Persistent molecular scars and gut-brain axis remodeling after acute DSS colitis.

The acute inflammatory phase of dextran sodium sulfate (DSS)-induced colitis has been extensively characterized, often neglecting the long-term systemic consequences that emerge during recovery. Here, we mapped the recovery landscape following acute DSS-induced colitis over a 28-day period, enabling to differentiate transient inflammation from enduring pathophysiological alterations both at peripheral and central level. Colonic recovery showed a transition to an altered steady state, characterized by an increased immune reactivity and vulnerability, rather than a return to baseline. While overt inflammation subsided, persistent molecular scars remained, characterized by early, sustained colonic fibrosis and a shift from acute myeloid infiltration to chronic CD4+ T cell predominance. Similarly, the gut microbiota did not fully revert to its pre-injury composition during late recovery, indicating the establishment of a reconfigured microbial ecosystem with potentially distinct functional properties. This peripheral picture extended to the central nervous system, where, despite partial recovery of neuroinflammatory markers, structural and metabolic alterations persisted. Notably, lateral ventricle dilation and sustained complement C3 activation highlighted a prolonged central dysregulation. Furthermore, sustained depletion of the neuroprotective metabolite taurine and impaired energy homeostasis (Cr/PCr) defined a window of neurological vulnerability, eventually compensated by restoring the balance between excitatory and inhibitory neurotransmission. Overall, a single DSS insult induces persistent immunological and structural remodeling establishing a new post-inflammatory homeostasis that provides a mechanistic link between colonic injury and delayed neurological sequelae, emphasizing the need for therapeutic strategies that extend far beyond the resolution of acute gastrointestinal symptoms.