Ex Vivo Human Colonic Explants Identify Metabolic Alterations and Cytokine Dysregulation in Ulcerative Colitis: A...

Mitochondrial dysfunction has been implicated in ulcerative colitis (UC), but human data evaluating mucosal bioenergetics alongside inflammatory responses remain limited. The contribution of metabolism to irritable bowel syndrome (IBS) is also unclear. This study aimed to characterise ex vivo colonic metabolic and inflammatory profiles across healthy control (HC), IBS, UC in remission, and active UC cohorts, and to assess associations with clinical characteristics including disease duration and progression.

Sigmoid biopsies from HC, IBS, UC in remission, and active UC were prospectively collected and underwent Seahorse analysis to quantify oxidative phosphorylation (OCR) and glycolysis (ECAR). Explant-conditioned media was analysed for ten cytokines and normalised to tissue protein. Group comparisons, principal component analysis, correlations, and multivariable regression were performed.

Twenty-four participants were included (HC n = 6, IBS n = 6, UC remission n = 6, active UC n = 8). OCR was significantly lower in UC remission (78.3 pmol O2/min/µg protein; p = 0.024) and active UC (67.1 pmol O2/min/µg protein; p = 0.004) compared with HC (571.7 pmol O2/min/µg protein). OCR:ECAR ratios were similarly reduced in UC remission (2.1; p = 0.013) and active UC (2.7; p = 0.008) versus HC (18.7). Active UC demonstrated markedly elevated IL-4, IL-6, IFN-γ, and IL-1β compared with HC. ECAR was independently associated with UC disease duration (β = 0.03; p = 0.043). IBS showed no significant metabolic or cytokine differences relative to HC.

UC is characterised by impaired oxidative phosphorylation, enhanced cytokine secretion, and greater glycolytic activity with longer disease duration. These findings support progressive mucosal metabolic alteration as a feature of chronic UC.