The Gut Microbiota and Diabetes: Research, Translation, and Clinical Applications-2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum

Abstract

This article summarizes the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organized by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: 1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g., genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomization in humans; 2) the highly individualized nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; 3) because single-time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and 4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.

Figure 1

Microecological and physiological differences along the GI tract (103,234). Environmental conditions vary along the GI tract depending on physical, nutritional, and biological host factors, which translate into adaptations and differences in the intestinal bacteria inhabiting the different regions and their physiological functions through multidirectional interactions that may affect glucose metabolism and diabetes risk. The main factors affecting the microbial load and composition in the different regions are as follows. 1) pH values increase drastically from the stomach (pH 1.0–4.4) to the small intestine (pH 5.5–7.0) and then more progressively to the colon, where the pH can drop again (pH 5.5) as a consequence of the microbial fermentation of complex carbohydrates (fiber). The pH increases again in feces (up to pH 7.8). 2) Intestinal transit is shorter and peristaltic movements are more intense in the small intestine than in the large intestine. 3) Small intestinal host epithelial cells (Paneth cells) secrete AMPs, acting as an innate defensive barrier reducing bacterial colonization, and M cells of Peyer’s patches also pick up bacteria from the intestinal lumen. 4) Oxygen levels are also progressively reduced from the small intestine to the large intestine. 5) Dietary nutrients (proteins, lipids, and simple carbohydrates) are primarily digested by host enzymes and rapidly absorbed in the small intestine, limiting the accessibility of nutrients to intestinal bacteria; in contrast, partially undigested dietary residues (complex carbohydrates and partially hydrolyzed proteins/amino acids) accumulate in the large intestine, where they serve as nutrients for bacteria. 6) Host glycans forming part of the mucous layer (produced by goblet cells), which is remarkably thicker in the large intestine than in the small intestine, also represents a nutrient source for intestinal bacteria, supporting their growth. 7) Bile acids are secreted to the small intestine, inhibiting and favoring the growth of specific bacteria that participate in their metabolism and recirculation. Altogether, those abiotic and biotic factors affect the ecological conditions that facilitate the survival of denser populations of bacteria moving to the most distal parts of the intestine (from 10²–10⁴bacterial cells/g in the duodenum to 10⁷–10⁹ in the ileum and 10¹¹–10¹² in the colon) and account for differences in bacterial composition, with facultative anaerobes preferentially colonizing the small intestine and strict anaerobes dominating the microbiota of the large intestine, including butyrate producers. In the large intestine, EECs, mainly L-cells, are stimulated by SCFAs (butyrate and propionate) to induce the hormones GLP-1 and PYY, which contribute to insulin secretion and glucose homeostasis and regulate appetite. In the small intestine, other EECs, such as I-cells, predominate and produce the hormone CCK, which induces digestive enzymes and bile and suppresses appetite. This is also the main region where nutrient signals are sensed by the enteric neurons and vagal afferents and thus signal to the brain to control energy homeostasis, although knowledge of the role of the gut microbiota in their regulation is limited. SCFAs, especially butyrate, can also induce immunoregulatory T cells (T-regs) that protect against obesity-induced proinflammatory macrophages and prevent LPS translocation. AA, amino acid; AMPs, antimicrobial peptides; CCK, cholecystokinin; PYY, peptide YY.

Figure 2

GM metabolites and signaling molecules linked to glucose metabolism and type 2 diabetes. Structural and secreted GM proteins are involved in the modulation of immune responses and inflammation, as shown for a protein secreted by F. prausnitzii (microbial anti-inflammatory molecule [MAM]), which is able to inhibit the nuclear factor-κB (Nf-κB) pathway. Another example is Amuc_1100, an outer membrane protein of A. muciniphila, which improves the gut barrier and decreases inflammation. The GM also produces SCFAs, which stimulate the release of incretin hormones and improve peripheral tissue metabolism. In addition, SCFAs modulate immune cell function, improve the gut barrier, and stimulate enteric neuron signaling. The SCFA butyrate also provides energy to colonocytes and increases colonocyte β-oxidation (β-ox) by activating peroxisome proliferator-activated receptor-γ (PPARγ). Bile acid signaling through the bile acid receptors FXR and TGR5 modulates metabolic responses in several different tissues. GM tryptophan metabolites, such as indolepropionic acid (IPA) and indoleacrylic acid (IA), modulate immune and metabolic responses by improving the gut barrier through the pregnane X receptor (PXR) and by signaling through the aryl hydrocarbon receptor (AHR) on intestinal immune cells and increasing the production of interleukin-22 (IL-22). In the bloodstream, IPA and IA also provide antioxidant and anti-inflammatory functions. Imidazole propionate and BCAAs impair insulin signaling through activation of the mechanistic target of rapamycin complex 1 (mTORC1). The GM also produces ethanol, which is linked to fatty liver disease and insulin resistance. IL-10, interleukin-10; IRS1, insulin receptor substrate 1; PYY, peptide YY. Adapted from Caesar (235) with permission from Elsevier.

Figure 3

GM interactions with glucose-lowering medications. GM metabolites are involved in the mechanism of action of metformin, including bile acid (BA) signaling through the bile acid receptors FXR and TGR5 and production of SCFAs, which modulate the release of incretin hormones such GLP-1, gastric inhibitory polypeptide (GIP), and peptide YY (PYY) from enteroendocrine cells (K- and L-cells). Other GM-dependent mechanisms involved in the action of metformin include improved glucose sensing through sodium–glucose cotransporter 1 (SGLT1) and an improved gut barrier (e.g., restoration of tight junctions and increase in mucin-producing goblet cells [236,237]). However, through the expression of DPP-4 isozymes, the GM might decrease GLP-1 activity and affect the efficacy of glucose-lowering drugs. Adapted from Caesar (235) with permission from Elsevier.