Exocrine Pancreatic Function Modulates Plasma Metabolites Through Changes in Gut Microbiota Composition

Abstract

Purpose: Exocrine pancreatic function is critically involved in regulating the gut microbiota composition. At the same time, its impairment acutely affects human metabolism. How these 2 roles are connected is unknown. We studied how the exocrine pancreas contributes to metabolism via modulation of gut microbiota.

Design: Fecal samples were collected in 2226 participants of the population-based Study of Health in Pomerania (SHIP/SHIP-TREND) to determine exocrine pancreatic function (pancreatic elastase enzyme-linked immunosorbent assay) and intestinal microbiota profiles (16S ribosomal ribonucleic acid gene sequencing). Plasma metabolite levels were determined by mass spectrometry.

Results: Exocrine pancreatic function was associated with changes in the abundance of 28 taxa and, simultaneously, with those of 16 plasma metabolites. Mediation pathway analysis revealed that a significant component of how exocrine pancreatic function affects the blood metabolome is mediated via gut microbiota abundance changes, most prominently, circulating serotonin and lysophosphatidylcholines.

Conclusion: These results imply that the effect of exocrine pancreatic function on intestinal microbiota composition alters the availability of microbial-derived metabolites in the blood and thus directly contributes to the host metabolic changes associated with exocrine pancreatic dysfunction.

Keywords: 16S rDNA; metabolome; microbiome.

Figure 1.

Design idea of the present study. Triangles fulfilling all 3 criteria were selected for mediation analysis. Abbreviations: OLS: ordinary linear regression; q: q-value correcting p-values for multiple testing by controlling the false discovery rate.

Figure 2.

Associations of pancreatic elastase, gut microbiota, and plasma metabolites. The upper part of the figure displays all gut microbiota at genus level that were significantly associated with variation in fecal pancreatic elastase levels, whereas the lower part shows all significant associations of changes in plasma metabolites with pancreatic elastase. Metabolites found to be significantly associated with changes in gut microbiota are connected by either red (positive association) or blue (inverse association) lines with the corresponding taxon. Unclassified taxa at genus level: family (f), class (c), order (o), and phylum (p). Abbreviations: H1, hexose; PC, phosphatidylcholine; SM (OH), hydroxylated sphingomyelin.

Figure 3.

Mediation analysis between significantly associated plasma metabolites and gut microbiota. Heatmap of the proportion mediated by microbiotic measures on plasma metabolite levels significantly associated with stool elastase. Darker colors indicate a higher proportion mediated, and thick frames indicate a significant indirect effect after correction for multiple testing (P < 0.0023). Microbiota and metabolites were clustered based on association patterns. Shaded boxes indicate significant mediations in which case the proportion of effect mediation could not be estimated. Grey boxes indicated not tested associations. Unclassified taxa at genus level: family (f) and phylum (p). Abbreviations: PC, phosphatidylcholin; SM (OH), hydrodroxylated sphingomyelin.