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5-methoxy tryptophan (5-MTP) is an anti-fibrotic metabolite made by fibroblasts and epithelial cells, present in a micromolar concentrations in human blood, and is associated with the progression of fibrotic kidney disease, but the mechanism is unclear. Here, we show by microscopy and functional assays that 5-MTP influences mitochondria in human peripheral blood monocyte-derived macrophages. As a result, the mitochondrial membranes are more rigid, more branched, and are protected against oxidation. The macrophages also change their metabolism by reducing mitochondrial import of acyl-carnitines, intermediates of fatty acid metabolism, driving glucose import. Moreover, 5-MTP increases the endocytosis of collagen by macrophages, and experiments with inhibition of glucose uptake showed that this is a direct result of their altered metabolism. However, 5-MTP does not affect the macrophages following pathogenic stimulation, due to 5-MTP degradation by induced expression of indole-amine oxygenase-1 (IDO-1). Thus, 5-MTP is a fibrosis-protective metabolite that, in absence of pathogenic stimulation, promotes collagen uptake by anti-inflammatory macrophages by altering the physicochemical properties of their mitochondrial membranes. Schematic overview of the effects of 5-MTP on human monocyte derived macrophages. 5-MTP promotes mitochondrial fusion, protecting against oxidative stress, and increases glucose uptake which drive collagen uptake. However, IDO is able to negate any anti-inflammatory effects by breaking down 5-MTP. [Display omitted] • 5-MTP increases collagen uptake in macrophages. • 5-MTP protects against mitochondrial oxidative stress. • Macrophages increase their sugar metabolism in the presence of 5-MTP. • Macrophages are able to breakdown 5-MTP via indoleamine oxygenase (IDO). [ABSTRACT FROM AUTHOR]

The gut microbiota plays a pivotal role in health and disease. The use of probiotics as microbiota-targeted therapies is a promising strategy to improve host health. However, the molecular mechanisms involved in such therapies are often not well understood, particularly when targeting the small intestinal microbiota. In this study, we investigated the effects of a probiotic formula (Ecologic®825) on the adult human small intestinal ileostoma microbiota. The results showed that supplementation with the probiotic formula led to a reduction in the growth of pathobionts, such as Enterococcaceae and Enterobacteriaceae , and a decrease in ethanol production. These changes were associated with significant alterations in nutrient utilization and resistance to perturbations. These probiotic mediated alterations which coincided with an initial increase in lactate production and decrease in pH were followed by a sharp increase in the levels of butyrate and propionate. Moreover, the probiotic formula increased the production of multiple N-acyl amino acids in the stoma samples. The study demonstrates the utility of network theory in identifying novel microbiota-targeted therapies and improving existing ones. Overall, the findings provide insights into the dynamic molecular mechanisms underlying probiotic therapies, which can aid in the development of more effective treatments for a range of conditions.