Gut Akkermansia muciniphila ameliorates metabolic dysfunction-associated fatty liver disease by regulating the metabolism of L-aspartate via gut-liver axis

Abstract

The gut bacterium Akkermansia muciniphila has been increasingly recognized for its therapeutic potential in treating metabolic disorders, including obesity, diabetes, and metabolicdysfunctionassociated fatty liver disease (MAFLD). However, its underlying mechanism involved in its wellknown metabolic actions needs further evaluation. The present study explored the therapeutic effect and mechanism of A. muciniphila in intervening MAFLD by using a high-fat and highcholesterol (HFC) diet induced obese mice model. Mice treated with A. muciniphila efficiently reversed MAFLD in the liver, such as hepatic steatosis, inflammatory, and liver injury. These therapeutic effects persisted after long-term drug withdrawal and were slightly weakened in the antibiotics-treated obese mice. A. muciniphila treatment efficiently increased mitochondrial oxidation and bile acid metabolism in the gut-liver axis, ameliorated oxidative stress-induced cell apoptosis in gut, leading to the reshaping of the gut microbiota composition. These metabolic improvements occurred with increased L-aspartate levels in the liver that transported from the gut. The administration of L-aspartate in vitro or in mice displayed the similar beneficial metabolic effects mentioned above and efficiently ameliorated MAFLD. Together, these data indicate that the anti-MAFLD activity of A. muciniphila correlated with lipid oxidation and improved gut-liver interactions through regulating the metabolism of L-aspartate. A. muciniphila could be a potential agent for clinical intervention in MAFLD.

Serum metabolite profiling yields insights into health promoting effect of A. muciniphila in human volunteers with a metabolic syndrome

“…In line with this, a recent in vivo study in mice confirmed that A. muciniphila inoculation not only promoted efflux of fatty acids through positive modulation of genes involved in hepatic lipid transport, but also resulted in a higher number of mitochondria. 60 Our hypothesis is further substantiated by recent research, including studies performed in our lab, showing that direct inoculation or indirect diet-mediated A. muciniphila enrichment in rodents activates a network of genes involved in lipid oxidation in adipose and liver tissue. 3 , 60–67 These include gene encoding for PPARα, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α), and carnitine palmitoyl‐transferase I (CPT‐I).…”

“… 60 Our hypothesis is further substantiated by recent research, including studies performed in our lab, showing that direct inoculation or indirect diet-mediated A. muciniphila enrichment in rodents activates a network of genes involved in lipid oxidation in adipose and liver tissue. 3 , 60–67 These include gene encoding for PPARα, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α), and carnitine palmitoyl‐transferase I (CPT‐I). PPARα is a key sensor of fatty acid flux whose activation, together with PGC1α, stimulated the expression of CPT-I isoform α.…”

“… 41 As for our result regarding amino-acid metabolism, this is also in line with numerous murine studies showing that A. muciniphila lowers hepatic inflammation and steatosis. 60 , 78–80 …”

Hyperoxia Provokes Time- and Dose-Dependent Gut Injury and Endotoxemia and Alters Gut Microbiome and Transcriptome in Mice

“…The bacterial DNA was extracted from the fecal pellets with a Guide S96 DNA kit (Tiangen, Beijing, China), according to the instructions of the manufacturer. PCR amplification was carried out using 16S rRNA primers targeting the variable region V3-V4: 5′-ACTCCTACGGGAGGCAGCA-3′ and 5′-GGACTACHVGGGTWTCTAAT-3′ ( 25 ). Sequencing libraries were constructed and paired-ended sequencing was conducted on an Illumina NovaSeq 6000 platform (Illumina, San Diego, CA, USA) at Biomarker Technologies Company (Beijing, China).…”

Surface-Displayed Amuc_1100 From Akkermansia muciniphila on Lactococcus lactis ZHY1 Improves Hepatic Steatosis and Intestinal Health in High-Fat-Fed Zebrafish

“…Akkermansia muciniphila is a human intestinal gram-negative anaerobic bacteria, with promising probiotic activities against many metabolic-related diseases such as obesity, diabetes, inflammatory bowel disease, etc. (3)(4)(5)(6)(7). Amuc_1100 (AM protein), a highly abundant pili-like membrane protein of A. muciniphila, partly recapitulates the beneficial effects of A. muciniphila (8,9).…”