Divergent immune responses to commensal bacteria bearing distinct motility signatures

Adaptive immune responses to commensal flagellins are hallmarks of Crohn’s disease (CD), but it is unclear whether flagellins themselves promote inflammation or whether flagellated commensals can also be colitogenic. Here, we show that the arrangement of motility loci and the diversity of encoded flagellins can separate flagellated gut-derived Clostridia into at least two functionally distinct groups. In gnotobiotic mice, both groups induce tolerogenic responses, but only one group promoted tissue inflammation after barrier disruption. Specific flagellins expressed by members of this proinflammatory group displayed a heightened capacity for TLR5 activation that could be modulated by modification of a defined region of the flagellin D0 domain. Bacteria belonging to the proinflammatory group were also found to be elevated in CD biopsies. Together, this study identified key features of specific commensal bacteria that have colitogenic potential and revealed one mechanism whereby these organisms can potentially initiate intestinal inflammation.