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

AbstractIntestinal 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. IntroductionThe role of intestinal microbes in the regulation of the immune system, metabolism of nutrients, and production of neuroactive compounds has established them as key modulators of the gut-brain axis1,2,3,4, the homeostatic, reciprocal communication between the human intestine and the brain2,5,6,7. Disorders of gut-brain interactions, like irritable bowel syndrome (IBS), are characterized by low-grade inflammation and altered bowel habits, but they are also often associated with altered central nervous system (CNS) processing of gut sensory signals, as well as anxiety and depression8,9,10. Although growing evidence has suggested that the gut microbiota impact brain function and behavior, mainly in the context of neurodegenerative and psychiatric disorders, the potential underlying molecular and cellular mechanisms remain vastly uncovered2,4,11,12,13,14.The translocation of certain gut microbiota-derived compounds from the luminal/mucosal side to the basolateral/serosal side of the intestine, and subsequently into the bloodstream, can affect gut-brain signaling. This translocation influences CNS function by modulating systemic levels of neuroactive compounds that can eventually cross or modulate the permeability of the blood-brain barrier (BBB)2,12,15,16.Gut microbiota may influence microbial and human metabolism, such as of tryptophan17, which is utilized for the biosynthesis of 5-hydroxytryptamine (5-HT), also known as serotonin. Although 95% of the total 5-HT is synthesized by enterochromaffin cells in the gut, gut microbiota can also moderate or contribute to that synthesis18,19,20,21,22. Intestinal 5-HT is unable to pass through the BBB; however, it can bind to 5-HT3 receptors on afferent vagal neurons locally and ultimately affect stress response and behavior in th Read More