Defining a pathogen in the context of chronic disease and the microbiome is challenging because it often violates the traditional one-bug–one-disease paradigm and foundational microbiological principles such as Koch’s postulates. In many complex chronic diseases—particularly those involving the human gut—pathogenicity emerges not from a single organism but from a consortium of microbes whose collective activity forms a dysbiosis that promotes disease. Despite these challenges, several resident gut bacteria are increasingly associated with disease states. This includes members of the Lachnospiraceae, particularly Enterocloster species and Mediterraneibacter gnavus. Our laboratory has been investigating the properties of these bacteria and have found that their diverse bile-acid-metabolizing capacities and distinctive metabolite profiles are linked to disease in multiple contexts. For example, certain Enterocloster species are associated with improved outcomes in individuals with IBD, whereas others are enriched during disease flares. Unique metabolites produced by Enterocloster spp., including N-acylated polyamines—typically harmless in most settings—are associated with failure of immune checkpoint inhibitor therapy in various cancers. Ultimately, it is the collective metabolic output of a dysbiotic microbiome that determines its impact on human health or disease. Even with the complexity of the gut microbiome and the wide range of conditions that arise from it, some universal “bad actors” are beginning to emerge, offering potential targets for microbiome-mediated therapeutics.