Probiotics Mitigate High-cholesterol Diet-driven Fatty Liver and Pancreatic Cancer by Restoring Macrophage Homeostasis.

BACKGROUND & AIMS: High dietary cholesterol is a known risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and its associated hepatic carcinogenesis; however, its effect on pancreatic ductal adenocarcinoma (PDAC) is yet to be investigated. The current study explored the mechanistic association between high dietary cholesterol, MASLD, and PDAC. Importantly, we aimed to evaluate the effect of a multi-strain probiotic formulation on hypercholesterolemia-driven MASLD and PDAC. METHODS: In this study, wild-type (C57BL/6) and KC (Pdx-1 Cre; Kras(LSL-G12D)) mice were fed either with regular diet or high cholesterol and cholic acid diet (HCCD) and received an oral probiotic consortium LR+F15 (Lactobacillus rhamnosus GG and Lactiplantibacillus plantarum ILSF15). Additionally, we also used a syngeneic orthotopic murine PDAC model to evaluate the efficacy of this probiotic consortium. For mechanistic studies, pancreas, liver, intestine, peri-pancreatic fats, peritoneal cells/lavage, and blood were evaluated for metabolic, inflammatory, and malignant changes through histology, enzyme-linked immunosorbent assay, flow cytometry, and quantitative reverse transcription polymerase chain reaction. RESULTS: HCCD induced nonobese MASLD and PDAC progression, which was eased upon probiotics intervention. Importantly, it also increased the survival of the HCCD-fed KC mice. The probiotic intervention protected against HCCD-induced leaky gut, gut microbiota translocation, and inflammatory milieu in different tissues. Interestingly, HCCD significantly increased the population of pro-inflammatory/pro-tumorigenic peritoneal macrophages, which got normalized upon probiotic administration. CONCLUSIONS: The probiotic formulation LR+F15 significantly suppressed HCCD-induced MASLD and PDAC progression partly through suppressing leaky gut and normalizing peritoneal macrophages' inflammatory properties. These findings encourage evaluation of the potential benefits of this probiotic consortium in combination with the existing therapies against PDAC in the future.