A Pathobiont of the Microbiota Balances Host Colonization and Intestinal Inflammation

The mammalian gastrointestinal tract harbors a diverse microbiota residing in intimate contact with the host immune system. Though most associations are symbiotic or commensal, some resident bacteria (termed pathobionts) have the potential to induce disease in immunocompromised hosts. Type VI secretion systems (T6SSs) have recently emerged as a novel mechanism for forging microbial-host interactions during infection. We reveal here a unique protective role for the T6SS of Helicobacter hepaticus, a Gram-negative bacterium of the murine intestinal microbiota. The T6SS of H. hepaticus targets effector substrates to intestinal epithelial cells (IECs). Mutants in T6SSs display higher intracellular and cell-associated numbers upon incubation with IECs, and exhibit increased bacterial colonization of the gastrointestinal tract compared to wild-type bacteria. The T6SS accordingly directs an anti-inflammatory gene expression profile in IECs co-cultured with H. hepaticus. Remarkably, T6SS mutants induce an exacerbated pro-inflammatory response in an experimental model of colitis. CD4+ T cells isolated from T6SS mutant-colonized animals produce increased T-helper 17 (Th17) cytokines in response to IECs presenting H. hepaticus antigens. These data demonstrate that H. hepaticus intimately interacts with IECs and employs type VI secretion to establish a balanced host relationship by limiting microbial colonization and intestinal inflammation. We propose that altering host-bacterial equilibriums that lead to dysbiosis of the microbiota contributes to human disorders such as inflammatory bowel disease and colon cancer. RNA was harvested from MODE-K intestinal epithelial cells incubated for 6hr with either wild-type H. hepaticus, ΔIcmF mutant, or no bacteria. RNA was prepared using TRIzol. RNA was labeled and hybridized to Agilent microarrays (Whole Mouse Genome Microarray) following manufacturer's instructions. Microarrays were scanned using an Agilent DNA Microarray Scanner G2565CA, and data were acquired using Agilent's Feature Extraction Software version 10.1.1.1. Significant genes were selected based on p<0.05 and fold change >1.5.