Immune cell death in sepsis: Linking resilience, dysbiosis, and EGFR signaling.
TL;DR
This framework provides a testable model and supports interventional studies to determine whether restoration of SCFA signaling-such as through early administration of butyrate-producing microbes or tributyrin (a stable butyrate triglyceride)-can favorably alter immune trajectories and improve clinical outcomes.
Abstract
Accumulating evidence suggests that outcomes are shaped not only by age and comorbidities, but also by preexisting biological states. A key determinant is immune resilience-the capacity to restore immune function and organ homeostasis. Aging-or accelerated biological aging-promotes accumulation of senescent cells and the senescence-associated secretory phenotype (SASP), driving chronic low-grade inflammation ("inflammaging"), impairing immune function, and reducing host resilience. SASP may also prime the immune system for exaggerated inflammatory responses in sepsis, contributing to cytokine storm. Notably, hyperinflammatory and immunosuppressive responses often emerge concurrently rather than sequentially. Immune cell death pathways help explain this apparent contradiction, as highlighted in the review featured in this issue of the Journal. These pathways provide a mechanistic bridge between these seemingly opposing states. They are not merely consequences of sepsis but active determinants of immune trajectory. Loss of SCFA- producing microbiota may impair immune regulation and promote dysregulated cell death, sustaining both hyperinflammatory and immunosuppressive states. This framework provides a testable model and supports interventional studies to determine whether restoration of SCFA signaling-such as through early administration of butyrate-producing microbes or tributyrin (a stable butyrate triglyceride)-can favorably alter immune trajectories and improve clinical outcomes.