Nowadays, with a growing number of people from low-altitude come to high-altitude for travelling, mountaineering or strategic reasons, acute high-altitude reaction has become particularly prominent. Although much attention has been paid to respiratory, cardiac and neurological symptoms in acute high-altitude exposure, there is scarcity of reports on gut microflora. In this study, acute exposure to simulated high-altitude hypoxia altered gut microbiota in mice, as indicated by the increase of shannon, simpson and Akkermansia, and the decrease of Firmicutes to Bacteroidetes ratio and Bifidobacterium.
Among the numerous studies describing disease-associated microbiota, loss of microbiota diversity is a general feature of most dysbiosis. The increase in community diversity such as shannon and simpson in mice under acute hypoxia exposure observed in our study could reflect a beneficial response to environmental stress. This finding is consistent with individuals who experienced acute mountain sickness. Moreover, Jiang et al reported an elevated microbiome alpha diversity in mice during spaceflight. However, attention should be given to the new perspective that more diversity is not always better. Indeed, alpha diversity estimation revealed higher microbiota diversity in patients with colorectal adenomas. For men who were HIV-infected, the alpha diversity of the Bacteroidetes phylum was positively correlated with viral load. Therefore, the real drivers of microbiome biodiversity in host are worth investigating.
More than 75% gut bacteria are in 1 of 2 phyla: Firmicutes and Bacteroidetes. On the one hand, Firmicutes to Bacteroidetes ratio can influence cardiorespiratory fitness. In healthy young adults, Durk et al found that maximal oxygen consumption was positively associated with Firmicutes to Bacteroidetes ratio. Voluntary exercise increased proportionally to the ΔCt ratio of Firmicutes:Bacteroidetes. On the other hand, relatively high ratio of Firmicutes to Bacteroidetes is associated with highly efficient energy harvest. In youth, Firmicutes to Bacteroidetes ratio was positively associated with body mass index, visceral and hepatic fat. Both Tibetans and Chinese Han living at high-altitude had a high abundance of Firmicutes and a low abundance of Bacteroidete. Similarly, animals living in high-altitude such as Tibetan antelopes, European mouflon and blue sheep had higher Firmicutes to Bacteroidetes ratio than their counterparts living in low-altitude. Unlike these residents and animals at high-altitude, our results showed a decrease in Firmicutes and an increase in Bacteroidetes after acute hypoxic exposure. This contradiction indicated that Firmicutes to Bacteroidetes ratio may be involved in the process of long-term high-altitude adaptation.
At genus level, the lower abundance of Firmicutes was mainly caused by a significant decrease in Dubosiella and Faecalibaculum. The higher abundance of Bacteroidetes was mainly caused by a significant increase in Bacteroides and Parabacteroides. A recent study showed that high-fat diet enlarged Dubosiella and Faecalibaculum. In addition, Bacteroides and Parabacteroides were negatively associated with obesity. Our functional analysis also indicated that acute exposure to simulated high-altitude hypoxia upregulated metabolism. In fact, basal metabolic rate was 27% greater than at sea level in men at high-altitude. Kong et al indicated that the acute phase response signaling, liver X receptor/retinoid X receptor and farnesoid X receptor/retinoid X receptor pathways were activated in Holstein dairy cows exposed to high-altitude hypoxia.
Bifidobacterium and Akkermansia are considered to be beneficial to the host. In seven mountaineers who took part in German expedition to the Nepalese Himalayas, Kleessen et al observed a significant decrease in Bifidobacterium at the high camp. Furthermore, Bifidobacteria deficiency has been identified as a disorder of the ecological barrier after flights in astronauts. Consist with these studies, our result also showed a decrease in Bifidobacterium. Unexpectedly, Akkermansia was increased in the hypoxia group. It may be a protective reaction against acute hypoxia exposure. Akkermansia is known to play a vital role in the regulation of energy homeostasis. Gao et al found that A. muciniphila treatment promoted the browning of inguinal fat pad, reduced energy efficiency and improved metabolic disorders in the high fat diet-fed mice. Besides, multiple sclerosis patients also had a higher Akkermansia, and transfer from their fecal microbiota ameliorated disease in recipients by expanding Akkermansia. Likewise, A. muciniphila was significantly increased in IFNγ-deficient mice and restoration of IFNγ level decreased A. muciniphila.
Intriguingly, acute exposure to simulated high-altitude hypoxia did not result in phenotypic variation in oxygen utilizing, including aerobic, anaerobic and facultatively anaerobic. On the contrary, it was found that the strict anaerobes and obligate anaerobes were increased in large intestine and small intestine under simulated hypobaric hypoxia for 30 days. The difference of exposure time may lead to such discrepancy. In addition, the decrease of mobile element containing and the increase of potentially pathogenic and stress tolerant shed light on the harmful effects of acute hypoxia. It is consistent with the results obtained from functional analysis, including decreased environmental information processing and increased cellular processes and organismal systems. The underlying mechanisms include promotion of glycolytic capacity and suppression of oxidative metabolism. Future studies are needed to confirm the phenotypic and functional prediction spectrum of the flora. Moreover, exact details of physiological adaptability in the high-altitude environment remain to be resolved.
A limitation of the study is that only one option for exposure time and altitude was administrated, so the time-dependent and altitude-dependent intestinal flora changes have yet to be described. In addition, besides hypoxia other high-altitude environment variable such as cold, wind and ultraviolet radiation were not fully considered. It is an important developing direction to investigate how the gut microbiota respond to high-altitude environment.