Macrophages activated by the gram negative bacterial product lipopolysaccharide (LPS) switch their core metabolism from oxidative phosphorylation to glycolysis1. Inhibition of glycolysis with 2-deoxyglucose (2DG) suppressed LPS-induced Interleukin-1 beta (IL-1β) but not Tumour necrosis factor alpha (TNFα) in macrophages. A comprehensive metabolic map of LPS-activated macrophages revealed up-regulation of glycolytic and down-regulation of mitochondrial genes, which correlated directly with the expression profiles of altered metabolites. LPS strongly increased the TCA cycle intermediate succinate. Glutamine-dependent anerplerosis was the major source of succinate with the ‘Gamma-Aminobutyric Acid (GABA)-shunt’ pathway also playing a role. LPS-induced succinate stabilized Hypoxia-inducible factor 1α (HIF-1α), an effect inhibited by 2DG, with IL-1β as an important target. LPS also increases succinylation of several proteins. Succinate is therefore identified as a metabolite in innate immune signalling which leads to enhanced IL-1β production during inflammation.
The inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), are multifactorial, chronic conditions of the gastrointestinal tract. While IBD has been associated with dramatic changes in the gut microbiota, changes in the gut metabolome -- the molecular interface between host and microbiota -- are less-well understood. To address this gap, we performed untargeted LC-MS metabolomic and shotgun metagenomic profiling of cross-sectional stool samples from discovery ( n =155) and validation ( n =65) cohorts of CD, UC, and non-IBD control subjects. Metabolomic and metagenomic profiles were broadly correlated with fecal calprotectin levels (a measure of gut inflammation). Across >8,000 measured metabolite features, we identified chemicals and chemical classes that were differentially abundant (DA) in IBD, including enrichments for sphingolipids and bile acids, and depletions for triacylglycerols and tetrapyrroles. While >50% of DA metabolite features were uncharacterized, many could be assigned putative roles through metabolomic “guilt-by-association” (covariation with known metabolites). DA species and functions from the metagenomic profiles reflected adaptation to oxidative stress in the IBD gut, and were individually consistent with previous findings. Integrating these data, however, we identified 122 robust associations between DA species and well-characterized DA metabolites, indicating possible mechanistic relationships that are perturbed in IBD. Finally, we found that metabolome- and metagenome-based classifiers of IBD status were highly accurate and, like the vast majority of individual trends, generalized well to the independent validation cohort. Our findings thus provide an improved understanding of perturbations of the microbiome-metabolome interface in IBD, including identification of many potential diagnostic and therapeutic targets.
SUMMARY Cancer cells reprogram their metabolism using different strategies to meet energy and anabolic demands to maintain growth and survival. Understanding the molecular and genetic determinants of these metabolic programs is critical to successfully exploit them for therapy. Here, we report that the oncogenic melanocyte lineage-specification transcription factor MITF drives PGC1α (PPARGC1A) overexpression in a subset of human melanomas and derived cell lines. Functionally, PGC1α positive melanoma cells exhibit increased mitochondrial energy metabolism and ROS detoxification capacities that enables survival under oxidative stress conditions. Conversely, PGC1α negative melanoma cells are more glycolytic and sensitive to ROS-inducing drugs. These results demonstrate that differences in PGC1α levels in melanoma tumors have a profound impact in their metabolism, biology and drug sensitivity.
SUMMARY Cultured cells convert glucose to lactate and glutamine is the major source of tricarboxylic acid (TCA) cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells.
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