Emerging concepts in intestinal immune control of obesity-related metabolic disease

Abstract

The intestinal immune system is an important modulator of glucose homeostasis and obesity-associated insulin resistance. Dietary factors, the intestinal microbiota and their metabolites shape intestinal immunity during obesity. The intestinal immune system in turn affects processes such as intestinal permeability, immune cell trafficking, and intestinal hormone availability, impacting systemic insulin resistance. Understanding these pathways might identify mechanisms underlying treatments for insulin resistance, such as metformin and bariatric surgery, or aid in developing new therapies and vaccination approaches. Here, we highlight evolving concepts centered on intestinal immunity, diet, and the microbiota to provide a working model of obesity-related metabolic disease.

Fig. 1. Obesity alters the intestinal immune compartment.

A Under lean homeostatic conditions, the intestinal immune environment is dominated by tolerogenic and mucosal barrier maintaining immune cells. These cells include interleukin (IL)-10 producing regulatory T (Treg) cells, IL-22 producing group 3 innate lymphoid cells (ILC3s), and IL-17 secreting protective T helper (Th) 17 cells. Furthermore, under lean conditions, IgA⁺ antibody-secreting cells (ASCs) are abundant within the lamina propria and produce secretory IgA (SIgA), which interface with the intestinal bacteria. The lean intestinal environment also consists of tolerogenic CX3CR1⁺ MHC-II⁺ macrophages and CD103+ CD11b+ dendritic cells (DCs), which have been linked to protective Th17, ILC3, and IgA responses within the intestines. B During diet-induced obesity in mice, there is a shift in the inflammatory potential of the intestinal immune environment, leading to increased numbers of lamina propria Th1 and CD8⁺ T cells, CD44⁺ MAIT cells, intestinal homing CCR2⁺ macrophages, and intestinal intra-epithelial CD8αβ⁺ T cells, as well as a decrease in the number of the aforementioned tolerogenic cell types. Additionally, small intestine ILC2s have been shown to promote obesity via an IL-2 feedback system, and further work may delineate the basis of this axis. In human subjects with obesity, there is an increase in intestinal CD8αβ⁺ T cells. These changes result in an inflammatory environment that is linked with intestinal dysfunction, facilitating dysregulated glucose homeostasis during diet-induced obesity.

Fig. 2. Mechanisms of intestinal immune cell-driven metabolic dysfunction.

During obesity, intestinal immune cells contribute to insulin resistance and/or glucose dysregulation, via at least three potential mechanisms. A Changes in immune compartments in the presence of an obesogenic diet promote leakage of bacterial products. This intestinal permeability is facilitated through local changes in cytokines, such as increases in pro-inflammatory cytokines interferon (IFN)γ and tumor-necrosis factor (TNF), coupled with a loss in anti-inflammatory and barrier protective cytokines interleukin (IL)-17, IL-22, and IL-10, anti-microbial peptides (AMPs) and epithelial mucin. Changes in such factors also contribute to the degradation of epithelial tight junction proteins. Increased leakage of bacterial products can drain into metabolic tissues, such as the visceral adipose tissue (VAT) and liver, where they further stimulate local immune cells, such as hepatic Kupffer cells and VAT M1-like macrophages, further enhancing their pro-inflammatory profile and leading to systemic insulin resistance. B Intestinal lymphocytes can potentially sequester gastrointestinal hormones such as glucagon-like peptide (GLP)1, via their GLP1 receptor (GLP1R), thereby limiting its bioavailability and further contributing to metabolic dysfunction. C Finally, evidence indicates that some intestinal immune cells, such as anti-inflammatory IgA⁺ antibody-secreting cells (ASCs), can potentially migrate to distant inflamed sites in the body, resulting in the reduced intestinal presence of ASC products such as IL-10 and IgA.

Fig. 3. Immune-microbiota crosstalk regulates metabolic disease.

A During obesity, altered intestinal immune cell function is tightly linked with intestinal dysbiosis and a loss in bacterial diversity. Mononuclear phagocytes (MNPs; macrophages and dendritic cells - CX3CR1+ macrophages shown in figure as an example) have an altered ability to produce factors necessary for IgA class switching, such as transforming growth factor-beta (TGF-β), interleukin-5 (IL-5), retinoic acid (RA) via retinaldehyde dehydrogenase (RALDH) enzymes, and a proliferation-inducing ligand (APRIL). This reduction would directly affect the amount and quality of secretory IgA (SIgA) present to bind bacteria, enabling the expansion of opportunistic and pathogenic taxa, such as Proteobacteria, and promoting obesity-associated dysbiosis. Defects in MNP functionality is further affiliated with reduced secretion of factors linked to IgA antibody-secreting cell (ASC) function, and reduced ability to induce T helper 17 (Th17) and regulatory T (Treg) cells. These defects potentially can be further affected by a decreased colony-stimulating factor (Csf)-2 production, as obesity induces a reduction in intestinal group 3 innate lymphoid cells (ILC3s), but this remains to be examined. Simultaneously, pro-inflammatory signaling in intestinal epithelial cells, T cells, and potentially enteric neurons, alters the production of anti-microbial peptides (AMPs), or can directly hinder the beneficial function of beneficial taxa like Akkermansia, contributing to microbial dysbiosis. B The microbiota in turn exert control on immune cells through secretion of metabolites, which are affected by diet-induced obesity. For example, short-chain fatty acids (SCFAs) function through their receptors, such as G-protein coupled receptors (GPRs), to promote levels of intestinal secretory IgA, boost Treg cell responses and promote CX3CR1⁺ MNP function. Aryl hydrocarbon receptor (AhR) ligands have been associated with increased interleukin (IL)-22 and IL-10 cytokine production, AMP production, and the promotion of epithelial layer mucus and tight junction proteins. Via receptors such as the farnesoid x receptor (FXR) and G-protein coupled bile acid receptor (TGR5), bile acid metabolites might also regulate the intestinal immune landscape through the promotion of Treg cells. These processes are potentially reduced or altered with a Western diet, contributing to inflammatory immunological changes in the intestines during obesity.

Fig. 4. A working model of intestinal-driven metabolic disease.

We propose that early life factors induce microbial dysbiosis, which can extend to adult life and potentiate the microbiome towards an obesogenic phenotype. Consumption of a Western diet results in a dietary trigger that further establishes pro-obesity intestinal microbial dysbiosis and a shift in the intestinal immune landscape towards a pro-inflammatory phenotype with limited intestinal IgA responses. Intestinal immune changes are also poised to alter intestinal hormone bioavailability. Low-grade inflammation coupled with dietary factors promotes intestinal permeability and facilitates the leakage of microbial ligands systemically. Consequently, penetration of microbial antigens and colonization of microbes at metabolic sites, such as the liver and visceral adipose tissue (VAT), affects tissue-specific metabolic processes and tissue-specific immune cell functionality. These processes are consistently affected by interactions between the host environment and genetics, ultimately resulting in the development of metabolic complications such as insulin resistance and non-alcoholic fatty liver disease.