175P The effect of pancreatic enzyme replacement therapy on the gut microbiome and immune response of patients with pancreatic ductal adenocarcinoma associated pancreatic enzyme insufficiency

Background
Pancreatic Enzyme Insufficiency (PEI) affects 70% of patients with Pancreatic Adenocarcinoma (PDAC) and is a negative prognostic factor. Increasing evidence demonstrates that PEI is associated with gut microbiome (GM) dysbiosis. Pancreatic Enzyme Replacement Therapy (PERT) is the mainstay of PEI treatment and has been shown to improve outcomes, but the underlying mechanism is unclear. PERT-associated modulation of the GM and immune response have been suggested as potential mechanisms. The aim of this study was to evaluate how PERT of PDAC associated PEI simultaneously affects gut microbiome composition and peripheral immune profile.

Methods
This work is part of a prospective observational cohort study of patients being treated for pancreatic disease at a single centre. Eligible participants were patients diagnosed with PDAC and PEI, with PEI status confirmed at recruitment using published diagnostic criteria. After informed consent stool and peripheral blood samples were collected from recruited participants. Pre-PERT samples were taken before treatment was started and post-PERT samples were obtained after at least 3 weeks of treatment. Stool-extracted DNA was sequenced by shotgun metagenomics to determine GM composition. Peripheral immune profiles were determined by Cytometry by Time-of-Flight analysis. Differences between the two groups were compared using Mann-Whitney Tests.

Results
8 stool samples (Pre-PERT n = 3, post-PERT n = 5) and 9 peripheral blood samples (Pre-PERT n = 4, Post-PERT n = 5) were included in the analysis. PERT was associated with significantly increased abundance of beneficial GM species, including Faecalibacterium prausnitzii, and decreased pathobionts (p<0.01), such as Prevotella denticola and Streptococcus thermophilus. PERT was also associated with significantly reduced peripheral Natural Killer cells (p=0.032).

Conclusions
Our findings suggest that PERT causes significant GM rebiosis and improves cytotoxic anti-tumour immune responses in patients with PDAC-associated PEI. This may contribute to the survival benefits seen with PERT treatment in PDAC.