Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway.

The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo. By activity-based protein purification and identification, we identified an enzyme annotated as ß-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila. Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.

The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice.

Polycystic ovary syndrome (PCOS), an endocrine disorder afflicting 6-20% of women of reproductive age globally, has been linked to alterations in the gut microbiome. We previously showed that in PCOS, elevation of Bacteroides vulgatus in the gut microbiome was associated with altered bile acid metabolism. Here we show that B. vulgatus also induces a PCOS-like phenotype in female mice via an alternate mechanism independent of bile acids. We find that B. vulgatus contributes to PCOS-like symptoms through its metabolite agmatine, which is derived from arginine by arginine decarboxylase. Mechanistically, agmatine activates the farnesoid X receptor (FXR) pathway to subsequently inhibit glucagon-like peptide-1 (GLP-1) secretion by L cells, which leads to insulin resistance and ovarian dysfunction. Critically, the GLP-1 receptor agonist liraglutide and the arginine decarboxylase inhibitor difluoromethylarginine ameliorate ovarian dysfunction in a PCOS-like mouse model. These findings reveal that agmatine-FXR-GLP-1 signalling contributes to ovarian dysfunction, presenting a potential therapeutic target for PCOS management.

Border fences reduce potential for transboundary migration of Marco Polo Sheep (Ovis ammon polii) in the Pamir Plateau.

Border fences have severely impeded the transboundary migration of a number of large mammals worldwide, with central Asia being one of the most impacted. The Marco Polo sheep (Ovis ammon polii), an iconic species of Pamir, is threatened in its transboundary movement by increasing border fencing among their five distributed countries, including Tajikistan, Kyrgyzstan, China, Afghanistan, and Pakistan. In this study, by building ensemble species distribution models, we found that eastern Tajikistan had the largest suitable Macro Polo sheep habitat (about 42 % of the total suitable habitat), followed by China (about 32 %). We used least-cost paths to identify 51 ecological corridors including 5 transboundary ecological corridors, which may be important to maintain connectivity in both domestic and transboundary regions. To assess the potential barrier effect of border fences, we assessed four scenarios (30, 40, 50 and 60°) corresponding to the upper limit of the slope for the construction of fences. In areas too steep for fencing, these could be used by wild sheep to cross barriers or borders and may represent migration or movement routes, defined as natural passages. In the most pessimistic Scenario 60, only 25 migratory passages along the border fences were identified, compared to 997 in the most optimistic scenario (Scenario 30), indicating a strong negative effect of intensive border fencing on the transboundary movement of Marco Polo sheep. The establishment of transnational conservation parks, and ensuring permeability is maintained in key areas, could have a positive impact on the connectivity and persistence of Marco Polo sheep populations, and provide important lessons for other large migratory mammals in transboundary regions.