Macrophage–microbiome–metabolite crosstalk in diverticular disease

Diverticular disease is increasingly considered a dynamic disorder in which structural susceptibility of the colonic wall intersects with microbial ecology, mucosal immunity, and metabolic signaling. Macrophages occupy a pivotal position in this network because they translate luminal microbial and metabolite cues into programs of antimicrobial defense, inflammatory amplification, resolution, and matrix remodeling. Disease-associated microbial configurations can weaken colonization resistance, alter epithelial energetics, and reshape the metabolite pool available to mucosal macrophages. Conversely, macrophage-derived cytokines, reactive intermediates, and trophic factors remodel the epithelial niche and thereby influence microbial selection. Short-chain fatty acids (SCFAs) restrain inflammatory transcription while enhancing antimicrobial and reparative functions through histone deacetylase inhibition and metabolite-sensing receptors. Microbially modified bile acids engage TGR5 and FXR, coupling bile acid chemistry to inflammasome activity, cytokine release, and motility. Tryptophan-derived indoles activate aryl hydrocarbon receptor programs that reinforce barrier defense and metabolic fitness, whereas kynurenine and serotonin pathways add further layers of immune-neural regulation. Succinate, lactate, polyamines, and microbial lipids broaden this signaling architecture by controlling hypoxia responses, protein acylation, mitochondrial function, and efferocytosis. In diverticular disease, disruption of these interlocking circuits can convert a mechanically vulnerable diverticulum into a permissive niche for persistent inflammation, impaired healing, and fibrosis. This review integrates microbial, immunological, and metabolic findings across diverticulosis, symptomatic uncomplicated diverticular disease, and diverticulitis and develops a mechanistic framework for biomarker discovery and metabolite-guided intervention.