Western-type diet influences mortality from necrotising pancreatitis and demonstrates a central role for butyrate

Abstract

ObjectiveThe gut microbiota are the main source of infections in necrotising pancreatitis. We investigated the effect of disruption of the intestinal microbiota by a Western-type diet on mortality and bacterial dissemination in necrotising pancreatitis and its reversal by butyrate supplementation.DesignC57BL/6 mice were fed either standard chow or a Western-type diet for 4 weeks and were then subjected to taurocholate-induced necrotising pancreatitis. Blood and pancreas were collected for bacteriology and immune analysis. The cecum microbiota composition of mice was analysed using 16S rRNA gene amplicon sequencing and cecal content metabolites were analysed by targeted (ie, butyrate) and untargeted metabolomics. Prevention of necrotising pancreatitis in this model was compared between faecal microbiota transplantation (FMT) from healthy mice, antibiotic decontamination against Gram-negative bacteria and oral or systemic butyrate administration. Additionally, the faecal microbiota of patients with pancreatitis and healthy subjects were analysed.ResultsMortality, systemic inflammation and bacterial dissemination were increased in mice fed Western diet and their gut microbiota were characterised by a loss of diversity, a bloom of Escherichia coli and an altered metabolic profile with butyrate depletion. While antibiotic decontamination decreased mortality, Gram-positive dissemination was increased. Both oral and systemic butyrate supplementation decreased mortality, bacterial dissemination, and reversed the microbiota alterations. Paradoxically, mortality and bacterial dissemination were increased with FMT administration. Finally, patients with acute pancreatitis demonstrated an increase in Proteobacteria and a decrease of butyrate producers compared with healthy subjects.ConclusionButyrate depletion and its repletion appear to play a central role in disease progression towards necrotising pancreatitis.

Spatioregional assessment of the gut microbiota in experimental necrotizing pancreatitis

“…In general, results from the present study were complementary to similar studies in this area 1 , 2 , 4 , 48 and parallel findings in patients with acute pancreatitis 4 , 6 , 39 , 49–51 . Table 1 shows taxa from human studies that were significantly over- and under-represented in patients with acute pancreatitis compared with healthy subjects.…”

“…Pancreas and intestinal contents were aseptically removed and stored in saline with 10 per cent glycerol as cryopreservative at -80°C until analysis. Histology of pancreatic tissue was performed as previously described 13 . No technical replicates were used.…”

“…Statistical analysis and visualization were done using R packages phyloseq and ggplot2 17 , 18 . A panel of butyrate-producers based on genus taxonomy was constructed as described previously 13 , 19 . The Inverse Simpson index was used as measure for alpha diversity which takes abundance into account.…”

“…Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) 2 tool that predicts functional aspects from 16S rRNA amplicon data using Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaCyC metabolic databases were used with QIIME2. Significant differences between predicted functional pathways were calculated using the R package Aldex2 13 , 22 . Blast was used for reads to determine a match at the species level 23 .…”

Role of Interleukin-17 in Acute Pancreatitis

“…In fact, acetate boosts IL-10-producing T cells in a stable state and affects Th1 and Th17 cells in active immune responses. Butyrate depletion appears to play a central role in disease progression towards necrotizing pancreatitis ( 101 ). The decrease in butyrate production was associated with the phylum Proteobacteria and the genera Escherichia/Shigella and Streptococcus increasing in patients with AP.…”