Hypoxia and Inactivity Related Physiological Changes (Constipation, Inflammation) Are Not Reflected at the Level of Gut Metabolites and Butyrate Producing Microbial Community: The PlanHab Study

Abstract

We explored the assembly of intestinal microbiota in healthy male participants during the run-in (5 day) and experimental phases [21-day normoxic bed rest (NBR), hypoxic bedrest (HBR)], and hypoxic ambulation (HAmb) in a strictly controlled laboratory environment, 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; ~4,000 m simulated altitude), respectively. A number of parameters linked to intestinal transit spanning Bristol Stool Scale, defecation rates, zonulin, α1-antitrypsin, eosinophil derived neurotoxin, bile acids, reducing sugars, short chain fatty acids, total soluble organic carbon, water content, diet composition, and food intake were measured (167 variables). The abundance, structure, and diversity of butyrate producing microbial community were assessed using the two primary bacterial butyrate synthesis pathways, butyryl-CoA: acetate CoA-transferase (but) and butyrate kinase (buk) genes. Inactivity negatively affected fecal consistency and in combination with hypoxia aggravated the state of gut inflammation (p < 0.05). In contrast, gut permeability, various metabolic markers, the structure, diversity, and abundance of butyrate producing microbial community were not significantly affected. Rearrangements in the butyrate producing microbial community structure were explained by experimental setup (13.4%), experimentally structured metabolites (12.8%), and gut metabolite-immunological markers (11.9%), with 61.9% remaining unexplained. Many of the measured parameters were found to be correlated and were hence omitted from further analyses. The observed progressive increase in two immunological intestinal markers suggested that the transition from healthy physiological state toward the developed symptoms of low magnitude obesity-related syndromes was primarily driven by the onset of inactivity (lack of exercise in NBR) that were exacerbated by systemic hypoxia (HBR) and significantly alleviated by exercise, despite hypoxia (HAmb). Butyrate producing community in colon exhibited apparent resilience toward short-term modifications in host exercise or hypoxia. Progressive constipation (decreased intestinal motility) and increased local inflammation marker suggest that changes in microbial colonization and metabolism were taking place at the location of small intestine.

Towards Individualized Use of Probiotics and Prebiotics for Metabolic Syndrome and Associated Diseases Treatment: Does Pathophysiology-Based Approach Work and Can Anticipated Evidence Be Completed?

“…The genus Bacteroides and proteins involved in iron acquisition and metabolism, cell wall, capsule, virulence and mucin degradation were enriched at the end of HBR suggest that both constipation and EC decreased intestinal metal availability leading to modified expression of co-regulated genes in Bacteroides genomes [213,214]. Exercise prevent the crosstalk between the microbial physiology, mucin degradation and proinflammatory immune activities in the host [213].…”

“…during exercise in normoxic and severe acute hypoxic conditions can be a target for microbiota associsted interventions [214]. Gut microbiota effects via by regulating gut mucosal pro-inflammatory and anti-inflammatory actions through the activity of reactive oxygen species (ROS) required for normal cellular homeostasis and physiological function including muscles [214,215].…”

“…The epithelium overlying all mucosal tissues is supported by a rich vasculature. In these settings, even small perturbations in blood flow can result in relatively large decreases in O2 delivery (hypoxia) to the supporting epithelium [213,214].…”

“…Using mathematical modeling, e.g.,Bayesian network analysis was used to derive the first hierarchical model of initial inactivity mediated deconditioning steps over time [214]; considering use of alpha, beta, and gamma diversities (alpha x beta = gamma) among the fundamental descriptive variables of ecology [313]. Shannon measures were shown to be the only standard diversity measures which can be decomposed into meaningful independent alpha and beta components when community weights are unequal [313].…”

“…Tissue (NBR) and combination of tissue and systemic hypoxia (HBR) increased inflammatory responses in inactive variants were recently linked to central inflammatory mediators nuclear factor kappa B (NF-kB) and transcription factor hypoxia inducible factor 1 (HIF-1) as a regulator of the cellular response to low oxygen levels to shape nutritional-immunity status of the gut and induce the release of reactive oxygen and nitrogen species[261].However, it was reported[214] that a short-term modifications in host exercise levels and constipation or systemic hypoxia do not change significantly gut permeability, concentration of crucial intestinal metabolites, structure and abundance of butyrate producing microbial community; but progressive constipation (decreased intestinal motility) and increased local inflammation markers suggest that changes in microbial colonization and metabolism were taking place at the location of small intestine[214].According to our recent observations a long stay in extreme conditions of Antarctica evoke adaptive reactions associated with hypoxia and mitochondrial dysfunction, determined by a set of molecular-genetic mechanisms that trigger the expression of the corresponding genes and alter the mitochondria ultrastructure, leading to the death of organelles, and subsequently the cells, and are associated with pronounced oxidative stress[262].The mesenteric blood flow redistribution can impact on the gut microbiota and potential probtioc effect[263]. The higher release of short-chain fatty acids (SCFAs) was reported by the distal intestines relative to the proximal intestines.…”