Abstract

The maintenance of immune homeostasis is critical for tissue health and longevity, yet the regulatory mechanisms linking immune modulation to aging remain poorly understood. Here we found that the transcription factor cAMP response element-binding protein (CREB), activated by JNK signaling in aging guts, transcriptionally suppresses peptidoglycan recognition protein SC2( PGRP-SC2) —a homolog of anti-inflammatory PGLYRP1–4 with amidase activity. 16S rRNA sequencing revealed that CREB modulates not only microbial load but also microbiota composition. Elevated CREB activity decreased the Firmicutes/Bacteroidetes (F/B) ratio—a hallmark of age-associated dysbiosis in animals. Genetic enhancement of PGRP-SC2 rescues age-related gut hyperplasia, microbiota imbalance, and lifespan shortening induced by overactivation of CREB or its coactivator CRTC. Notably, CREB’s regulation of PGRP-SC2 operates independently of canonical immune pathways such as Imd/Relish, revealing a previously unrecognized layer of immune modulation. Our findings establish CREB as a central player in age-associated immune dysregulation and propose targeting the CREB-PGRP-SC2 axis as a potential therapeutic strategy for mitigating gut aging and its systemic consequences.