Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals

By Meimei Shan, M. Gentile, John R Yeiser, A. C. Walland, V. U. Bornstein, Kang Chen, B. He, L. Cassis, A. Bigas, M. Cols and 9 more. Science, 2013

613 citations recorded by the source corpus.

Guardian of the Gut The intestine is able to tolerate continual exposure to large amounts of commensal bacteria and foreign food antigens without triggering an inappropriate inflammatory immune response. In the large intestine, this immunological tolerance is thought to occur via a physical separation between environment and host imposed by a continuous mucous layer built up from the secreted mucin protein, MUC2. However, in the small intestine, this mucous layer is porous, necessitating an additional layer of immune control. Shan et al. (p. 447, published online 26 September; see the Perspective by Belkaid and Grainger) now report that in the small intestine, MUC2 plays an active role in immunological tolerance by activating a transcription factor in resident dendritic cells, thereby selectively blocking their ability to launch an inflammatory response. This work identifies MUC2 as a central mediator of immune tolerance to maintain homeostasis in the gut and possibly at other mucosal surfaces in the body. Mucus not only forms a physical barrier in the intestine but also promotes immunological tolerance of bacteria and foods. [Also see Perspective by Belkaid and Grainger] A dense mucus layer in the large intestine prevents inflammation by shielding the underlying epithelium from luminal bacteria and food antigens. This mucus barrier is organized around the hyperglycosylated mucin MUC2. Here we show that the small intestine has a porous mucus layer, which permitted the uptake of MUC2 by antigen-sampling dendritic cells (DCs). Glycans associated with MUC2 imprinted DCs with anti-inflammatory properties by assembling a galectin-3–Dectin-1–FcγRIIB receptor complex that activated β-catenin. This transcription factor interfered with DC expression of inflammatory but not tolerogenic cytokines by inhibiting gene transcription through nuclear factor κB. MUC2 induced additional conditioning signals in intestinal epithelial cells. Thus, mucus does not merely form a nonspecific physical barrier, but also constrains the immunogenicity of gut antigens by delivering tolerogenic signals.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2d42be8ec4ebaa0bfeea8ce2fc98ccbe97f97090

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Citations in the corpus

The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system (2014, neutral): “The mechanism of why and how the goblet cells and CD103 DCs cooperate to promote tolerance is far from understood, but recently, it was suggested that the MUC2 mucin has a special role in this process (127).”
The composition of the gut microbiota throughout life, with an emphasis on early life (2015, background): “In addition to its association with the protection, lubrication and hydration of the intestinal epithelium, mucus plays a critical role in the maintenance of intestinal homeostasis by promoting microbial interactions with commensal bacteria, acting as decoys for pathogens and enhancing immune regula”
The treatment-naive microbiome in new-onset Crohn's disease. (2014, background): “Mucosal-associated microbes are uniquely positioned to influence the immune system (Belkaid and Naik, 2013); particularly, the porous mucus layer in the ileum has been shown to educate the immune system to develop tolerance towards commensals (Shan et al., 2013).”
Interaction between microbiota and immunity in health and disease (2020, background): “However, MUC2 not only offers protection by static shielding, but also constrains the immunogenicity of intestinal antigens by imprinting enteric dendritic cells (DCs) towards an anti-inflammatory state.(44) Tight junctions are a critical structure in restricting trans-epithelial permeability.”
The composition of the gut microbiota shapes the colon mucus barrier (2014, positive): “The small intestinal mucus not only excludes the microbiota, but is also important for immune system development [11 – 13].”