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Review
. 2023 Sep;18(6):1635-1646.
doi: 10.1007/s11739-023-03329-1. Epub 2023 Jul 4.

Role of mucosal immunity and epithelial-vascular barrier in modulating gut homeostasis

Antonio Di Sabatino  1   2   3 , Giovanni Santacroce  4   5 , Carlo Maria Rossi  4   5 , Giacomo Broglio  4   5 , Marco Vincenzo Lenti  4   5
Affiliations
Review

Role of mucosal immunity and epithelial-vascular barrier in modulating gut homeostasis

Antonio Di Sabatino et al. Intern Emerg Med. 2023 Sep.

Abstract

The intestinal mucosa represents the most extensive human barrier having a defense function against microbial and food antigens. This barrier is represented externally by a mucus layer, consisting mainly of mucins, antimicrobial peptides, and secretory immunoglobulin A (sIgA), which serves as the first interaction with the intestinal microbiota. Below is placed the epithelial monolayer, comprising enterocytes and specialized cells, such as goblet cells, Paneth cells, enterochromaffin cells, and others, each with a specific protective, endocrine, or immune function. This layer interacts with both the luminal environment and the underlying lamina propria, where mucosal immunity processes primarily take place. Specifically, the interaction between the microbiota and an intact mucosal barrier results in the activation of tolerogenic processes, mainly mediated by FOXP3+ regulatory T cells, underlying intestinal homeostasis. Conversely, the impairment of the mucosal barrier function, the alteration of the normal luminal microbiota composition (dysbiosis), or the imbalance between pro- and anti-inflammatory mucosal factors may result in inflammation and disease. Another crucial component of the intestinal barrier is the gut-vascular barrier, formed by endothelial cells, pericytes, and glial cells, which regulates the passage of molecules into the bloodstream. The aim of this review is to examine the various components of the intestinal barrier, assessing their interaction with the mucosal immune system, and focus on the immunological processes underlying homeostasis or inflammation.

Keywords: Chronic inflammation; Epithelial monolayer; Gut–vascular barrier; Microbiota; Mucosal immunity.

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Conflict of interest statement

None to disclose.

Figures

Fig. 1
Fig. 1
Representation of the main components of the intestinal barrier: epithelial barrier, mucus barrier and lamina propria. The intestinal epithelial monolayer is composed of absorptive enterocytes interspersed with specialized cells: goblet cells, which regulate mucus production; Paneth cells, dedicated to the secretion of anti-microbial peptides; enterochromaffin cells, that are neuroendocrine cells; intestinal stem cells, resident deep within intestinal crypts; dendritic cells, intercalated between epithelial cells for luminal antigens uptake and immune response activation; M cells, underlying Peyer’s plaques facilitating antigens presentation to immune cells. Above the intestinal epithelium, the mucus barrier, composed by mucin, secretory immunoglobulin (sIg)A dimers, and antibacterial peptide (especially defensins), play an antibacterial role, preventing microbial adhesion and invasion. The subepithelial region consists of the lamina propria, composed by (innate and adaptive) immune cells, including lymphoid structures such as Peyer’s patches; network of neurons and glial cells forming the enteric nervous system; connective tissue produced by fibroblasts. Created with “BioRender.com”. sIgA secretory immunoglobulin A
Fig. 2
Fig. 2
Intestinal homeostasis and inflammation. Mucosal layer and intestinal epithelium act as first barrier against microorganisms and luminal antigens. The intervention of immune system, composed by cells of innate immunity (epithelial cells, dendritic cells (DCs), macrophages and natural killers) and adaptive immunity (B and T cells), is required to mount a specific response. The interaction of epithelial cells (interconnected by junctions) with commensal bacteria, through Toll-Like Receptors, activates a process of tolerance and homeostasis (left of the figure). Specifically, the epithelium produces thymic stromal lymphopoietin, transforming growth factor β, and retinoic acid that stimulate CD103+ DCs to modulate a differentiation toward regulatory T cells (FOXP3+). Also, activated DCs induce maturation of B cells into IgA-secreting plasma cells. CXC3R1 DCs, intercalated between epithelial cells, take up luminal antigens and maintain mucosal tolerance, through the production of IL-10. The impairment of mucus layer and epithelial barrier, associated with dysbiosis, may account for an inflammatory response, leading to disease development (right of the figure). DCs and macrophages, after the interaction with pathogens, direct a differentiation of Th1, Th2, and Th17 cells (also through tumor necrosis factor α, interleukine-12 and -23), and determine the activation of innate immune cells (neutrophils, eosinophils etc.), leading to inflammation. Created with “BioRender.com”. IL interleukin, NK natural killer, RA retinoic acid, sIgA secretory immunoglobulin A, TGF β transforming growth factor β, TLR tool like receptor, TNF α tumor necrosis factor, Treg regulatory T cell, TSLP thymic stromal lymphopoietin
Fig. 3
Fig. 3
Gut–vascular barrier. The gut–vascular barrier (GVB), placed beneath the intestinal epithelium, forms the inner layer of intestinal defense against microbes dissemination. It is made up of a monolayer of endothelial cells, sealed by adherent and tight junctions, surrounded by pericytes and enteric glial cells. Its semi-permeability is regulated by plasmalemma vesicle protein 1. Created with “BioRender.com”
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