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Metabolic regulation of microbiota The gut microbiota affects human health, but we are only just beginning to develop a mechanistic understanding of some of the host-microbe interactions involved. Litvak et al. review how host colon epithelial cells mediate the symbiosis. Healthy colonocytes maintain anaerobic conditions in the gut lumen because their metabolism ensures rapid oxygen consumption. Such conditions select for obligate anaerobic organisms. These tend to be those that consume dietary fiber and produce short-chain fatty acids beneficial to the host. If there is a shift in colonocyte metabolism—because of disease, diet, or other damage—the epithelium becomes oxygenated. The presence of oxygen allows expansion of facultative aerobic organisms. Microbes in genera that include pathogens are often oxygen-tolerant, and dysbiosis can be the result. Science, this issue p. eaat9076 BACKGROUND An imbalance in the colonic microbiota might underlie many human diseases, but the mechanisms that balance our microbial self during homeostasis have long remained elusive. Understanding how our immune system maintains homeostasis is of particular interest in the colon, because this organ harbors the largest microbial community in our body. Recent advances in high-throughput sequencing link an imbalance in this microbial community (dysbiosis) to many chronic human illnesses. Yet it is a daunting task to define what constitutes a balanced microbial community in the colon, because the resident microbiota is highly diverse, differs between individuals, and shifts with changes in the diet. In turn, not knowing what features characterize a balanced colonic microbiota has hampered progress in specifying immune functions or cell types required for maintaining homeostasis in the colon. ADVANCES Clues about immune functions important for balancing the microbiota have emerged by viewing coevolution of microbial communities with their hosts from an ecological perspective, which suggests that our immune system evolved to maintain homeostasis by shaping the microbiota to be beneficial. The central role of colonic epithelial cells (colonocytes) in maintaining homeostasis by shaping the colonic microbiota to provide benefit is now beginning to be appreciated. Recent insights suggest that, similar to macrophages, differentiated colonocytes can polarize metabolically into distinct effector phenotypes. During gut homeostasis, the metabolism of surface colonocytes is directed toward oxidative phosphorylation and oxidation of fatty acids, resulting in high epithelial oxygen consumption. The consequent epithelial hypoxia helps to maintain a microbial community dominated by obligate anaerobic bacteria, which provide benefit by converting fiber into fermentation products that are absorbed by the host. Conditions that shift the metabolism of colonocytes away from lipid oxidation cause an increase in the amount of oxygen emanating from the mucosal surface, thereby driving a shift in the microbial community from obligate to facultative anaerobes, a hallmark of dysbiosis in the colon. Thus, the metabolism of colonocytes functions as a control switch of the gut microbiota, mediating a shift between homeostatic and dysbiotic communities. Subversion of colonocyte cell metabolism by enteric pathogens is a recently uncovered virulence strategy that enables these intruders to escape niche protection conferred by the gut microbiota. OUTLOOK The concept that colonocyte metabolism is a common driver of dysbiosis in the large bowel has ramifications for the design of intervention strategies. Because our immune system already has a way to balance the colonic microbiota by maintaining an epithelial surface that is metabolically polarized toward oxidative phosphorylation, harnessing this host control mechanism for therapeutic means could provide an alternative to targeting the microbes themselves for remediation of dysbiosis. Metabolic reprogramming of colonocytes to restore epithelial hypoxia represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases. Epithelial metabolism shapes the colonic microbiota. Left: During gut homeostasis, obligate anaerobic bacteria convert fiber into fermentation products (butyrate) to maintain the epithelium in a metabolic state characterized by high oxygen consumption. This metabolic polarization of differentiated colonocytes (C2) maintains epithelial hypoxia (<1% oxygen) to limit the amount of oxygen (O2) diffusing into the gut lumen. Right: A metabolic reorientation of terminally differentiated colonocytes toward low oxygen consumption (C1) increases the concentration of respiratory electron acceptors (O2 and NO3–) emanating from the epithelial surface, thereby causing a shift in the microbial community from obligate to facultative anaerobic bacteria. The color scale at the bottom indicates O2 levels. SC, stem cell; TA, undifferentiated transit-amplifying cell; C2, terminally differentiated C2-skewed colonocyte; C1, terminally differentiated C1-skewed colonocyte; GC, goblet cell; NO, nitric oxide. An imbalance in the colonic microbiota might underlie many human diseases, but the mechanisms that maintain homeostasis remain elusive. Recent insights suggest that colonocyte metabolism functions as a control switch, mediating a shift between homeostatic and dysbiotic communities. During homeostasis, colonocyte metabolism is directed toward oxidative phosphorylation, resulting in high epithelial oxygen consumption. The consequent epithelial hypoxia helps to maintain a microbial community dominated by obligate anaerobic bacteria, which provide benefit by converting fiber into fermentation products absorbed by the host. Conditions that alter the metabolism of the colonic epithelium increase epithelial oxygenation, thereby driving an expansion of facultative anaerobic bacteria, a hallmark of dysbiosis in the colon. Enteric pathogens subvert colonocyte metabolism to escape niche protection conferred by the gut microbiota. The reverse strategy, a metabolic reprogramming to restore colonocyte hypoxia, represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases.