Akkermansia muciniphila: is it the Holy Grail for ameliorating metabolic diseases?

Abstract

The increasing prevalence of metabolic diseases has become a severe public health problem. Gut microbiota play important roles in maintaining human health by modulating the host's metabolism. Recent evidences demonstrate that Akkermansia muciniphila is effective in improving metabolic disorders and is thus considered as a promising "next-generation beneficial microbe". In addition to the live A. muciniphila, similar or even stronger beneficial effects have been observed in pasteurized A. muciniphila and its components, including the outer membrane protein Amuc_1100, A. muciniphila-derived extracellular vesicles (AmEVs), and secreted protein P9. Hence, this paper presents a systemic review of recent progress in the effects and mechanisms of A. muciniphila and its components in the treatment of metabolic diseases, including obesity, type 2 diabetes mellitus, cardiovascular disease, and nonalcoholic fatty liver disease, as well as perspectives on its future study.

Keywords: Akkermansia muciniphila; AmEVs; Amuc_1100; P9; metabolic diseases; pasteurized A. muciniphila.

Figure 1.

Effects of Akkermansia muciniphila and its derived parts on ameliorating metabolic disorders. The level of A. muciniphila decreased in several metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), and nonalcoholic fatty liver disease (NAFLD). Many interventions based on the diet and surgery have been reported for improving the human health in context of metabolic disorder, which accompanied by the increase of A. muciniphila. A. muciniphila and its different parts, including live or pasteurized A. muciniphila, Amuc_1100, P9, as well as AmEVs, have shown to reduce body weight and fat mass gain, and regulate glucose homeostasis and intestinal barrier. Mechanistically, A. muciniphila and its different parts have shown to improve the intestinal barrier through up-regulating the expression of tight-junction proteins and reducing the leakage of LPS, thus reducing inflammation. In addition, live A. muciniphila produces acetate, propionate, and 1,2-propandiol through the fermentation of mucin. It has a nutritional interaction with butyrate-producing bacteria to stimulate the production of butyrate. These SCFAs can active GPR41 and GPR43 to affect glucose and lipid metabolism. The activation of GPR41 and GPR43 induces the intestinal L cells producing peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2) to decrease food intake. Butyrate promotes the epithelial barrier function by increasing the expression of hypoxia-inducible factor-1α (HIF-1α). Moreover, A. muciniphila, live or pasteurized, can normalize the mucus thickness and increase the number of goblet cells. Pasteurized A. muciniphila specifically decreases the expression of hepatic flavin monooxygenase 3 (FMO3), increases the excretion of TMAO and TMA in urine, and decreases the level of plasma TMAO. It may also increase fecal energy excretion to reduce obesity. Amuc_1100 can act on TLR2 to regulate intestinal homeostasis. Furthermore, the newly identified secreted protein P9 can bind to ICAM-2 to trigger the secretion of GLP-1 by L cells. Both P9 and AmEVs can simulate IL-6, leading to further secretion of GLP-1. The above mechanism was summarized based on existing articles; however, there may be other mechanisms