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-ÎČ-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
.