Ascending the gut–brain axis: does the microbiome affect acclimatization to high altitude?

The gut microbiome is a complex ecosystem of microorganisms residing within the gastrointestinal tract. It is associated with important modulatory effects on cardiovascular homeostasis, including blood pressure regulation. It is becoming increasingly evident that gastrointestinal microbial status can influence cardiorespiratory control, through a bi-directional pathway termed the gut–brain axis (O'Connor et al., 2020). Recently, it was demonstrated that negative disruptions to the gut microbiota depressed ventilatory responsiveness to chemostimuli in rats (O'Connor et al., 2019). Whether manipulation of the gut microbiota affects cardiorespiratory responses to hypoxia in humans was unclear. In this issue of Experimental Physiology, Seredyński et al. (2021) investigated the potential link between gut microbial activity and cardiorespiratory responses to transient hypoxia in humans. Participants ingested either placebo or lactulose to stimulate gut fermentation. Lactulose is a non-absorbable sugar that is metabolized by the gut microbiota to yield short-chain fatty acids, which are implicated in gut–brain axis signalling (O'Connor et al., 2020). Baseline cardiorespiratory parameters were unchanged by lactulose intervention. However, lactulose ingestion resulted in a significant increase in the acute hypoxic ventilatory response (HVR), evaluated using the transient 100% N2 test. Moreover, the increase in the magnitude of the HVR following lactulose ingestion was positively correlated with the amount of hydrogen produced via fermentation, evaluated by exhaled breath analysis. These results reveal the apparent capacity for increased gut fermentation to augment ventilatory responses to transient hypoxia, implying a functional connection between microbiota-derived metabolites and the peripheral chemoreflex in humans. Sojourners to high altitude are exposed to progressive reductions in atmospheric pressure, with resultant systemic hypoxia. The HVR, mediated by oxygen-sensing glomus cells in the carotid body, causes hyperventilation, which partially corrects high altitude hypoxaemia. With sustained exposure to hypoxia, a temporal cascade of integrative processes is triggered within the cardiorespiratory, haematological and renal systems, resulting in a process termed acclimatization. Acute mountain sickness (AMS) can manifest during high altitude exposure, even in circumstances of slow ascent. AMS symptoms include headache, fatigue, weakness, light-headedness and dizziness, often accompanied by gastrointestinal symptoms, such as nausea and anorexia. In addition, traveller's diarrhoea is common and can be debilitating for trekkers. Although the development of AMS is multi-factorial, we have previously demonstrated an inverse relationship between the magnitude of ventilatory acclimatization to hypoxia and the development of AMS (Leacy et al., 2021). Thus, factors affecting the HVR and high altitude acclimatization may be relevant to AMS, and the gut microbiota is a modifiable factor of interest. Studies of the ‘high altitude gut microbiome’ are emerging, but are typically limited to observational studies in native and non-native populations, or high altitude simulation (hypobaria) in animal models. Assessment of the effects of high altitude on the gut microbiota are challenging in field expeditions, considering the many potentially contributing factors, including travel, diet, physical activity and hypoxia, which can be difficult to control, such that findings are hard to unravel. During high altitude exposure, the gut microbiome plays a crucial role in increased energy harvest, due to an upregulation of carbohydrate fermentation (Suzuki et al., 2019). However, exposure to high altitude promotes increased gastrointestinal inflammation, permeability, oxidative stress, and region-specific changes in aerobe and anaerobe microbial composition (Karl et al., 2018). Interestingly, specific compositional changes within the microbiome during high altitude exposure have been shown to influence AMS severity (Karl et al., 2018). In light of the findings by Seredyński et al. (2021), we suggest that it would be fascinating to determine whether a high altitude microbiota signature affects the time-dependent, integrative, multi-system processes that characterize ventilatory acclimatization to hypoxia. Might positive manipulation of the microbiota via pre- and/or probiotic interventions enhance respiratory chemoreflexes at high altitude, enhancing acclimatization? This exciting new frontier in integrative physiology adds another organ to the multi-system control of cardiorespiratory function in response to acute and chronic hypoxic stress. Much remains to be determined by way of exploration of causal mechanistic links between gut microbiota status and established sites of cardiorespiratory control. The first steps have been taken in this new high altitude adventure, with a long way to go. Our gut feeling is that the only way is up! No competing interests declared. Sole author.