Hypoxia and inactivity related physiological changes precede or take place in absence of significant rearrangements in bacterial community structure: The PlanHab randomized trial pilot study

Abstract

We explored the assembly of intestinal microbiota in healthy male participants during the randomized crossover design of run-in (5 day) and experimental phases (21-day normoxic bed rest (NBR), hypoxic bed rest (HBR) and hypoxic ambulation (HAmb) in a strictly controlled laboratory environment, with balanced fluid and dietary intakes, controlled circadian rhythm, microbial ambiental burden and 24/7 medical surveillance. The fraction of inspired O2 (FiO2) and partial pressure of inspired O2 (PiO2) were 0.209 and 133.1 ± 0.3 mmHg for NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg for both hypoxic variants (HBR and HAmb; ~4000 m simulated altitude), respectively. A number of parameters linked to intestinal environment such as defecation frequency, intestinal electrical conductivity (IEC), sterol and polyphenol content and diversity, indole, aromaticity and spectral characteristics of dissolved organic matter (DOM) were measured (64 variables). The structure and diversity of bacterial microbial community was assessed using 16S rRNA amplicon sequencing. Inactivity negatively affected frequency of defecation and in combination with hypoxia increased IEC (p < 0.05). In contrast, sterol and polyphenol diversity and content, various characteristics of DOM and aromatic compounds, the structure and diversity of bacterial microbial community were not significantly affected over time. A new in-house PlanHab database was established to integrate all measured variables on host physiology, diet, experiment, immune and metabolic markers (n = 231). The observed progressive decrease in defecation frequency and concomitant increase in IEC suggested that the transition from healthy physiological state towards the developed symptoms of low magnitude obesity-related syndromes was dose dependent on the extent of time spent in inactivity and preceded or took place in absence of significant rearrangements in bacterial microbial community. Species B. thetaiotamicron, B. fragilis, B. dorei and other Bacteroides with reported relevance for dysbiotic medical conditions were significantly enriched in HBR, characterized with most severe inflammation symptoms, indicating a shift towards host mucin degradation and proinflammatory immune crosstalk.

Effects of Psychological, Environmental and Physical Stressors on the Gut Microbiota

“…Of some relevance are recent reports that provided comprehensive insight into the independent effects of hypoxia on the gut microbiota by comparing subjects maintained on bed rest under normoxic or normobaric hypoxic (∼4000 m simulated altitude) conditions for 21 days ( Sket et al, 2017a , b , 2018 ). That study reported a hypoxia-induced enrichment of Bacteroides relative abundance ( Sket et al, 2017b , 2018 ) and of bacterial genes related to iron metabolism, virulence and mucin degradation ( Sket et al, 2018 ), but little effect on the microbial metabolome ( Sket et al, 2017a , 2018 ). Unfortunately, these findings cannot be extrapolated to high altitude environments as some of the hypoxia-mediated effects were mitigated when subjects were not confined to bed rest, and due to uncertainty regarding whether normobaric hypoxia fully reproduces the physiologic effects of hypobaric hypoxia ( Millet et al, 2012 ).…”

Intestinal Metagenomes and Metabolomes in Healthy Young Males: Inactivity and Hypoxia Generated Negative Physiological Symptoms Precede Microbial Dysbiosis

“…Most studies thus far focused on the beneficial effects of re-introduction of exercise to obese population to alleviate these negative effects on one side, and to understand the effects of athletic overtraining on the other (Clarke et al, 2014 ; Barton et al, 2017 ). Recent studies clearly illustrated how exercise, microbiota and its metabolic functions are mutually dependent and responsive to physiological variations due to exercise (Clarke et al, 2014 ; Barton et al, 2017 ; Monda et al, 2017 ; Šket et al, 2017a , b ). However, there is an obvious lack of data on the initial changes in human microbiome and physiology during acute cessation of exercise.…”

“…In order to improve our understanding of consequences of acute and prolonged inactivity and hypoxia on human pathophysiology the PlanHab experimental setup was adopted (Debevec et al, 2014 ; Simpson et al, 2016 ; Šket et al, 2017a , b ). The PlanHab experiment was conducted according to European Space Agency (ESA) and NASA core bedrest data collection SOP (Standardization of bed rest study conditions 1.5, August 2009), included controlled daily water and nutritional intake in addition to controlled atmospheric oxygen content, circadian rhythm, microbial ambiental burden and 24/7 medical surveillance (Debevec et al, 2014 ; Simpson et al, 2016 ; Šket et al, 2017a , b ).…”

“…In this study, multifaceted nature of the intestinal microbiota of healthy male test participants was explored during the 5-day run-in and three consecutive experimental phases [21-day normoxic bed rest (NBR), hypoxic bedrest (HBR) and hypoxic ambulation (HAmb); (Šket et al, 2017a , b )]. A number of variables linked to the interplay between intestinal microbiome and intestinal environment were measured: (i) Shot-gun metagenomes of intestinal microbial communities at taxonomic and functional levels, (ii) intestinal nuclear magnetic resonance ( 1 H-NMR and 13 C-NMR) metabolomes; (iii) X-ray fluorescence (XRF) spectroscopy of elements, and (iv) Bayesian network analysis of significantly different intestinal parameters and metabolites (Figure 1 ).…”

“…A number of negative physiological symptoms related to obesity and metabolic syndrome have been observed to a large extent in the PlanHab study in a dose dependent manner over the course of 21-day experimental period in HBR and NBR, but were absent from HAmb variant (Debevec et al, 2014 , 2016 ; Rittweger et al, 2016 ; Simpson et al, 2016 ; Stavrou et al, 2016 ; Šket et al, 2017a , b ; Strewe et al, 2017 ). In addition, the observed negative symptoms faded effectively in 14, 10, <4 days for HBR, NBR, and HAmb, respectively (Debevec et al, 2014 ; Šket et al, 2017a , b ).…”