Intestinal mucus barrier: a missing piece of the puzzle in food allergy
Authors: Amy Parrish, Marie Boudaud, Annette Kuehn, Markus Ollert, Mahesh S. Desai
Journal: Trends in Molecular Medicine (2021)

The sudden rise in food allergy over recent decades has led to various theories including the role of environmental factors in sensitization.Gastrointestinal (GI) mucins have recently been implicated in maintaining gut homeostasis: mice lacking a functional mucus layer (Muc2−/− mice) are more susceptible to colitis and GI infection, in addition to severe oral tolerance breakdown following sensitization with a food allergen. Thus, further research will be necessary to understand how functional changes in O-glycosylated mucins might contribute to the epidemic of food allergy.Factors including reduced consumption of dietary fiber and/or increased consumption of food additives are emerging as key determinants of altered mucus barrier function and mucin−gut microbiota interactions which appear to play an important role in regulating food allergy. The prevalence of food allergies has reached epidemic levels but the cause remains largely unknown. We discuss the clinical relevance of the gut mucosal barrier as a site for allergic sensitization to food. In this context, we focus on an important but overlooked part of the mucosal barrier in pathogenesis, the glycoprotein-rich mucus layer, and call attention to both beneficial and detrimental aspects of mucus–gut microbiome interactions. Studying the intricate links between the mucus barrier, the associated bacteria, and the mucosal immune system may advance our understanding of the mechanisms and inform prevention and treatment strategies in food allergy. The prevalence of food allergies has reached epidemic levels but the cause remains largely unknown. We discuss the clinical relevance of the gut mucosal barrier as a site for allergic sensitization to food. In this context, we focus on an important but overlooked part of the mucosal barrier in pathogenesis, the glycoprotein-rich mucus layer, and call attention to both beneficial and detrimental aspects of mucus–gut microbiome interactions. Studying the intricate links between the mucus barrier, the associated bacteria, and the mucosal immune system may advance our understanding of the mechanisms and inform prevention and treatment strategies in food allergy. Western countries have been experiencing rising rates of food allergies without a clearly identified cause [1.Gupta R.S. et al.Prevalence and severity of food allergies among US adults.JAMA Netw. Open. 2019; 2e185630Crossref PubMed Scopus (250) Google Scholar, 2.Lyons S.A. et al.Food allergy in adults: substantial variation in prevalence and causative foods across Europe.J. Allergy Clin. Immunol. 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Food allergen sensitization (see Glossary) occurs when regulatory immune responses fail to keep up with the induction of allergen-specific proinflammatory immune responses [3.Stephen-Victor E. et al.Dietary and microbial determinants in food allergy.Immunity. 2020; 53: 277-289Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. This drastic increase in food allergy prevalence has led researchers and clinicians to propose that modern lifestyles and environmental changes are a trigger [3.Stephen-Victor E. et al.Dietary and microbial determinants in food allergy.Immunity. 2020; 53: 277-289Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. Identifying the underlying mechanisms that causually connect environmental factors to sensitization is an upcoming area of research that would inform treatment options and prevention strategies. Food allergies can manifest at all ages, and the large spectrum of symptoms and immune profiles range from immediate IgE-mediated responses to delayed non-IgE-mediated responses [4.Connors L. et al.Non-IgE-mediated food hypersensitivity.Allergy, Asthma Clin. Immunol. 2018; 14: 56Crossref PubMed Scopus (22) Google Scholar,5.Anvari S. et al.IgE-mediated food allergy.Clin. Rev. Allergy Immunol. 2019; 57: 244-260Crossref PubMed Scopus (42) Google Scholar]. Sensitization to allergens and the initiation of allergic disease begin at barrier sites which share key protective features such as a cohesive epithelium that overlies a dynamic immune system (Figure 1). Atopic march often refers to atopic dermatitis in the newborn, food allergies in childhood, and asthma that can persist as chronic rhinitis into adulthood [6.Zhu T.H. et al.Epithelial barrier dysfunctions in atopic dermatitis: a skin–gut–lung model linking microbiome alteration and immune dysregulation.Br. J. 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As the broader aspects of the gut microbiome links in sensitization have been reviewed elsewhere [3.Stephen-Victor E. et al.Dietary and microbial determinants in food allergy.Immunity. 2020; 53: 277-289Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,9.Kemter A.M. Nagler C.R. Influences on allergic mechanisms through gut, lung, and skin microbiome exposures.J. Clin. Invest. 2019; 129: 1483-1492Crossref PubMed Scopus (25) Google Scholar,22.Wesemann D.R. Nagler C.R. The microbiome, timing, and barrier function in the context of allergic disease.Immunity. 2016; 44: 728-738Abstract Full Text Full Text PDF PubMed Google Scholar], and evidence is mounting about how the commensal microbiota impacts the integrity and maintenance of the mucus layer [23.Desai M.S. et al.A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility.Cell. 2016; 167: 1339-1353Abstract Full Text Full Text PDF PubMed Scopus (935) Google Scholar, 24.Schroeder B.O. et al.Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration.Cell Host Microbe. 2018; 23: 27-40Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 25.Earle K.A. et al.Quantitative imaging of gut microbiota spatial organization.Cell Host Microbe. 2015; 18: 478-488Abstract Full Text Full Text PDF PubMed Google Scholar], we focus our attention on the mucus–microbe interactions. We present a novel perspective on the functioning of the intestinal mucus layer, and we discuss both the beneficial and detrimental roles of mucus–microbe interactions in food allergy. Mucus layers are composed of highly O-glycosylated mucin glycoproteins that are secreted by goblet cells (GCs) and expand on the apical surface of the epithelium [26.Javitt G. et al.Assembly mechanism of mucin and von Willebrand factor polymers.Cell. 2020; 183: 717-729Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. This organized layer works as a barrier to exclude gut microbes while remaining permeable to essential nutrients and macromolecules [27.Ermund A. et al.Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches.Am. J. Physiol. Gastrointest. Liver Physiol. 2013; 305: G341-G347Crossref PubMed Scopus (197) Google Scholar] (Figure 2). 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Intriguingly, these populations could be distinguished by differential lectin staining, revealing different glycosylation patterns of the secreted mucins [44.Nyström E.E.L. et al.An intercrypt subpopulation of goblet cells is essential for colonic mucus barrier function.Science. 2021; 372eabb1590Crossref PubMed Scopus (10) Google Scholar]. This study paves the way towards a high-resolution understanding of the diverse roles of the mucus at the interface between the microbiota and the immune system. Mucin production is regulated by luminal microbial products as well as by immune factors [14.Johansson M.E.V. Hansson G.C. Immunological aspects of intestinal mucus and mucins.Nat. Rev. Immunol. 2016; 16: 639-649Crossref PubMed Scopus (310) Google Scholar]. 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Although TNF-α is considered to affect epithelial permeability principally by downregulating the expression of tight junction proteins, its impact on intestinal GCs and mucus secretion has not been studied extensively. In mouse pups, TNF-α induced mucus secretion in a TNFRI-dependent manner and Muc2 mRNA expression in a TNFRII-dependent manner [58.McElroy S.J. et al.Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis.Am. J. Physiol. Gastrointest. Liver Physiol. 2011; 301: 656-666Crossref PubMed Scopus (0) Google Scholar]; in addition, these two pathways developed differentially during the postnatal period. Cytokine-induced mucus depletion in the immature ileum emerged through TNFRI-mediated secretion, whereas TNFRII-mediated replenishment was effective only in the mature ileum [58.McElroy S.J. et al.Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis.Am. J. Physiol. Gastrointest. Liver Physiol. 2011; 301: 656-666Crossref PubMed Scopus (0) Google Scholar]. This study highlights the level of complexity when studying MUC2 expression, production, and secretion, and emphasizes the need to explore mRNA as well as protein expression levels. In human mucus-secreting colonic cancer cell lines, TNF-α was reported to induce Muc2 mRNA expression [59.Iwashita J. et al.mRNA of MUC2 is stimulated by