Anaerostipes hadrus, a butyrate-producing bacterium capable of metabolizing 5-fluorouracil.

Anaerostipes hadrus (A. hadrus) is a dominant species in the human gut microbiota and considered a beneficial bacterium for producing probiotic butyrate. However, recent studies have suggested that A. hadrus may negatively affect the host through synthesizing fatty acid and metabolizing the anticancer drug 5-fluorouracil, indicating that the impact of A. hadrus is complex and unclear. Therefore, comprehensive genomic studies on A. hadrus need to be performed. We integrated 527 high-quality public A. hadrus genomes and five distinct metagenomic cohorts. We analyzed these data using the approaches of comparative genomics, metagenomics, and protein structure prediction. We also performed validations with culture-based in vitro assays. We constructed the first large-scale pan-genome of A. hadrus (n = 527) and identified 5-fluorouracil metabolism genes as ubiquitous in A. hadrus genomes as butyrate-producing genes. Metagenomic analysis revealed the wide and stable distribution of A. hadrus in healthy individuals, patients with inflammatory bowel disease, and patients with colorectal cancer, with healthy individuals carrying more A. hadrus. The predicted high-quality protein structure indicated that A. hadrus might metabolize 5-fluorouracil by producing bacterial dihydropyrimidine dehydrogenase (encoded by the preTA operon). Through in vitro assays, we validated the short-chain fatty acid production and 5-fluorouracil metabolism abilities of A. hadrus. We observed for the first time that A. hadrus can convert 5-fluorouracil to α-fluoro-ß-ureidopropionic acid, which may result from the combined action of the preTA operon and adjacent hydA (encoding bacterial dihydropyrimidinase). Our results offer novel understandings of A. hadrus, exceptionally functional features, and potential applications. IMPORTANCE: This work provides new insights into the evolutionary relationships, functional characteristics, prevalence, and potential applications of Anaerostipes hadrus.

Gut commensal Christensenella minuta modulates host metabolism via acylated secondary bile acids.

A strong correlation between gut microbes and host health has been observed in numerous gut metagenomic cohort studies. However, the underlying mechanisms governing host-microbe interactions in the gut remain largely unknown. Here we report that the gut commensal Christensenella minuta modulates host metabolism by generating a previously undescribed class of secondary bile acids with 3-O-acylation substitution that inhibit the intestinal farnesoid X receptor. Administration of C. minuta alleviated features of metabolic disease in high fat diet-induced obese mice associated with a significant increase in these acylated bile acids, which we refer to as 3-O-acyl-cholic acids. Specific knockout of intestinal farnesoid X receptor in mice counteracted the beneficial effects observed in their wild-type counterparts. Finally, we showed that 3-O-acyl-CAs were prevalent in healthy humans but significantly depleted in patients with type 2 diabetes. Our findings indicate a role for C. minuta and acylated bile acids in metabolic diseases.