Gut barrier disruption and chronic disease

by Jan Martel, Shih-Hsin Chang, Yun-Fei Ko, Tsong-Long Hwang, John D. Young & David M. Ojcius

Maintenance of gut barrier integrity is indispensable for health as the gut barrier protects the host against gut microbes, food antigens, and toxins.

• Many factors such as enteric infection, antibiotics, low-fiber diets, circadian rhythm disruption, and psychological stress can affect gut barrier integrity and lead to systemic, low-grade inflammation due to translocation of bacteria and their components.

• While the body can resist transient gut barrier disruption, it may be overwhelmed by mild insult due to genetic predisposition, chronic stress, and aging, which may contribute to the development of autoimmune, metabolic, and mental health disorders.

• Consideration of the various intrinsic and extrinsic factors that affect gut barrier integrity and microbiota composition is needed to maintain or restore human health.

The intestinal barrier protects the host against gut microbes, food antigens, and toxins present in the gastrointestinal tract. However, gut barrier integrity can be affected by intrinsic and extrinsic factors, including genetic predisposition, the Western diet, antibiotics, alcohol, circadian rhythm disruption, psychological stress, and aging. Chronic disruption of the gut barrier can lead to translocation of microbial components into the body, producing systemic, low-grade inflammation. While the association between gut barrier integrity and inflammation in intestinal diseases is well established, we review here recent studies indicating that the gut barrier and microbiota dysbiosis may contribute to the development of metabolic, autoimmune, and aging-related disorders. Emerging interventions to improve gut barrier integrity and microbiota composition are also described.

Structure and function of the gut barrier

Maintenance of epithelial and endothelial barriers in the gut, skin, blood vessels, respiratory tract, and the brain is critical for human health [1]. The intestine forms the largest and one of the most important internal barriers in the body as it protects the host from noxious substances and microbes present in the gut lumen. The gut barrier consists of the mucus layer, commensal bacteria, epithelial cells, and immune cells residing in the lamina propria (see Glossary) (Figure 1A). In the intestinal epithelium, goblet cells secrete mucus glycoproteins that prevent direct contact between gut microbes and colonocytes [2], while the mucus in the small intestine is loose and allows passage of bacteria [3]. In the small intestine, Paneth cells secrete antimicrobial proteins that can specifically lyse bacterial cells [4]. In the lamina propria, B cells secrete IgA that can bind to bacteria and their toxins to prevent their translocation into the body [5]. Commensal microbes of the gut microbiota help to maintain gut homeostasis in various ways (Figure 1A). For instance, they oppose colonization by pathogens [6] and promote differentiation of regulatory T (Treg) cells, which induce tolerance to lumen antigens [7]. When sequestered into the lumen, microbe-associated molecular patterns (MAMPs) such as flagellin, lipopolysaccharide (LPS), and peptidoglycan strengthen the gut barrier by binding to Toll-like receptors (TLRs) on the apical surface of intestinal cells to induce production of antimicrobial proteins [5]. Commensal bacteria can induce the production of mucus from goblet cells by activating interleukin (IL)-22 secretion by innate lymphoid cells [8]. Commensals also convert dietary fiber into short-chain fatty acids (SCFAs), which protect the gut barrier in various ways, including by providing energy for colonocytes and stimulating the production of mucus, antimicrobial proteins, and Treg cells [5]. Depletion of commensals and their replacement by pathogens, a condition termed dysbiosis, may therefore affect the gut barrier and produce detrimental effects on the host (Figure 1B–F). Absorption of nutrients and water by the intestine can occur via the transcellular and paracellular pathways (Figure 2). Intestinal cells are linked by a series of proteins forming junctional complexes consisting of tight junctions, adherens junctions, and desmosomes, allowing absorption of water and small solutes (<8 Å) via the ‘pore’ pathway [9,10]. Transient and reversible rearrangement of the actin cytoskeleton and tight junctions allows passage of larger molecules (<100 Å) via the ‘leak’ pathway [9,10] (Figure 2). For instance, activation of glucose-Na+ co-transport following food intake increases the leak pathway [11], which enhances absorption of food nutrients but also small food antigens and MAMPs (Figure 2). Proinflammatory cytokines such as tumor-necrosis factor-alpha (TNF-α) [12] can also activate the leak pathway and cause diarrhea, which may help to expulse proinflammatory stimuli into the gut lumen. Intestinal erosion, ulceration, and epithelial cell death may allow larger particles, including MAMPs and bacteria, to unrestrictedly cross the intestinal epithelium and induce inflammation [9] (Figure 2). Read more at: https://www.sciencedirect.com/science/article/pii/S1043276022000029