Gut bacteria turn plant sterols into sulfates that build up in aging mouse tissues

The body absorbs only about 5% of dietary phytosterols, versus roughly 50% of dietary cholesterol, largely because ABCG5/ABCG8 transporters efficiently export phytosterols from intestinal cells. Mutations in these transporters are associated with abnormal phytosterol accumulation and disorders including premature atherosclerosis. This study examined whether gut bacteria alter phytosterol metabolism through sulfation and whether the resulting metabolites accumulate in mouse tissues.

The researchers reanalyzed published untargeted lipidomics datasets and conducted bacterial culture and enzyme experiments. In feces from 2-month-old germ-free mice versus specific pathogen-free mice, with three mice per group, sitosterol sulfate (SIS) and stigmasterol sulfate were reduced by 98.2% and 99.2%, respectively. Campesterol sulfate fell 87.4%, and coprostanol sulfate fell 64.6%. Cholesterol sulfate was not significantly reduced, suggesting a minor microbial contribution to fecal cholesterol sulfate under these conditions. SIS, campesterol sulfate, stigmasterol sulfate, and coprostanol sulfate were also significantly reduced after antibiotic treatment. Brassicasterol sulfate was detected in that fecal dataset.

Six of ten tested Bacteroidota species produced both cholesterol sulfate and SIS in sterol-supplemented cultures: Parabacteroides goldsteinii, P. johnsonii, Bacteroides uniformis, B. fragilis, B. caccae, and B. thetaiotaomicron. Each carried a sult homolog with 75–98% amino-acid sequence identity to the P. merdae query protein. Expressing these homologs in E. coli enabled SIS production. The other four species produced neither metabolite, and no corresponding homolog was detected in the reported searches.

Purified bacterial, mouse, and human sulfotransferases all produced SIS, but their relative substrate preferences differed. With each enzyme's cholesterol sulfate quantity normalized to 100%, SIS production was 51.6% for B. thetaiotaomicron Sult, 19.5% for mouse Sult2b1b, and 11.4% for human SULT2B1b. These are relative product quantities, not substrate conversion percentages or kinetic rates.

The abstract reports that SIS accumulated in mouse tissues in a microbiota- and age-dependent manner, whereas unconjugated phytosterols were mostly undetectable. The available tissue-results section describes an analysis of 19-month-old male mice, but ends before detailed SIS results. It therefore does not verify the number of SIS-positive tissues, tissue-specific concentrations, or the magnitude of age-related increases.

The findings identify a microbial pathway that changes phytosterol metabolism and tissue distribution. They do not establish that SIS affects aging, lifespan, or disease. Its physiological effects in mice and humans remain largely unknown, and the supplied text does not report human plasma detection or a Crohn's disease association. The fecal comparison used small groups, the bacterial panel covered ten species, and the truncated source limits assessment of the tissue experiments and additional limitations.