Systematic Investigations on the Metabolic and Transcriptomic Regulation of Lactate in the Human Colon Epithelial Cells

Abstract

Lactate, primarily produced by the gut microbiota, performs as a necessary “information transmission carrier” between the gut and the microbiota. To investigate the role of lactate in the gut epithelium cell–microbiota interactions as a metabolic signal, we performed a combinatory, global, and unbiased analysis of metabolomic and transcriptional profiling in human colon epithelial cells (Caco-2), using a lactate treatment at the physiological concentration (8 mM). The data demonstrated that most of the genes in oxidative phosphorylation were significantly downregulated in the Caco-2 cells due to lactate treatment. Consistently, the levels of fumarate, adenosine triphosphate (ATP), and creatine significantly decreased, and these are the metabolic markers of OXPHOS inhibition by mitochondria dysfunction. The one-carbon metabolism was affected and the polyol pathway was activated at the levels of gene expression and metabolic alternation. In addition, lactate significantly upregulated the expressions of genes related to self-protection against apoptosis. In conclusion, lactate participates in gut–gut microbiota communications by remodeling the metabolomic and transcriptional signatures, especially for the regulation of mitochondrial function. This work contributes comprehensive information to disclose the molecular mechanisms of lactate-mediated functions in human colon epithelial cells that can help us understand how the microbiota communicates with the intestines through the signaling molecule, lactate.

Short-chain fatty acids reprogram metabolic profiles with the induction of reactive oxygen species production in human colorectal adenocarcinoma cells

“…Our previous RNA-seq data demonstrated that lactate, a microbial metabolite like the SCFAs, significantly upregulated ROS metabolism and disturbed mitochondrial function by downregulating the electron transport chain and oxidative phosphorylation in Caco-2 cells [35] , which endogenously generated ROS in the mitochondria [4] . Consistently, ROS-mediated fluorescence was significantly promoted by increasing the concentrations of SCFAs ( Fig.…”

“…Dysfunctional mitochondria induce transcriptomic and metabolic disturbances [35] . Our results showed that SCFAs led to mitochondrial activity dysfunctions, such as the electron transport chain and oxidative phosphorylation and alterations in the expression of several genes related to mitochondrial function, such as decreased MT-NDs , MT-CO1 , and MT-ATP6 and increased PIP5KL1 , UCP1 , and C15ORF48 ( Fig.…”

In vitro screening of the impact of dietary prebiotic components, probiotic strains, and their symbiotic combinations on colonic microbiota in children with cystic fibrosis

“…44 In turn, the highest lactate production, was found in the samples treated with L. rhamnosus which coincides with a previous study of our group, in which L. rhamnosus supplementation reflected the increase in lactate after 20 days of supplementation on colonic microbiota of children with CF. 18 This finding is relevant since it is known that lactate is a beneficial metabolite that exerts a positive role on the body such as regulating the biological processes of intestinal function, produces an indirect inhibition of the growth of pathogenic bacteria, and the genus Lactobacillus is related to its biosynthesis to produce propionate, butyrate, or acetate 45,46 In the case of the production of acetic acid and propionic acid, the combination of pectin with L. rhamnosus allowed for a twofold increase of the amount of these metabolites with respect to the initial content. Besides, SCFAs and the genus Bacteroides showed a positive correlation, suggesting a symbiotic effect of pectin-L. rhamnosus: the changes induced in the microbiota, such as the increase in Bacteroides, seem to modify the metabolism of pectin, resulting in higher short-chain fatty acids production.…”

“…44 In turn, the highest lactate production, was found in the samples treated with L. rhamnosus which coincides with a previous study of our group, in which L. rhamnosus supplementation reflected the increase in lactate after 20 days of supplementation on colonic microbiota of children with CF. 18 This finding is relevant since it is known that lactate is a beneficial metabolite that exerts a positive role on the body such as regulating the biological processes of intestinal function, produces an indirect inhibition of the growth of pathogenic bacteria, and the genus Lactobacillus is related to its biosynthesis to produce propionate, butyrate, or acetate 45,46…”

Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression

“…Prior research has demonstrated lactate's ability to modulate the binding of H3K27ac to promoter regions and cis -regulatory elements, influencing chromatin accessibility [ 64 ]. Similarly, incubating cells with lactate has been shown to induce a less compact chromatin structure, creating a transcriptionally permissive chromatin conformational state that facilitates DNA transcriptional machinery [ 65 , 66 ]. In our investigation, we observed that lactate-mediated chromatin accessibility was, at least partly, driven by increased binding of JUNB to the chromatin.…”