Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells

IRAPORDA, C; ERREA, A; ROMANIN, D; CAYET, D; PEREYRA, E; PIGNATARO, O; SIRARD, JC; GARROTE, G; ABRAHAM, AG; RUMBO, M

IMMUNOBIOLOGY.

ELSEVIER GMBH

Año: 2015 vol. 220 p. 1161 - 1169

0171-2985

The use of short chain fatty acids to modulate gastrointestinal inflammatory conditions such as ulcera-tive colitis has produced encouraging results either in animal models or also in clinical trials. Identifyingthe key cellular and molecular targets of this activity will contribute to establish the appropriate combi-nations/targeting strategies to maximize the efficacy of anti-inflammatory interventions. In the presentwork, we evaluatedin vitrothe interaction of lactate, acetate, propionate and butyrate on cells relevantfor innate immune response of the gastrointestinal tract. All molecules tested regulate the production ofproinflammatory cytokines by TLR-4 and TLR-5 activated intestinal epithelial cells in a dose responsemanner. Furthermore SCFAs and lactate modulate cytokine secretion of TLR-activated bone marrowderived macrophages and also TLR-dependent CD40 upregulation in bone marrow derived dendritic ina dose-dependent manner. Butyrate and propionate have been effective at concentrations of 1 to 5mMwhereas acetate and lactate produced modulatory effects at concentrations higher than 20?50mM indifferent assays. Our results indicate that in concentrations similar to found in large bowel lumen, allSCFAs tested and lactate can modulate activity of relevant sentinel cell types activated by TLR signals.Modulatory activity was not inhibited by pertussis toxin treatment indicating that the effects are notrelated to Gisignaling. The use of these molecules in combined or separately as intervention strategyin conditions where epithelial or myeloid cells are main triggers of the inflammatory situation seemsappropriate.