The role of the immune system in governing host-microbe interactions in the intestine

Brown, Eric; Sadarangani, Manish; Finlay, B. Brett

doi:10.1038/ni.2611

Cited by 340 publications

(238 citation statements)

References 105 publications

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“…The interdependence of the host and the gut microbiome under homeostatic and inflammatory conditions is well established (13,57). We confirmed that the intestinal microbiota composition and activity were dramatically shifted upon DSS treatment (10,21,24).…”

Section: Discussionsupporting

confidence: 67%

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Hainzl

Stockinger

Rauch

et al. 2015

The Journal of Immunology

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In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2−/− mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22–STAT3 target genes is reduced in IECs from healthy and colitic Tyk2−/− mice. Experiments with conditional Tyk2−/− mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22–Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22–dependent colitis was confirmed in Citrobacter rodentium–induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3.

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Section: Discussionsupporting

confidence: 67%

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Hainzl

Stockinger

Rauch

et al. 2015

The Journal of Immunology

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“…The commensal microbiome also plays an important role in the structural, barrier, immunological and metabolic functions of the intestine; however, a description of the microbiome at various mucosal surfaces is beyond the scope of this article (Brown et al, 2013;Rosenstiel, 2013). The junctions between the epithelial cells, tight and adherens junctions, which join cells to each other at the apical end of the lateral membrane (Schneeberger and Lynch, 2004), play very important roles in the homeostasis of the intestine and the maintenance of mucosal immunity.…”

Section: Resultsmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

124

103

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SummaryModels of the outer epithelia of the human body -namely the skin, the intestine and the lung -have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

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“…Compared with modulation of gut microbiota by external factors, information is limited on how host immunity regulates its gut microbiota Brown et al, 2013). Recent findings suggest an important role for the innate immune system.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, mice deficient in recombination-activating gene 2 (Rag2) or activation-induced cytidine deaminase had increased segmented filamentous bacteria in the small intestine (Suzuki et al, 2004). Both mutations lead to the lack of IgA (immunoglobulin A) in the intestine, which provides 'an immunological buffer' between the host and microbiota (Brown et al, 2013). Besides IgA (Cebra, 1999;Suzuki et al, 2004;Macpherson and Uhr, 2004;Suzuki and Fagarasan, 2008), T-cell-mediated responses are also hypothesized to shape microbiota in the intestine but evidence is scarce.…”

Section: Introductionmentioning

confidence: 99%

Host adaptive immunity alters gut microbiota

et al. 2014

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It has long been recognized that the mammalian gut microbiota has a role in the development and activation of the host immune system. Much less is known on how host immunity regulates the gut microbiota. Here we investigated the role of adaptive immunity on the mouse distal gut microbial composition by sequencing 16 S rRNA genes from microbiota of immunodeficient Rag1 À / À mice, versus wild-type mice, under the same housing environment. To detect possible interactions among immunological status, age and variability from anatomical sites, we analyzed samples from the cecum, colon, colonic mucus and feces before and after weaning. High-throughput sequencing showed that Firmicutes, Bacteroidetes and Verrucomicrobia dominated mouse gut bacterial communities. Rag1 À mice had a distinct microbiota that was phylogenetically different from wildtype mice. In particular, the bacterium Akkermansia muciniphila was highly enriched in Rag1 À / À mice compared with the wild type. This enrichment was suppressed when Rag1 À / À mice received bone marrows from wild-type mice. The microbial community diversity increased with age, albeit the magnitude depended on Rag1 status. In addition, Rag1 À / À mice had a higher gain in microbiota richness and evenness with increase in age compared with wild-type mice, possibly due to the lack of pressure from the adaptive immune system. Our results suggest that adaptive immunity has a pervasive role in regulating gut microbiota's composition and diversity.

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The role of the immune system in governing host-microbe interactions in the intestine

Cited by 340 publications

References 105 publications

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Host adaptive immunity alters gut microbiota

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