effects on animal models and their expressed phenotypes, adding a complex and important variable into basic research and pre-clinical studies. In this article, we review some of the most common sources of GM variability in rodent models, and discuss measures to address this variability for improved reproducibility.

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Reprogrammed and transmissible intestinal microbiota confer diminished susceptibility to induced colitis in TMF ^−/− mice

Cited by 54 publications

References 32 publications

Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon

Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon

Oral Administration of a Select Mixture of Bacillus Probiotics Affects the Gut Microbiota and Goblet Cell Function following Escherichia coli Challenge in Newly Weaned Pigs of Genotype MUC4 That Are Supposed To Be Enterotoxigenic E. coli F4ab/ac Receptor Negative

Microbiota and reproducibility of rodent models

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Reprogrammed and transmissible intestinal microbiota confer diminished susceptibility to induced colitis in TMF −/− mice

Cited by 54 publications

References 32 publications

Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon

Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon

Oral Administration of a Select Mixture of Bacillus Probiotics Affects the Gut Microbiota and Goblet Cell Function following Escherichia coli Challenge in Newly Weaned Pigs of Genotype MUC4 That Are Supposed To Be Enterotoxigenic E. coli F4ab/ac Receptor Negative

Microbiota and reproducibility of rodent models

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Reprogrammed and transmissible intestinal microbiota confer diminished susceptibility to induced colitis in TMF ^−/− mice