The influence of Akkermansia muciniphila on intestinal barrier function

Abstract

Intestinal barriers play a crucial role in human physiology, both in homeostatic and pathological conditions. Disruption of the intestinal barrier is a significant factor in the pathogenesis of gastrointestinal inflammatory diseases, such as inflammatory bowel disease. The profound influence of the gut microbiota on intestinal diseases has sparked considerable interest in manipulating it through dietary interventions, probiotics, and fecal microbiota transplantation as potential approaches to enhance the integrity of the intestinal barrier. Numerous studies have underscored the protective effects of specific microbiota and their associated metabolites. In recent years, an increasing body of research has demonstrated that Akkermansia muciniphila (A. muciniphila, Am) plays a beneficial role in various diseases, including diabetes, obesity, aging, cancer, and metabolic syndrome. It is gaining popularity as a regulator that influences the intestinal flora and intestinal barrier and is recognized as a 'new generation of probiotics'. Consequently, it may represent a potential target and promising therapy option for intestinal diseases. This article systematically summarizes the role of Am in the gut. Specifically, we carefully discuss key scientific issues that need resolution in the future regarding beneficial bacteria represented by Am, which may provide insights for the application of drugs targeting Am in clinical treatment.

Keywords: Akkermansia muciniphila; Cross-feeding; Immunity; Inflammation; Intestinal barrier.

Fig. 1

Intestinal barrier structure. The mechanical barrier includes intact epithelial cells, a lipid bilayer with tight brush borders of epithelial cells, and cell junctions at the lateral borders of the cells. The chemical barrier consists of digestive juices secreted by the gastrointestinal tract, digestive enzymes, and antibacterial substances produced by the normal intestinal microbiota. The immune barrier is primarily composed of gut-associated lymphoid tissue and secretory immunoglobulins. The biological barrier represents an interdependent and interacting microecosystem composed of the resident intestinal microbiota

Fig. 2

The mechanism by which Am increases intestinal integrity. (A): Am upregulates the expression of the NLRP6 inflammasome, which accelerates autophagy in goblet cells and reduces endoplasmic reticulum stress, thereby promoting mucus secretion. (B): Am increases the expression of the Wnt signaling pathway and promotes the production of SCFAs, which interact with GPCR41/43 to maintain the proliferation of ISCs and promote the differentiation of Paneth cells and goblet cells

Fig. 3

Am promotes the secretion of GLP-1. The surface membrane proteins of Am and its metabolites, SCFAs, can interact with various receptors (GPCRs, TLR2, ICAM2) on IECs to directly or indirectly increase the production of GLP-1, which inhibits the inflammatory response

Fig. 4

Am regulates Immune environment. The surface membrane proteins of Am can enhance the immune microenvironment by modulating CTLs, promoting T cell differentiation, and inducing macrophage activation

Fig. 5

eCB systems are also affected by Am. Am stimulates the IECs of the eCB system to produce 2-OG and 1-PG/2-PG, ultimately promoting the production of GLP-1 and/or GLP-2. It also activates PPARs to promote fatty acid oxidation, control energy metabolism, and reduce inflammation. Additionally, Amuc-1100 reduces intestinal permeability by upregulating the expression of genes encoding tight junctions while downregulating CB1 receptor

Fig. 6

Cross-feeding between Am and Clostridia. In the Am, fucosidase and sialidase eliminate all recognized sialic acid and fucosylmucin caps while generating locations for O-glycopeptidase to initiate Am development. The sialic acid and fucose produced during this process are cross-fed to Clostridium to form butyrate