Gut barrier disruption and chronic disease
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.
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).
Effect of gut barrier dysfunction on intestinal diseases
Gut barrier dysfunction is involved in intestinal diseases such as enteric infections, intestinal bowel disease (IBD), and celiac disease [13]. For example, pathogenic bacteria and viruses such as Salmonella and rotaviruses can breach the intestinal epithelium and alter tight junctions, causing diarrhea via water and electrolyte loss into the gut lumen [14,15] (Figure 1B). Gastrointestinal infections can lead to bacterial translocation to the gut mucosa (Figure 1B), producing inflammation that further increases gut barrier dysfunction and may result in a vicious cycle [16].
IBD, which consists of Crohn’s disease and ulcerative colitis, is characterized by excessive immune reaction towards the gut microbiota and mucosa of the small and large intestine, respectively. More than 200 single nucleotide polymorphisms (SNPs) in various genes coding for NOD-like receptors (NLRs), antimicrobial proteins, and cytokines have been implicated in IBD [17]; however, only a fraction of ulcerative colitis subjects have a family history of IBD [18], indicating the importance of environmental triggers. Mice that lack the major mucus glycoprotein, mucin-2, show gut barrier dysfunction and spontaneously develop colitis and colorectal cancer [19,20], illustrating the role of mucus in maintaining homeostasis [21]. Moreover, mice fed a high-glucose diet develop more severe dextran sodium sulfate (DSS)-induced colitis than controls due to increased mucolytic bacteria in the gut and reduced mucus barrier, leading to bacterial translocation to the lamina propria [22] (Figure 1B). In humans, weakening of the colonic mucus barrier is an early event in the development of ulcerative colitis [23] and bacterial DNA is increased in the blood of IBD subjects compared with healthy controls [24]. The development of IBD is therefore associated with genetic and environmental factors that lead to intestinal erosion and inflammation in susceptible individuals.
Celiac disease is a well-known condition involving gut barrier disruption. In this disease, gluten from wheat and other grains has been identified as the environmental trigger of autoimmune reactions in genetically susceptible individuals (Table 1). Gliadin proteins found in gluten induce the release of the protein zonulin from the gut epithelium [25] (Figure 1B). Zonulin is a mammalian ortholog of the zonula occludens toxin (Zot) from the cholera pathogen Vibrio cholerae. Similar to the cholera toxin, zonulin induces tight junction disassembly and increases gut permeability to peptides larger than three amino acids [25]. Celiac patients harbor SNPs in various genes, including human leukocyte antigens (HLAs) (e.g., HLA-DQ2 and HLA-DQ8) that render gliadin peptides capable of activating T cells and inducing autoimmune reactions [26]. In addition, increased gut permeability and antibodies against LPS and flagellin have been observed in people with non-celiac gluten sensitivity [27], which may involve SNPs in non-HLA genes [26]. Given the difficulty in identifying gluten sensitivity and the observation that gliadin can induce the release of zonulin even in healthy individuals [26], it is likely that gluten sensitivity is more prevalent than presently recognized. A combination of genetic and environmental factors thus affects gut barrier integrity and is involved in the development of intestinal diseases.
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Figure 1. Gut barrier and disease conditions.
(A) The gut barrier consists of gut commensal microbes, mucus, the intestinal epithelium, and immune cells in the lamina propria. Dendritic cells (DC) continually sample the lumen and promote proliferation of regulatory T (Treg) cells in response to commensals, therefore inducing a default state of tolerance. DCs also stimulate B cells to secrete immunoglobulin (Ig)A, which prevents translocation of bacteria into the mucosa. Dietary fibers are converted by the gut microbiota into short-chain fatty acids (SCFAs), which induce mucus production by goblet cells and expression of tight junctions (TJs). Paneth cells secrete antimicrobial peptides (AMPs) in response to Toll-like receptor-2 (TLR2) signaling induced by the gut microbiota. (B) Intestinal diseases involve gut barrier disruption due to pathogens, genes, and poor diet. (C) Metabolic diseases, including obesity, type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD) have been linked with food additives, bile acid metabolism, low-fiber diets, and dysbiosis, which together may affect gut barrier integrity. (D) Autoimmune diseases are associated with genetic predisposition and environmental factors that affect gut barrier integrity. (E) Mental health issues may be linked with psychological stress, poor sleep, diet, and circadian rhythm disruption, which can affect the gut barrier, producing systemic inflammation that in turn affects the blood–brain barrier (BBB). (F) Aging eventually leads to gut dysbiosis, exhaustion of intestinal stem cells (ISCs), and inflammaging, which may induce a vicious cycle of inflammation and gut barrier dysfunctions. Abbreviations: IBD, inflammatory bowel disease; MAMPs, microbe-associated molecular patterns; MS, multiple sclerosis; NLRs, NOD-like receptors; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1D, type 1 diabetes.
