Intestinal Barrier Function and Immune Homeostasis Are Missing Links in Obesity and Type 2 Diabetes Development

Abstract

Noncommunicable diseases, such as type 2 diabetes (T2D), place a burden on healthcare systems worldwide. The rising prevalence of obesity, a major risk factor for T2D, is mainly attributed to the adoption of Westernized diets and lifestyle, which cause metabolic dysfunction and insulin resistance. Moreover, diet may also induce changes in the microbiota composition, thereby affecting intestinal immunity. The critical role of intestinal immunity and intestinal barrier function in the development of T2D is increasingly acknowledged, however, limited studies have investigated the link between intestinal function and metabolic disease. In this review, studies reporting specific roles of the intestinal immune system and intestinal epithelial cells (IECs) in metabolic disease are highlighted. Innate chemokine signaling, eosinophils, immunoglobulin A (IgA), T helper (Th) 17 cells and their cytokines were associated with obesity and/or dysregulated glucose homeostasis. Intestinal epithelial cells (IECs) emerged as critical modulators of obesity and glucose homeostasis through their effect on lipopolysaccharide (LPS) signaling and decontamination. Furthermore, IECs create a link between microbial metabolites and whole-body metabolic function. Future in depth studies of the intestinal immune system and IECs may provide new opportunities and targets to develop treatments and prevention strategies for obesity and T2D.

Keywords: intestinal barrier function; intestinal epithelial cells; intestinal immune system; leaky gut; obesity; type 2 diabetes.

Figure 1

The role of intestinal barrier dysfunction and leaky gut syndrome in metabolic disease. A high fat and/or westernized diet affects and/or changes microbiota composition. Microbiota composition was associated with metabolic diseases in a large number of studies that investigated these in conjunction with metabolic outcomes, such as increased or decreased body weight, changes in glucose metabolism and effects on metabolically active tissues such as adipose tissue, liver and muscles (grey arrows) (, –28). However, increasingly research is focusing on the role of the leaky gut, particularly investigating the role of the intestinal barrier and its different layers, including chemical, physical and immunological barriers (see insert), as mediators of interactions with diet and microbiota in the development of metabolic diseases (red arrows). Studies in this area are relatively limited, but this review summarizes compelling evidence for a leading role of the gut in development of metabolic disease through modulation of this complex intestinal barrier. IgA, immunoglobulin A; LPS, lipopolysaccharide; Th17, T helper cells 17; Treg, regulatory T cells.

Figure 2

Specific and diverse roles of IECs in HFD-induced metabolic disease. The roles of intestinal epithelial cells (IECs) in body weight gain and glucose homeostasis can be categorized into immune crosstalk/chemokine signaling (90), pathways involving the endocannabinoid system (166), pathways involving microbial metabolites (167, 168) and signaling pathways related to LPS signaling (63, 66, 124). While most pathways exerted adverse effects on glucose metabolism and weight gain in response to HFD feeding, IEC specific knockout of CCL2 and MyD88 decreased body weight gain and improved glucose metabolism during high-fat diet feeding (90, 124). CCL2 and MyD88 knockout improved intestinal barrier function by increasing claudin 1 levels and decreased expression of inflammatory cytokines, respectively (highlighted in red). AMPs, antimicrobial peptides; CCL2, C-C motif chemokine ligand 2; HDAC3, histone deacetylase 3; HFD, high fat diet; IAP, intestinal alkaline phosphatase; IDO, Indolamine 2;3-dioxygenase; IEC, intestinal epithelial cells; KO, knockout; LPS, lipopolysaccharides; Mφ, macrophages; MyD88, myeloid differentiation primary response gene 88; NAPE PLD, N-acylphosphatidylethanolamine phospholipase D; POMC, pro-opiomelanocortin; SCFA, short chain fatty acids; TLR4, toll-like receptor 4; Treg, regulatory T cells.

Figure 3

Complexity and cross-talk between contributors to obesity and T2D. Westernized diets [1], gut microbiota [2], the intestinal barrier and immune system [3] and metabolic inflammation [4] play a significant role in the development of obesity [5] and type 2 diabetes [6]. [1] Diet likely exerts a “one way effect” (indicated by red arrows) on glucose homeostasis, while high fat diets also affect the intestinal immune system and barrier function which can lead to [4] metabolic inflammation (indirect effects are indicated with dashed arrows). [2] Changes in microbiota composition and diversity have been associated with obesity, dysregulated glucose metabolism and T2D, with metabolic inflammation, and the intestinal immune and barrier system. Conversely, microbiota may also affect the dietary intake through inducing behavioral changes and cravings. [3] The intestines are known to shape microbiota and facilitate metabolic inflammation through barrier defects, but the intestines can also directly affect body weight and glucose homeostasis through gut hormone production and via expression of effector molecules and pathways in intestinal epithelial cells. [4] Metabolic inflammation contributes to obesity and T2D development through inducing insulin resistance. How metabolic inflammation may directly affect microbiota is not yet clear, but may occur indirectly through effects on intestinal barrier and immune function. [5] Obesity contributes to metabolic inflammation, but is associated with intestinal inflammation, barrier dysfunction and altered microbiota. Obesity may also influence diet and/or food intake through dysregulation in signaling related to satiety. A potentially direct effect of obesity on T2D development may involve the increased release of free fatty acid from adipose tissue which can induce insulin resistance through oxidative stress and lipid metabolites. [6] Type 2 diabetes and dysregulated glucose homeostasis may induce obesity in the sense that insulin resistance and hyperglycemia lead to increased lipogenesis and lipid storage but a direct pathway to increased body weight is likely the result of anti-diabetic drugs and their side effects. Hyperglycemia may induce metabolic inflammation directly via increased oxidative stress and indirectly through decreasing intestinal barrier function and altered microbiota composition. IgA, immunoglobulin A; LPS, lipopolysaccharide; T2D, type 2 diabetes.