P0011 Differential Impact of Diet and FMT on Colonic and Ileal Inflammation in humanized IBD Models

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Abstract Background Fecal microbiota transplantation (FMT) has been shown to be a promising approach to treat active ulcerative colitis (UC). However, its use as a treatment for Crohn's disease (CD) is in its early stages, and scientific evidence for its effectiveness is currently limited. Also, diet plays a crucial role in shaping the gut microbiome and might affect the efficacy of FMT. Therefore, we aimed to investigate the additive effects of dietary interventions on multidonor FMT efficacy in preclinical humanized IBD models. Methods Age/sex-matched inbred ileitis-prone SAMP and C57BL/6 mice were treated with broad-spectrum antibiotics followed by humanization with either CD or UC multidonor patient-derived microbiota, and subsequently randomized to either Western, Mediterranean or Control diet in combination with healthy donor multidonor FMT or sham (n= 8/experimental grp; Fig1A). After one week, mice were subjected to DSS to induce acute colitis (7d, 2-2.5%), followed by another 7d of recovery. Disease activity indices (DAI) were determined and evaluated by area under the curve (AUC). Feces were collected every other day for 16S sequencing. At sacrifice, colonic lengths were measured, and blood and different tissues collected for histology, RNA and protein analysis. Results Independent from diet, FMT was shown to improve disease in SAMP mice (Fig1; P=0.047), whereas independent from FMT, SAMP and C57Bl/6 mice fed a Mediterranean diet showed significantly lower disease compared to both control and Western diets (all P<0.001). Dietary regimen appeared to primarily affect DAI, as among each diet no significant effect of FMT could be observed (Table 1). Nevertheless, C57Bl/6 mice receiving FMT in addition to Mediterranean diet had significantly higher survival rates (P=0.0096) compared to all other experimental groups. Moreover, ileitis was more severe in SAMP mice receiving FMT (Fig1; P=0.0119), while the opposite was observed for colonic inflammation, with a trend towards less severe colitis (P=0.0729). Further, a trend towards less severe ileitis was observed for SAMP fed a Mediterranean compared to a Western diet (P=0.080), which was not observed for colitis. Microbial analysis and RNA sequencing data might explain these findings (ongoing). Conclusion In conclusion, independently from each other, both FMT and Mediterranean diet lower disease activity in two humanized mouse models of IBD. Although a trend towards increased efficacy is observed when combining FMT and diet, the additive effect of FMT within each diet seems to be rather limited. Yet, FMT may decrease the severity of colitis, while surprisingly it may worsen ileitis in SAMP mice. Hence, further analyses are required to elucidate the specific mechanisms behind these findings.