Local Treatment with Lactate Prevents Intestinal Inflammation in the TNBS-Induced Colitis Model

Abstract

Lactate has long been considered as a metabolic by-product of cells. Recently, this view has been changed by the observation that lactate can act as a signaling molecule and regulates critical functions of the immune system. We previously identified lactate as the component responsible for the modulation of innate immune epithelial response of fermented milk supernatants in vitro. We have also shown that lactate downregulates proinflammatory responses of macrophages and dendritic cells. So far, in vivo effects of lactate on intestinal inflammation have not been reported. We evaluated the effect of intrarectal administration of lactate in a murine model of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The increase in lactate concentration in colon promoted protective effects against TNBS-induced colitis preventing histopathological damage, as well as bacterial translocation and rise of IL-6 levels in serum. Using intestinal epithelial reporter cells, we found that flagellin treatment induced reporter gene expression, which was abrogated by lactate treatment as well as by glycolysis inhibitors. Furthermore, lactate treatment modulated glucose uptake, indicating that high levels of extracellular lactate can impair metabolic reprograming induced by proinflammatory activation. These results suggest that lactate could be a potential beneficial microbiota metabolite and may constitute an overlooked effector with modulatory properties.

Characterization of Mucus-Related Properties of Streptococcus thermophilus: From Adhesion to Induction

“…Notably, lactate lowers the transcription of genes required for in vivo growth and catabolism of Campylobacter jejuni ( Luethy et al, 2017 ). A lactate-rich environment inside the gut may also promote tolerance to commensal bacteria ( Angelin et al, 2017 ) and attenuate pro-inflammatory pathways ( Iraporda et al, 2015 ; Iraporda et al, 2016 ). Therefore, lactate possesses a wide panel of beneficial activities inside the gut that may feed microbial communities, fight pathogens, alleviate inflammatory processes, and strengthen the intestinal barrier through mucus production.…”

Kefir micro-organisms: their role in grain assembly and health properties of fermented milk

“…On the other hand, when administered in drinking water no protection against acute intestinal inflammation was observed, probably due to the fact that lactate does not reach necessary levels in the colon because it was absorbed and/or consumed by colonic bacteria (Iraporda et al . ). However, lactate can appear in the gut via the consumption of probiotics and prebiotic containing foods.…”

In vitro and in vivo Effects of Lactate on Metabolism and Cytokine Production of Human Primary PBMCs and Monocytes

“…It has been suggested that GPR81 is required for the inhibitory effects of extracellular lactate on lipopolysaccharide (LPS)-induced IL-1β production of murine macrophages and human PBMCs in vitro ( 11 ). In vivo , anti-inflammatory effects are underscored by studies demonstrating reduced inflammation during hepatitis ( 11 ) and prevention of inflammation in a TNBS-induced colitis model ( 12 ) after lactate administration. Inhibition of NF-κB and inflammasome activation mediate anti-inflammatory effects of lactate ( 11 ), but exact underlying mechanisms remain unknown.…”