Litvak Y, Byndloss MX, Bäumler AJ. Science, 2018, volume 362, issue 6418, article eaat9076. doi:10.1126/science.aat9076
Background & Rationale
Dysbiosis, an imbalance in the composition of the colonic microbiota, has been associated with numerous chronic human conditions, including inflammatory bowel disease (IBD), colorectal cancer, obesity and metabolic disease. Despite this, the host mechanisms that establish and preserve a balanced colonic microbial community have remained incompletely defined, partly because the resident microbiota varies substantially between individuals and with dietary change. The authors note that dysbiosis in the colon is frequently characterised by an expansion of facultative anaerobic bacteria, particularly within the phylum Proteobacteria, at the expense of the obligate anaerobic bacteria that dominate under stable conditions. This review sets out the rationale that colonic epithelial cell, or colonocyte, energy metabolism, specifically the balance between oxidative phosphorylation and anaerobic glycolysis, regulates epithelial oxygen consumption, and thereby governs the oxygen and electron acceptor availability that determines which bacterial populations can expand within the gut lumen.
Study Design
This article is a narrative scientific review rather than a primary clinical trial. The authors synthesise mechanistic and correlative evidence describing how colonocyte metabolic state governs luminal oxygen and electron acceptor availability, drawing on studies of human colonic epithelial tissue, clinical observations in patients with ulcerative colitis, and correlative microbiota data from individuals with human immunodeficiency virus (HIV) infection. The review develops a conceptual framework proposing two opposing colonocyte metabolic states, termed C2, a homeostatic, oxidative state, and C1, an inflammation-associated, glycolytic state, drawn by analogy with the established M2 and M1 polarisation states of macrophages. As this is not an interventional study, no prespecified primary or secondary endpoints, randomisation or blinding procedures apply. Instead, the authors present evidence supporting their proposed model and identify questions requiring further investigation.
Patient Population
Rather than describing a single enrolled cohort, the review references clinical observations reported in separately published studies. Colonic epithelial biopsies from patients with ulcerative colitis have been reported to show reduced synthesis of peroxisome proliferator-activated receptor gamma (PPARγ) and reduced mitochondrial oxidation of butyrate compared with non-inflamed epithelium. Separately, individuals with HIV infection have been reported to show expansion of Proteobacteria within stool microbiota, correlating with markers of immune activation. No demographic or baseline characteristic data for a single defined study population are presented, consistent with the nature of the article as a review rather than a primary study.
Key Findings
The review describes that under stable conditions, colonocytes preferentially metabolise short-chain fatty acids, particularly butyrate, generated by obligate anaerobic bacteria through fermentation of dietary fibre. This drives colonocyte mitochondrial fatty acid oxidation through activation of PPARγ signalling, resulting in high epithelial oxygen consumption and a state of epithelial hypoxia, with oxygen levels reported to fall below one per cent. The authors describe this as limiting the amount of oxygen diffusing into the gut lumen, thereby favouring obligate anaerobic bacteria that convert fibre into fermentation products.
When colonocyte metabolism shifts towards anaerobic glycolysis, epithelial oxygen consumption falls and luminal oxygenation rises, alongside increased production of nitric oxide, which is converted to nitrate in the gut lumen. Both increased oxygen and nitrate availability are described as providing electron acceptors that support expansion of facultative anaerobic bacteria, a compositional shift consistently associated with dysbiosis.
In colonic tissue from patients with ulcerative colitis, the authors report reduced PPARγ synthesis and reduced mitochondrial oxidation of butyrate compared with non-inflamed tissue, consistent with loss of the homeostatic oxidative metabolic state. The established first-line therapy 5-aminosalicylic acid (5-ASA), described by the authors as a PPARγ agonist, has been reported in a separate clinical study to be associated with a reduction in the relative abundance of Proteobacteria in the microbiota of patients with ulcerative colitis. In HIV-infected individuals, expansion of Proteobacteria in stool has been reported to correlate with markers of immune activation, although the authors note that a causal link to colonocyte metabolism in this population has not been established and requires further study. As this is not a hypothesis-testing trial, no formal null results are reported.
Discussion
The authors discuss that colonocyte metabolic polarisation, characterised by opposing oxidative and glycolytic states, offers a unifying mechanistic explanation for the expansion of facultative anaerobic bacteria observed across a range of otherwise unrelated conditions, including IBD, antibiotic exposure and Western-style dietary patterns. They highlight a parallel with macrophage M1 and M2 polarisation, extending the concept of metabolically defined immune function to non-haematopoietic epithelial cells. Regarding practical relevance, the authors note that restoring a homeostatic oxidative colonocyte metabolism, for example through PPARγ agonism, represents a plausible therapeutic strategy for rebalancing the colonic microbiota, citing the established clinical use of 5-ASA in ulcerative colitis as supportive precedent. Because this article is a review rather than an interventional trial, no adverse event or tolerability data specific to a trial population are reported, and safety information relating to 5-ASA is not detailed beyond its established status as a first-line therapy for mild to moderate ulcerative colitis. No serious adverse events are discussed, as no interventional trial results are presented in this article.
Authors’ Conclusions
The authors conclude that colonocyte energy metabolism functions as a control switch mediating shifts between homeostatic and dysbiotic colonic microbial communities, and that enteric pathogens can subvert this metabolism to overcome colonisation resistance conferred by the resident microbiota. They state that metabolic reprogramming aimed at restoring colonocyte hypoxia represents a promising therapeutic approach for rebalancing the colonic microbiota across a broad range of human diseases. The authors acknowledge that further work is required to determine whether loss of this homeostatic colonocyte state underlies dysbiosis observed in conditions such as colorectal cancer, irritable bowel syndrome and diets high in fat.
Reference
Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science. 2018;362(6418):eaat9076. doi:10.1126/science.aat9076
This Scientific Publication Summary is an objective summary of the published trial for personal and educational use. It does not constitute clinical advice, endorsement of the intervention, or a recommendation to alter clinical practice.