Germ-free and Antibiotic-treated Mice are Highly Susceptible to Epithelial Injury in DSS Colitis

Hernández‐Chirlaque, Cristina; Aranda, Carlos J.; Ocón, Borja; Capitán-Cañadas, Fermín; Ortega‐González, Mercedes; Carrero, Juan Jesús; Suárez, Marı́a Dolores; Zarzuelo, Antonio; Martínez‐Augustin, Olga

doi:10.1093/ecco-jcc/jjw096

Cited by 217 publications

(158 citation statements)

References 46 publications

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“…Preliminary data also suggests other IL-1 family members are not required for steady-state LTi cell activation, suggesting that cells at SILT actively survey the microbiota and elicit Il22 activity regardless of SILT size or the presence or absence of B cells. Therefore, our work adds to a number of previous studies (37–42) highlighting the importance of a replete intestinal flora for steady-state IL-22 levels. These results are, however, contradicted by a previous report (43) showing diminishing activity from LTi cells taken from 8 week-old compared to 2 week-old mice, and suppression of IL-22 by the microbiota.…”

Section: Discussionmentioning

confidence: 68%

The Development of Steady-State Activation Hubs between Adult LTi ILC3s and Primed Macrophages in Small Intestine

Savage

Liang

Locksley

2017

The Journal of Immunology

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Group 3 innate lymphoid cells (ILC3s) are important for intestinal health, particularly in controlling inflammation in response to epithelial dysregulation, but their role during homeostasis remains less well understood. We generated IL-22 reporter mice to assess production of this key cytokine by ILC3s in the small intestine during development and under basal conditions. Although IL-22 is produced by a variety of lymphocyte populations, constitutively high IL-22 expression was limited to lymphoid-tissue inducer (LTi) cells residing in lymph node-like structures in the gut called small intestinal lymphoid tissues (SILT). Constitutive IL-22 expression was dependent on the microbiota and MyD88 signaling, appeared upon weaning, and was present across the spectrum of SILT, including in cryptopatches. Activated SILT LTi cells colocalized with a rare subpopulation of activated macrophages constitutively positive for IL-12/23 p40 and capable of activating neonatal LTi cells in response to TLR stimulus. Thus, weaning leads to the organization of innate immune activation hubs at SILT that mature and are continuously sustained by signals from the microbiota. This functional and anatomic organization constitutes a significant portion of the steady-state IL-23/IL-22 axis.

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Section: Discussionmentioning

confidence: 68%

The Development of Steady-State Activation Hubs between Adult LTi ILC3s and Primed Macrophages in Small Intestine

Savage

Liang

Locksley

2017

The Journal of Immunology

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“…The Il-10 −/− model is highly dependent on the intestinal commensal flora and subsequent germfree studies evaluating Irak-m expression further suggest that Irak-m −/− sensitivity in this experimental colitis model is dependent on the composition of the resident GI microbiota (Biswas et al, 2011). The microbiota composition cannot be underestimated for DSS based models as the severity to DSS colitis can drastically change based on the microbiota composition (Hernandez-Chirlaque et al, 2016). We postulate that differences observed between labs utilizing Irak-m −/− mice in DSS models could be due to altered microbiome compositions or differing percentages and lots of DSS used among labs.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

et al. 2017

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Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m−/− mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m−/− animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m−/− mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m−/− mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.

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“…SCFAs such as butyrate have also an impact on intestinal mucus production by enhancing expression of mucins [79]. Germ-free animals show impaired intestinal barrier due to decreased tight junction protein expression and low expression of mucus proteins, and therefore a high susceptibility to DSS-induced colitis [80]. These studies show a major role of the microbiota in protecting the gut integrity.…”

Section: Intestinal Microbiota and Gut Homeostasismentioning

confidence: 99%

Microbiota, Inflammation and Colorectal Cancer

Lucas

Barnich

Nguyen

2017

IJMS

264

134

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Colorectal cancer, the fourth leading cause of cancer-related death worldwide, is a multifactorial disease involving genetic, environmental and lifestyle risk factors. In addition, increased evidence has established a role for the intestinal microbiota in the development of colorectal cancer. Indeed, changes in the intestinal microbiota composition in colorectal cancer patients compared to control subjects have been reported. Several bacterial species have been shown to exhibit the pro-inflammatory and pro-carcinogenic properties, which could consequently have an impact on colorectal carcinogenesis. This review will summarize the current knowledge about the potential links between the intestinal microbiota and colorectal cancer, with a focus on the pro-carcinogenic properties of bacterial microbiota such as induction of inflammation, the biosynthesis of genotoxins that interfere with cell cycle regulation and the production of toxic metabolites. Finally, we will describe the potential therapeutic strategies based on intestinal microbiota manipulation for colorectal cancer treatment.

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Germ-free and Antibiotic-treated Mice are Highly Susceptible to Epithelial Injury in DSS Colitis

Abstract: We conclude that enteric bacteria are essential for the development of normal DSS-induced colitis. The absence of microbiota reduces DSS colonic inflammation dramatically but it also impairs barrier function, whereas subtotal microbiota depletion has intermediate effects at both levels.

Cited by 217 publications

References 46 publications

The Development of Steady-State Activation Hubs between Adult LTi ILC3s and Primed Macrophages in Small Intestine

The Development of Steady-State Activation Hubs between Adult LTi ILC3s and Primed Macrophages in Small Intestine

Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

Microbiota, Inflammation and Colorectal Cancer

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