L-Glutamate is one of the most abundant amino acids in alimentary proteins, but its concentration in blood is among the lowest. This is largely because l-glutamate is extensively oxidized in small intestine epithelial cells during its transcellular journey from the lumen to the bloodstream and after its uptake from the bloodstream. This oxidative capacity coincides with a high energy demand of the epithelium, which is in rapid renewal and responsible for the nutrient absorption process. l-Glutamate is a precursor for glutathione and N-acetylglutamate in enterocytes. Glutathione is involved in the enterocyte redox state and in the detoxication process. N-acetylglutamate is an activator of carbamoylphosphate synthetase 1, which is implicated in l-citrulline production by enterocytes. Furthermore, l-glutamate is a precursor in enterocytes for several other amino acids, including l-alanine, l-aspartate, l-ornithine, and l-proline. Thus, l-glutamate can serve both locally inside enterocytes and through the production of other amino acids in an interorgan metabolic perspective. Intestinal epithelial cell capacity to oxidize l-glutamine and l-glutamate is already high in piglets at birth and during the suckling period. In colonocytes, l-glutamate also serves as a fuel but is provided from the bloodstream. Alimentary and endogenous proteins that escape digestion enter the large intestine and are broken down by colonic bacterial flora, which then release l-glutamate into the lumen. l-Glutamate can then serve in the colon lumen as a precursor for butyrate and acetate in bacteria. l-Glutamate, in addition to fiber and digestion-resistant starch, can thus serve as a luminally derived fuel precursor for colonocytes.

Background: Although high-protein diets (HPDs) are frequently consumed for body-weight control, little is known about the consequences for gut microbiota composition and metabolic activity and for large intestine mucosal homeostasis. Moreover, the effects of HPDs according to the source of protein need to be considered in this context.

The intestinal microbiota metabolic activity towards the available substrates generates myriad bacterial metabolites that may accumulate in the luminal fluid. Among them, indole and indole-related compounds are produced by specific bacterial species from tryptophan. Although indole-related compounds are, first, involved in intestinal microbial community communication, these molecules are also active on the intestinal mucosa, exerting generally beneficial effects in different experimental situations. After absorption, indole is partly metabolized in the liver into the co-metabolite indoxyl sulfate. Although some anti-inflammatory actions of indole on liver cells have been shown, indoxyl sulfate is a well-known uremic toxin that aggravates chronic kidney disease, through deleterious effects on kidney cells. Indoxyl sulfate is also known to provoke endothelial dysfunction. Regarding the central nervous system, emerging research indicates that indole at excessive concentrations displays a negative impact on emotional behavior. The indole-derived co-metabolite isatin appears, in pre-clinical studies, to accumulate in the brain, modulating brain function either positively or negatively, depending on the doses used. Oxindole, a bacterial metabolite that enters the brain, has shown deleterious effects on the central nervous system in experimental studies. Lastly, recent studies performed with indoxyl sulfate report either beneficial or deleterious effects depending once again on the dose used, with missing information on the physiological concentrations that are reaching the central nervous system. Any intervention aiming at modulating indole and indole-related compound concentrations in the biological fluids should crucially take into account the dual effects of these compounds according to the host tissues considered.