The gut microbiota produce hundreds of molecules that are present at high concentrations in the host circulation. Unraveling the contribution of each molecule to host biology remains difficult. We developed a system for constructing clean deletions in spp., the source of many molecules from the gut microbiome. By applying this method to the model commensal organism , we knocked out genes for 10 -derived molecules that accumulate in host tissues. In mice colonized by a for which the production of branched short-chain fatty acids was knocked out, we discovered that these microbial products have immunoglobulin A-modulatory activity.