P089 Colonic explant lactate concentration and inflammatory protein secretion in ulcerative colitis

Abstract

Abstract Background Lactate, previously thought of as a waste product of cellular metabolism, is now known to act as an immunoregulator with pleiotropic effects. In murine models lactate has been shown to suppress colonic inflammation & restore colonic homeostasis. We aimed to investigate if lactate concentration in tissue cultured media (TCM) from ulcerative colitis (UC) patient-derived explants is associated with TCM concentration of inflammatory proteins known to be involved in UC pathogenesis. Methods UC patients were prospectively recruited in 2 cohorts: discovery (2018 – 2019) and validation (2020 - 2021). Endoscopic biopsies were collected from the sigmoid colon and TCM generated as per previously described methods. Total protein content of biopsies was quantified to allow normalisation of secretions. Patients demographics, baseline characteristics and disease behaviour were characterised. TCM secreted lactate was quantified using a colorimetric L-Lactate assay (Abcam, UK). Secreted inflammatory protein profiles were analysed via 54 V-plex ELISA (Meso Scale Diagnostics, USA). Results 52 patients were recruited (discovery cohort n=28, replication cohort n=24), baseline characteristics are described in Figure 1. Median follow up time was significantly longer in discovery compared with validation cohort p=0.02. In the discovery cohort TCM lactate concentration was inversely correlated with CRP and CRP/Albumin ratio, however, this correlation was not replicated in the validation cohort (Figure 2). Baseline explant TCM lactate concentration did not correlate with TCM CRP concentration. Baseline explant TCM lactate concentration was correlated with IL-2 and IL-31 concentration in both discovery and validation cohorts (Figures 3 & 4). Multivariate analysis, including prior biologic exposure, clinical and endoscopic Mayo scores demonstrated TCM lactate concentration to be independently associated with IL-2 concentration in discovery and validation cohorts, p<0.001 respectively. A similar multivariate analysis demonstrated TCM lactate concentration to be independently associated with IL-31 concentration in the discovery (p<0.001), however, not validation cohort. Conclusion TCM lactate concentration is directly correlated with IL-2 & IL-31 in UC explants. The proposed immunoregulatory properties of lactate are in keeping with its positive correlation with TCM IL-2 concentration given reduced IL-2 secretion has previously been associated with UC disease progression. Further studies are required to define the effects of lactate in the UC tissue microenvironment.