Urease in acetogenic <i>Lachnospiraceae</i> drives urea carbon salvage in SCFA pools

The gut microbiota produces short-chain fatty acids (SCFA) and acidifies the proximal colon which inhibits enteric pathogens. However, for many microbiota constituents, how they themselves resist these stresses is unknown. The anaerobic <i>Lachnospiraceae</i> family, which includes the acetogenic genus <i>Blautia</i>, produce SCFA, are genomically diverse, and vary in their capacity to acidify culture media. Here, we investigated how <i>Lachnospiraceae</i> tolerate pH stress and found that subunits of urease were associated with acidification in a random forest model. Urease cleaves urea into ammonia and carbon dioxide, however the role of urease in the physiology of <i>Lachnospiraceae</i> is unknown. We demonstrate that urease-encoding <i>Blautia</i> show urea-dependent changes in SCFA production, acidification, growth, and, strikingly, urease encoding <i>Blautia</i> directly incorporate the carbon from urea into SCFAs. In contrast, ureolytic <i>Klebsiella pneumoniae</i> or <i>Proteus mirabilis</i> do not show the same urea-dependency or carbon salvage. In agreement, the combination of urease and acetogenesis functions is rare in gut taxa. We find that <i>Lachnospiraceae</i> urease and acetogenesis genes can be co-expressed in healthy individuals and colonization of mice with a ureolytic <i>Blautia</i> reduces urea availability in colon contents demonstrating <i>Blautia</i> urease activity <i>in</i> <i>vivo</i>. In human and mouse microbial communities, the acetogenic recycling of urea carbon into acetate by <i>Blautia</i> leads to the incorporation of urea carbon into butyrate indicating carbon salvage into broader metabolite pools. Altogether, this shows that urea plays a central role in the physiology of health-associated <i>Lachnospiraceae</i> which use urea in a distinct manner that is different from that of ureolytic pathogens.