The role of gut-islet axis in pancreatic islet function and glucose homeostasis

Abstract

The gastrointestinal tract plays a vital role in the occurrence and treatment of metabolic diseases. Recent studies have convincingly demonstrated a bidirectional axis of communication between the gut and islets, enabling the gut to influence glucose metabolism and energy homeostasis in animals strongly. The 'gut-islet axis' is an essential endocrine signal axis that regulates islet function through the dialogue between intestinal microecology and endocrine metabolism. The discovery of glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP) and other gut hormones has initially set up a bridge between gut and islet cells. However, the influence of other factors remains largely unknown, such as the homeostasis of the gut microbiota and the integrity of the gut barrier. Although gut microbiota primarily resides and affect intestinal function, they also affect extra-intestinal organs by absorbing and transferring metabolites derived from microorganisms. As a result of this transfer, islets may be continuously exposed to gut-derived metabolites and components. Changes in the composition of gut microbiota can damage the intestinal barrier function to varying degrees, resulting in increased intestinal permeability to bacteria and their derivatives. All these changes contribute to the severe disturbance of critical metabolic pathways in peripheral tissues and organs. In this review, we have outlined the different gut-islet axis signalling mechanisms associated with metabolism and summarized the latest progress in the complex signalling molecules of the gut and gut microbiota. In addition, we will discuss the impact of the gut renin-angiotensin system (RAS) on the various components of the gut-islet axis that regulate energy and glucose homeostasis. This work also indicates that therapeutic approaches aiming to restore gut microbial homeostasis, such as probiotics and faecal microbiota transplantation (FMT), have shown great potential in improving treatment outcomes, enhancing patient prognosis and slowing down disease progression. Future research should further uncover the molecular links between the gut-islet axis and the gut microbiota and explore individualized microbial treatment strategies, which will provide an innovative perspective and approach for the diagnosis and treatment of metabolic diseases.

Keywords: glucose homeostasis; gut microbiota; gut–islet axis; incretin; renin–angiotensin system.

FIGURE 1

The regulation of enteroendocrine hormones on organismal metabolism and pancreatic function. The intestinal epithelium consists of a variety of cell types, including EECs such as L‐cells, K‐cells and I‐cells, which are responsible for secreting GLP‐1, GIP and CCK, respectively. The secretion of these hormones is triggered upon nutritional stimulation of G protein‐coupled receptors (GPCRS) in the cell membrane. Some of the nutrients responsible for the secretion of enteroendocrine hormones are glucose, lipids, some amino acids and proteins. After secretion, enteroendocrine hormones play a physiological role in the pancreas and extra‐pancreatic tissues such as central nervous system, liver, muscle, adipose tissue, digestive system, and so forth. CHOL, Cholesterol; FFA1, Free Fatty Acid Receptor; GcgR, glucagon receptor; GIP, Glucose‐dependent insulinotropic peptide; GLP‐1, Glucagon‐like peptide‐1; GLP‐2, Glucagon‐like peptide‐2; LCFA, Long‐chain fatty acid; NPYRs, Neuropeptide Y receptors; OXM, Oxyntomodulin; PYY, Peptide YY; SLC2A1, Glucose transporter type 1; SLC5A, Sodium‐dependent glucose cotransporter; TAG, Triacylglyceride; VLDL, Very‐low‐density lipoprotein.

FIGURE 2

The effects of gut microbiota and intestinal barrier integrity on islet function. (A) Healthy gut microbiota and intact intestinal barrier function have been shown to reduce oxidative stress and inflammatory status by maintaining intestinal homeostasis and the release of enteroendocrine hormones and limiting the contact of external intestinal organs with microbial antigens and their active metabolites. Therefore, this translates into higher storage of islet function, increased insulin synthesis and release, and exerts a protective effect on islet function. (B) A high‐fat diet affects the composition or diversity of microbiota, promotes dysregulation of gut microbiota, aggravates intestinal oxidative stress and LPS‐induced intestinal damage, resulting in loss of tight junction integrity and increased intestinal permeability, and reduces the release of enteroendocrine hormones such as GLP‐1. Elevated levels of intestine‐borne bacterial products in blood can exacerbate tissue inflammation and metabolic disorders. Intestinal bacterial translocations and their products accumulate in the pancreas, resulting in increased islet inflammation and impaired insulin secretion, significantly affecting the function and survival of pancreatic cells. AHR, Aryl Hydrocarbon Receptor; AMPs, Antimicrobial peptides; GLP‐1, Glucagon‐like peptide‐1; GLP‐2, Glucagon‐like peptide‐2; GPR43, G protein‐coupled receptor 43; IL‐1β, Interleukin‐1β; IL‐6, Interleukin‐6; LPS, lipopolysaccharide; NPYRs, Neuropeptide Y receptors; PYY, Peptide YY; SCFA, Short‐ chain fatty acid; TLRs, Toll‐like receptors; TNF‐α, Tumour Necrosis Factor‐α.

FIGURE 3

Major components of the Intestinal Barrier. (A) In the small intestine, Paneth cells secrete chemical barrier molecules, including antimicrobial peptides, that primarily help to separate gut microbiota from IECs. The gut microbiota triggers the activation of NK cells, ILC3 cells and CD4+ T cells by activating DC in the intestinal lamina propria. NK cells can secrete various cytokines (such as INF‐γ and TNF‐α) that help enhance the function of other immune cells and promote the repair of intestinal epithelial cells. The activation of ILC3s and CD4+ T cells can promote the secretion of mucus, AMPs and IgA in plasma cells and induce the production of chemical barrier molecules from IECs. In addition, CD8+ T cell activation induced by CD4+ T cells plays an inhibitory role in intestinal infection. (B) In the colon, the mucus layer consists of a polymerized MUC2 mucin mesh structure that separates a large number of gut microbiota from IECs. Lypd8 inhibits bacterial invasion of the mucosa by binding to gut microbiota, resulting in the separation of microbiota from IECs. In addition, connective molecules between intestinal epithelial cells, including tight junctions, block microbiota invasion through paracellular pathways and also constitute an important physical barrier to the gut. AMPs, Antimicrobial peptides; DC, Dendritic cell; ILC3, Type 3 innate lymphoid cell; IL‐17, Interleukin‐17; IL‐22, Interleukin‐22; INF‐γ, Interferon‐γ; MUC2, mucin 2; NK cell, Natural killer cell; SAA, Serum amyloid A; SFB, Segmented filamentous bacteria; TNF‐α, Tumour Necrosis Factor‐α.

FIGURE 4

The schematic diagram of the regulation of intestinal ACE2 on islet function. ① The expression of ACE2 can significantly inhibit the activation of the RAS in IECs, alleviate oxidative damage and inflammatory responses, modulate the gut microbiota and improve intestinal barrier function and absorption capabilities; ② ACE2 and B⁰AT1 form heterodimer structures on the luminal surface of intestinal epithelial cells and regulate the transport and absorption of Trp; ③ Once Trp is transported into the IECs via the B⁰AT1/ACE2 transporter, it can activate the mTOR signalling pathway, which regulates the expression of antimicrobial peptides and α‐defensins, thereby influencing the composition of the gut microbiota and maintaining intestinal homeostasis； ④ Trp can both act on the intestine to promote the secretion of enteroendocrine hormones and circulate to the pancreas to stimulate the secretion of endogenous GLP‐1 in islets, and regulate the function of islet cells. ACE2, Angiotensin‐converting enzyme 2; ACE, Angiotensin‐converting enzyme; Ang1‐7, Angiotensin 1–7; AngII, Angiotensin II; B⁰AT1, Neutral amino acid transporter; GLP‐1, Glucagon‐like peptide 1; GPR142, G‐protein coupled receptor 142; Trp, Tryptophan.