Selection pressure at altitude for genes related to alcohol metabolism: A role for endogenous enteric ethanol synthesis?

New Findings What is the topic of this review? Highland natives have undergone natural selection for genetic variants advantageous in adaptation to the hypobaric hypoxia experienced at high altitude. Why genes related to alcohol metabolism appear consistently selected for has not been greatly considered. We hypothesize that altitude‐related changes in the gut microbiome offer one possible explanation. What advances does it highlight? Low intestinal oxygen tension might favour the production of ethanol through anaerobic fermentation by the gut microbiome. Subsequent increases in endogenous ethanol absorption could therefore provide a selection pressure for gene variants favouring its increased degradation, or perhaps reduced degradation if endogenously synthesized ethanol acts as a metabolic signalling molecule. Reduced tissue availability of oxygen results from ascent to high altitude, where atmospheric pressure, and thus the partial pressure of inspired oxygen, fall (hypobaric hypoxia). In humans, adaptation to such hypoxia is necessary for survival. These functional changes remain incompletely characterized, although metabolic adaptation (rather than simple increases in convective oxygen delivery) appears to play a fundamental role. Those populations that have remained native to high altitude have undergone natural selection for genetic variants associated with advantageous phenotypic traits. Interestingly, a consistent genetic signal has implicated alcohol metabolism in the human adaptive response to hypobaric hypoxia. The reasons for this remain unclear. One possibility is that increased alcohol synthesis occurs through fermentation by gut bacteria in response to enteric hypoxia. There is growing evidence that anaerobes capable of producing ethanol become increasingly prevalent with high‐altitude exposure. We hypothesize that: (1) ascent to high altitude renders the gut luminal environment increasingly hypoxic, favouring (2) an increase in the population of enteric fermenting anaerobes, hence (3) the synthesis of alcohol which, through systemic absorption, leads to (4) selection pressure on genes relating to alcohol metabolism. In theory, alcohol could be viewed as a toxic product, leading to selection of gene variants favouring its metabolism. On the contrary, alcohol is a metabolic substrate that might be beneficial. This mechanism could also account for some of the interindividual differences of lowlanders in acclimatization to altitude. Future rese