Identification of unique bile acid-metabolizing bacteria from the microbiome of centenarians

Abstract

Centenarians, or individuals who have lived more than a century, represent the ultimate model of successful longevity associated with decreased susceptibility to ageing-associated illness and chronic inflammation. The gut microbiota is considered to be a critical determinant of human health and longevity. Here we show that centenarians (average 107 yo) have a distinct gut microbiome enriched in microbes capable of generating unique secondary bile acids, including iso-, 3-oxo-, and isoallo-lithocholic acid (LCA), as compared to elderly (85-89 yo) and young (21-55 yo) controls. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from a centenarian’s faecal microbiota, we identified Parabacteroides merdae and Odoribacteraceae strains as effective producers of isoalloLCA. Furthermore, we generated and tested mutant strains of P. merdae to show that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH) were responsible for isoalloLCA production. This secondary bile acid derivative exerted the most potent antimicrobial effects among the tested bile acid compounds against gram-positive (but not gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and vancomycin-resistant Enterococcus faecium. These findings suggest that specific bile acid metabolism may be involved in reducing the risk of pathobiont infection, thereby potentially contributing to longevity.

A Bacterial Bile Acid Metabolite Modulates TregActivity through the Nuclear Hormone Receptor NR4A1

“…This gene cluster is found in many prevalent Bacteroidetes strains, suggesting that this pathway may play an important role in the gut environment. Interestingly, isoalloLCA and other secondary bile acid metabolites, including deoxycholic acid (DCA), have been shown to inhibit the growth of non-Bacteroidetes species, affording a competitive advantage to the producing bacteria in a complex microbial community (Honda et al, 2020, under review) (Buffie et al, 2015). This study and our earlier work (Hang et al, 2019) suggest that isoalloLCA production by gut bacteria induces host immune tolerance through Treg induction, an immunoregulatory response that may benefit the host in the context of autoimmune and inflammatory diseases including IBD.…”