The architecture of gut microecological networks and the governance of host metabolic homeostasis

The gut microbiota operates as a multi-layered interaction network whose functional resilience depends on structural integrity. This review systematically dissects that architecture across several interconnected dimensions: interbacterial cross-feeding and autoinducer-2 (AI-2)-mediated quorum sensing; cross-kingdom bacterial-fungal coupling via biofilms and oxygen modulation; and the Paneth cell-driven antimicrobial peptide (AMP) system, which integrates microbial metabolic output into intestinal homeostasis. In the steady state, short-chain fatty acids (SCFAs) promote Il22 expression through GPR43-dependent mTOR/STAT3 signaling, while tryptophan catabolism supplies indole-3-acetic acid to activate the aryl hydrocarbon receptor (AhR) and upregulate Il22, linking microbial function to host neuroimmune health. Concurrently, fungal secondary metabolites are emerging as underexplored regulators of host enzymes and bile acid biotransformation. Notably, these bioactive fungal molecules constitute a distinct metabolic dimension offering untapped therapeutic targets for chronic metabolic disorders. Dysbiosis reflects the synchronized collapse of these mechanisms: dysbiosis unleashes abnormal fungal metabolite output and overall fungal diversity collapses, driving inflammatory bowel disease (IBD) and metabolic dysfunction-associated steatotic liver disease (MASLD) and highlighting the intrinsic limitations of single-node therapeutic strategies. We propose a holistic, microecological perspective beyond isolated strains or pathways in both mechanistic research and clinical intervention.