Modification of the Bacterial Metabolites by the Host after Absorption, and Consequences for the Peripheral Tissues’ Metabolism, Physiology, and Physiopathology

Abstract

After synthesis by the intestinal bacteria, several metabolites are absorbed and metabolized by host tissues giving rise to bioactive co-metabolites. In liver, some bacterial metabolites like trimethylamine, indole, p-cresol, and phenylacetate are metabolized, and resulting co-metabolites like trimethylamine N-oxide, indoxyl sulfate, and p-cresyl sulfate impair hepatocyte energy metabolism and viability when produced in excess. In contrast, the bacterial metabolites indole and indole-3 acetate appear protective in situation of hepatic damage. Regarding the gut–kidney axis, the bacterial metabolite p-cresol, as well as the co-metabolites p-cresyl sulfate and indoxyl sulfate act as uremic toxins when synthesized in excess. These latter compounds have been shown to affect mitochondrial function in renal tubular cells and to provoke an inflammatory response. Trimethylamine N-oxide has been identified as a co-metabolite which at excessive concentration increases in experimental work platelet responsiveness to agonists, favors thrombus development within internal carotid artery, and provokes endothelial cell dysfunction. Phenylacetylglutamine is another co-metabolite that is involved in the gut–cardiovascular axis. This compound binds to adrenergic receptors, enhancing platelet activation and clot formation within carotid artery. Other compounds like p-cresol and indoxyl sulfate have been shown to provoke endothelial dysfunction at excessive concentrations. Regarding the gut–brain axis, from experimental works, surprisingly, there are reasons to believe that the metabolic activity of the gut microbiota can influence parameters characteristic of mood disorders. Although the mechanisms involved remain far from being well understood, emerging data indicate that host neurophysiology may be affected by both direct and indirect ways including actions on vagus nerve, enteric nervous system, intestinal immune and neuro-endocrine systems. Interestingly, in animals with no intestinal microbiota, norepinephrine, dopamine, and serotonin turnover are modified in brain suggesting complex relationships between intestinal microbiota and its host. Some compounds derived from the metabolic activity of the gut microbiota, like NH₃ may cross the blood–brain barrier and exert adverse effects on the central nervous system in case of liver failure. Tryptamine is another example of bacterial metabolite that can cross the blood–brain barrier function. Among indole-related compounds, isatin and oxindole can enter within the brain, and affect behavior and brain functions. Lastly, the co-metabolite indoxyl sulfate appears to exert, depending on the doses used, both beneficial and deleterious effects on the central nervous system in experimental works.