Development of a novel humanized gut-brain axis model as a tool toward personalized nutrition

TL;DR

A new humanized gut-brain model was developed to study how gut metabolites affect the blood-brain barrier and serotonin metabolism.

Contribution

A novel ex vivo-in vitro gut-brain axis model was created to explore personalized nutrition effects on the brain.

Findings

Serosal fluids from colonic biopsies do not harm fibroblasts or alter tryptophan transporter expression.

Serosal fluids show protective effects on fibroblasts under oxidative stress.

The model supports studying dietary effects on the serotonergic system in health and disease.

Abstract

Intestinal luminal microbial metabolites affect tryptophan and serotonin metabolism, and cross or modify the blood-brain barrier (BBB). Understanding those mechanisms further necessitates integrated gut-brain axis model systems. Using an ex vivo-in vitro approach, H2O2-stressed or non-stressed human dermal fibroblasts – representing the BBB – are cultured with serosal fluids of healthy or irritable bowel syndrome human colonic biopsies collected from Ussing chamber experiments, after participant’s colon was exposed to butyrate in vivo, fecal fiber fermentation or control supernatant ex vivo. Culturing fibroblasts with serosal fluids does not compromise viability or have cytotoxic effects. Serosal fluids alone do not alter expression of tryptophan-related large amino acid membrane transporter genes and proteins, nor their activity (i.e., tryptophan uptake). However, adding serosal fluids to fibroblasts prior to oxidative stress indicate a protective role. This new model allows investigation of direct effects of serosal content on BBB-representing fibroblasts and is highly promising for more personalized applications.

Proof-of-concept of a humanised gut-brain axis ex vivo model with physiological coupling of intestinal and blood-brain barrier for mechanistical assessment of butyrate- or fiber-rich diets on the serotonergic system in healthy or diseased states.

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