Butyrate Rescues Oxidative Stress-Induced Transport Deficits of Tryptophan: Potential Implication in Affective or Gut-Brain Axis Disorders

Abstract

<b><i>Introduction:</i></b> Butyrate is a short-chain fatty acid metabolite produced by microbiota in the colon. With its antioxidant properties, butyrate has also been shown to alter the neurological functions in affective disorder models, suggesting it as a key mediator in gut-brain interactions. <b><i>Objective:</i></b> Here, we evaluated the negative effect of oxidative stress on the transport of the serotonin precursor tryptophan as present in affective disorders. Butyrate was hypothesized to be able to rescue these deficits due to its antioxidative capacities and its effect on transmembrane transport of tryptophan. Human skin-derived fibroblasts were used as cellular models to address these objectives. <b><i>Methods:</i></b> Human fibroblasts were treated with hydrogen peroxide to induce oxidative stress. Stressed as well as control cells were treated with different concentrations of butyrate. Tryptophan (<sup>3</sup>H) was used as a tracer to measure the transport of tryptophan across the cell membranes (<i>n</i> = 6). Furthermore, gene expression profiles of different amino acid transporters were analyzed (<i>n</i> = 2). <b><i>Results:</i></b> As hypothesized,<b><i></i></b>oxidative stress significantly decreased the uptake of tryptophan in fibroblast cells, while butyrate counteracted this effect. Oxidative stress did not alter the gene expression profile of amino acid transporters. However, treatment of stressed and control cells with different concentrations of butyrate differentially regulated the gene expression of large amino acid transporters 1 and 2, which are the major transporters of tryptophan. <b><i>Conclusions:</i></b>Gut microbiota-derived butyrate may have therapeutic potential in affective disorders characterized by either aberrant serotonergic activity or neuroinflammation due to its role in rescuing the oxidative stress-induced perturbations of tryptophan transport.

Staunch the Age Related Decline into Dementia, Cancer, Autoimmunity (POTS), Obesity, and Other Diseases with a Prebiotic, Probiotic, Postbiotic Triple Play

“…Butyrate enhances mitochondrial function during oxidative stress [136] and rescues tryptophan [137]. Serotonin cannot cross the BBB, but tryptophan can, and by rescuing tryptophan, butyrate can increase brain serotonin (inhibitory neurotransmitter).…”

Staunch the Age Related Decline into Depression, Dementia, Diabetes, Obesity, Cancer, Long Covid, and Other Diseases with a Prebiotic, Probiotic, Postbiotic Triple Play

“…Butyrate enhances mitochondrial function during oxidative stress [95] and rescues tryptophan [96]. Serotonin cannot cross the BBB, but tryptophan can, and by rescuing tryptophan, butyrate can increase brain serotonin (inhibitory neurotransmitter).…”

Epigenetic Aberrations in Major Psychiatric Diseases Related to Diet and Gut Microbiome Alterations

“…Butyrate is another SCFA and a secondary metabolite of the gut microbiome which acts as an endogenous inhibitor of class I HDACs, a well-known class of epigenetic modulatory genes [174,175]. Neuroprotective effects of butyrate against ASD have been linked to positive modulation of mitochondrial functions like enhancing oxidative phosphorylation and beta-oxidation, suppressing microglia-mediated neuroinflammation, regulating the microbiome-gut-brain axis, reducing oxidative stress-induced transport deficits of tryptophan or its activity as a histone deacetylase inhibitor [176][177][178][179]. Moreover, butyrate as an HDAC inhibitor can enhance acetylation around the promoters of neurotrophic factors such as BDNF and consequently promote their transcription [180,181].…”