Search

The intestinal microbiota regulates immunity across organ systems. Which symbionts control systemic immunity, the mechanisms they use, and how they avoid widespread inflammatory damage are unclear. We uncover host tolerance and resistance mechanisms that allow Firmicutes from the human microbiota to control systemic immunity without inducing immunopathology. Intestinal processing releases Firmicute glycoconjugates that disseminate, resulting in release of cytokine IL-34 that stimulates macrophages and enhances defenses against pneumonia, sepsis, and meningitis. Despite systemic penetration of Firmicutes, immune homeostasis is maintained through feedback control whereby IL-34-mediated mTORC1 activation in macrophages clears polymeric glycoconjugates from peripheral tissues. Smaller glycoconjugates evading this clearance mechanism are tolerated through sequestration by albumin, which acts as an inflammatory buffer constraining their immunological impact. Without these resistance and tolerance mechanisms, Firmicutes drive catastrophic organ damage and cachexia via IL-1β. This reveals how Firmicutes are safely assimilated into systemic immunity to protect against infection without threatening host viability. [Display omitted] • Intestinal Firmicutes control systemic immunity • Firmicute cell wall glycoconjugates control immunity via IL-34-MØ-mTORC1 • IL-34 prevents systemic accumulation of glycoconjugates—homeostasis by resistance • Albumin buffers the inflammatory impact of glycoconjugates—homeostasis by tolerance Jordan et al. report mechanisms of tolerance and resistance that integrate cell wall glycoconjugates from intestinal Firmicutes into systemic immunity, leading to enhanced protection against pneumonia, sepsis, and meningitis. Without these mechanisms, the assimilation of these Firmicutes components goes awry, leading to devasting inflammatory cachexia. [ABSTRACT FROM AUTHOR]