Band, V. I.; Gribonika, I.; Stacy, A.; Bouladoux, N.; Mistry, S.; Burns, A.; Perez-Chaparro, P. J.; Chau, J.; Enamorado, M.; Nagai, M.; Bhushan, V.; Golec, D. P.; Schwartzberg, P. L.; Hourigan, S. K.; Nita-Lazar, A.; Belkaid, Y.

Hydrogen sulfide is a gaseous, reactive molecule specifically enriched in the gastrointestinal tract. Here, we uncover a non-redundant role for sulfide in the control of both microbial and immune homeostasis of the gut. Notably, depletion of sulfide via both pharmaceutical and dietary interventions led to a profound collapse of CD4 T cells in the ileum of the small intestine lamina propria and significant impact on microbial ecology. As a result, mice with reduced sulfide within the gut were deficient in their ability to mount T cell dependent antibody responses to oral vaccine. Mechanistically, our results support the idea that sulfide could act directly on CD4 T cells via enhanced AP-1 activation, leading to heightened proliferation and cytokine production. This study uncovers sulfides as keystone components in gut ecology and provides mechanistic insight between diet, gut sulfide production and mucosal immunity.