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.

Alisol B 23-Acetate Ameliorates Lipopolysaccharide-Induced Intestinal Barrier Dysfunction by Inhibiting TLR4-NOX1/ROS Signaling Pathway in Caco-2 Cells

“…Numerous TJ proteins have thus been found, such as cytoplasmic proteins zonula occludens-1 (ZO-1), the transmembrane proteins occluding and claudins ( Clark et al, 2006 ). The gut TJ barrier disruption leads to a “leaky” TJ barrier, resulting in a rise in gut permeability, and permitting paracellular permeation of luminal antigens that enhance intestinal inflammation, which is associated with various diseases comprising irritable bowel syndrome, diabetes, coeliac disease, non-alcoholic fatty liver disease, Crohn’s disease and so on ( Barbara et al, 2021 ; Portincasa et al, 2021 ; Prospero et al, 2021 ; Riedel et al, 2021 ; Xu et al, 2021 ).…”

A Protocol for the Cryopreservation of Human Intestinal Mucosal Biopsies Compatible With Single-Cell Transcriptomics and Ex Vivo Studies

“…Dysfunction of the gut epithelium has long been associated with a number of both intestinal and systemic disease including: Obesity, metabolic syndrome, Type 2 Diabetes (T2D), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), microbial infections, cancers, among others ( Raybould, 2012 ; Van Der Heijden and Vermeulen, 2019 ; Barbara et al, 2021 ; Riedel et al, 2021 ). The heterogeneity of the intestinal epithelium has hindered our ability to understand the pathophysiology of distinct specialized cell types on a single-cell basis in human disease, especially in rare subtypes.…”

Commentary: Intestinal barrier function and immune homeostasis are missing links in obesity and type 2 diabetes development

“…We read with great interest the review by Riedel et al. highlighting the role of the intestinal system in the development of metabolic diseases ( 1 ). For a long time, type 2 diabetes (T2D) has been strongly bound to hyperglycemia.…”

“…As is well known, there is a prediabetes stage between patients with and without T2D, which strongly indicates that hyperglycemia is a gradual process. Given the crosstalk of the intestinal system and metabolic diseases ( 1 ), SIH and T2D could be considered two different stages of hyperglycemia accompanied by systematic inflammation, IBD, and other pathophysiological changes. In other words, instead of having a causal relationship where one condition leads to the other, SIH and T2D might be hyperglycemia with a different severity.…”

“…In addition, only those agents with the capability of lowering blood glucose are qualified to be called antidiabetic drugs. With the crosstalk of the intestinal system and metabolic diseases mentioned in Riedel’s review ( 1 ), temporarily dealing with hyperglycemia is unable to solve all problems of T2D since other pathophysiological changes like obesity, metabolic inflammation, and IBD are still going to cause adverse consequences. Although blood glucose is easy to monitor, it is far from being sufficient for the treatment of T2D.…”