Systems View of Deconditioning During Spaceflight Simulation in the PlanHab Project: The Departure of Urine 1 H-NMR Metabolomes From Healthy State in Young Males Subjected to Bedrest Inactivity and Hypoxia

Abstract

We explored the metabolic makeup of urine in prescreened healthy male participants within the PlanHab experiment. The run-in (5 day) and the following three 21-day interventions [normoxic bedrest (NBR), hypoxic bedrest (HBR), and hypoxic ambulation (HAmb)] were executed in a crossover manner within a controlled laboratory setup (medical oversight, fluid and dietary intakes, microbial bioburden, circadian rhythm, and oxygen level). The inspired O2 (FiO2) fraction next to inspired O2 (PiO2) partial pressure were 0.209 and 133.1 ± 0.3 mmHg for the NBR variant in contrast to 0.141 ± 0.004 and 90.0 ± 0.4 mmHg (approx. 4,000 m of simulated altitude) for HBR and HAmb interventions, respectively. 1H-NMR metabolomes were processed using standard quantitative approaches. A consensus of ensemble of multivariate analyses showed that the metabolic makeup at the start of the experiment and at HAmb endpoint differed significantly from the NBR and HBR endpoints. Inactivity alone or combined with hypoxia resulted in a significant reduction of metabolic diversity and increasing number of affected metabolic pathways. Sliding window analysis (3 + 1) unraveled that metabolic changes in the NBR lagged behind those observed in the HBR. These results show that the negative effects of cessation of activity on systemic metabolism are further aggravated by additional hypoxia. The PlanHab HAmb variant that enabled ambulation, maintained vertical posture, and controlled but limited activity levels apparently prevented the development of negative physiological symptoms such as insulin resistance, low-level systemic inflammation, constipation, and depression. This indicates that exercise apparently prevented the negative spiral between the host’s metabolism, intestinal environment, microbiome physiology, and proinflammatory immune activities in the host.

The Importance of Objective Stool Classification in Fecal 1H-NMR Metabolomics: Exponential Increase in Stool Crosslinking Is Mirrored in Systemic Inflammation and Associated to Fecal Acetate and Methionine

“…Consequently, the increased stool resistance to remodeling as measured in this study by MP in the PlanHab samples was apparently related to intestinal abrasions, diet associated mucus imprinting and surface pore clogging on stool. These parameters were all shown to exert selective pressure on gut microbiome, its gene expression and metabolic activities, generating thus metabolic makeup associated with observed local and systemic inflammation [3,8,13,14,16], mirrored also in the urinary metabolomes of the same PlanHab project [26]. This clearly showed that parameters other than BSS accurately described clinically relevant fecal hardness.…”

“…Fecal samples were collected from the prospective male-female random study that served to provide the backbone observations on the tripartite relationship between BSS, dry matter content and novel MP values. This relationship was further amended by superposition of samples collected within the PlanHab project ( [3,13,14,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]; Table S1; Figures S1 and S2) that was designed to capture systemic body deconditioning parameters in response to three-week controlled bed-rest inactivity and hypoxia, a simulation of the space exploration environment. In summary, the decision of the host to reduce physical activity to three-week 24/7 bed-rest resulted in significant increase in insulin resistance, muscle resorption, bone demineralization and other numerous adaptations, hence the complexity of human body physiological responses were collated from the PlanHab literature and summarized in Table S1.…”

“…Taken together, in this study we established an exponential relationship between BSS and MP on one side and a complex saturation curve -like relationship between dry matter and MP. The PlanHab samples with decreased BSS values (Figure S1) were reported to be associated with a number of detrimental physiological and psychological characteristics next to intestinal inflammation (Figure S2; Table S1; [3,13,14,26,27,36]). Consequently, the increased stool resistance to remodeling as measured in this study by MP in the PlanHab samples was apparently related to intestinal abrasions, diet associated mucus imprinting and surface pore clogging on stool.…”

“…In this study, BSS and classical parameters (total solids, water content) [24,25] were recorded for a heterogenous collection of samples and mapped to MP measured in longitudinal and lateral transects of fecal samples. Random samples from prospective male-female study were collected and upgraded with healthy young male samples collected within the controlled four-week bed-rest space-exploration project PlanHab [26]. Gut environment was explored from the perspective of ecosystem development [15] in order to elucidate the relationship between the progressive increase in stool consistency (MP, dry matter) and the progressive intestinal and systemic inflammation observed over the course of the PlanHab project.…”

“…Gut environment was explored from the perspective of ecosystem development [15] in order to elucidate the relationship between the progressive increase in stool consistency (MP, dry matter) and the progressive intestinal and systemic inflammation observed over the course of the PlanHab project. The MP values reported in this study were coupled to reanalysis of the PlanHab data and fecal 1H-NMR metabolomes reported before [3,13,14] to explore the association between stool consistency (MP), individual signatures in 1H-NMR metabolites and the elevated intestinal, systemic inflammation and other detrimental physiological deconditioning effects observed in the PlanHab participants reported before [3,13,14,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43].…”