Extended Data Fig. 9: OGDH targeting as an intervention for ulcerative colitis.

a, Dot plot of RNA expression of TCA-cycle enzymes in human colon from publicly available scRNA-seq data. The plot compares non-inflamed and inflamed tissue from individuals with inflammatory bowel disease and tissue from healthy volunteers. Each column shows expression of the indicated TCA-cycle enzyme. Colour intensity indicates expression level and dot size indicates the proportion of positive cells in that lineage. b, Immunofluorescence for OGDH, Ki67 and 5hmC, along with ABP staining in TMAs of human intestinal samples from individuals with or without colitis. c,d, Quantification (c) and correlations of expression (d) of OGDH, Ki67 and ABP in normal mucosa, chronic inflammation, ulcerative colitis and Crohn’s disease, based on the TMAs shown in b. The top row shows all individuals, and the bottom row shows only those with chronic inflammation or normal mucosa. Correlation coefficients (r) were derived from Pearson correlation analysis. The lines represent the best-fit linear regression. The R² values indicate the proportion of the variance in disease severity that can be explained by the level of the particular biomarker. Each dot represents a patient. e, Representative images from multiplex immunofluorescence analysis of human TMAs, showing the immune compartment (CD45, CD3 and CD163) and the epithelial compartment (OGDH and PanCK) in healthy individuals and patients with ulcerative colitis. f,g, UMAP illustrating the diversity of cell types in healthy individuals and patients with ulcerative colitis (f) and protein distribution (g), identified through multiplex immunofluorescence analysis. Each point represents a single cell, colour-coded based on its cell-type classification or expression of the indicated protein. Distinct clusters highlight populations of cells with similar phenotypes. h, Experimental scheme of DSS-induced colitis treatment with pulsatile OGDH inhibition in mice. i, Kaplan–Meier survival curves for continuous versus pulsatile doxycycline treatment (3 days ON/4 days OFF/week) in TRE-shOgdh^Cag-rtTA3 mice. j, Representative images showing length of colons from TRE-shOgdh^Cag-rtTA3 mice on day 9 under different conditions. k,l, Colon length (k) and number of ulcers (l) at day 9 in the indicated conditions. Each dot represents an independent mouse (n ≥ 4). m, Body weight in TRE-shRen^Villin-rtTA3 (n = 5) and TRE-shOgdh^Villin-rtTA3 (n = 13) conditions relative to weight at baseline. n, Representative images showing the length of colons from TRE-shRen^Villin-rtTA3 and TRE-shOgdh^Villin-rtTA3 mice after 9 days of the indicated treatments. o,p, Colon length (o) and number of ulcers (p) in TRE-shRen^Villin-rtTA3 and TRE-shOgdh^Villin-rtTA3 mice at day 9. Each dot represents one mouse (n ≥ 4). q, Longitudinal analysis of faecal lipocalin 2 (LCN2) during DSS treatment in TRE-shRen^Villin-rtTA3 (n = 5) and TRE-shOgdh^Villin-rtTA3 mice (n = 5). Each line represents one mouse. r,s, H&E and ABP staining (r) and ABP quantification (s) of intestinal sections from TRE-shRen^Villin-rtTA3 and TRE-shOgdh^Villin-rtTA3 mice at day 9 of treatment. This figure is adapted from our published patent (WO2024229094A1)⁵⁰. Statistical analysis: Data represent mean ± s.e.m. Statistical significance was determined using one-way ANOVA followed by Tukey’s HSD test for c,k,l,o,p,s. Survival probabilities were estimated using the Kaplan–Meier method, and statistical differences between the survival curves were assessed using the log-rank (Mantel–Cox) test in i. Two-way ANOVA followed by Tukey’s HSD test was used in m,q. Asterisks denote statistical significance (*P < 0.05, **P < 0.01, ***P < 0.001).

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