An integrated omics analysis: impact of microgravity on host response to lipopolysaccharide in vitro

Chakraborty, Nabarun; Gautam, Aarti; Muhie, Seid; Miller, Stacy‐Ann; Jett, Marti; Hammamieh, Rasha

doi:10.1186/1471-2164-15-659

Cited by 22 publications

(38 citation statements)

References 58 publications

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“…Recent studies further linked spaceflight to immune deficiencies, metabolic syndrome, bioenergetics dysfunction, and vascular remodeling. (14)(15)(16)(17)(18) Each of these factors individually has shown detrimental effects on musculoskeletal health; in this perspective, this Rodent Research 4 (RR4) project presented us a unique opportunity to investigate the cumulative effects of all of these stress factors on muscle fitness. Our previous studies (11,19) showed that femoral and tibial trabecular bone volume was significantly reduced during spaceflight.…”

Section: Discussionmentioning

confidence: 99%

“…In either case, it is also notable that our data on the immune functions in spaceflight correlated well with previous works that have associated these immunodeficiencies to energy deprivation in space. (12,16,46) It is known that oxidative stress and inflammation have a negative impact on muscle health and contribute to sarcopenia, (45,46) and it has been speculated that to mitigate this damage, cells downregulate metabolism and immune functions that typically produce reactive oxygen species. (49) At the background of the rampant negative consequences of spaceflight on healthy rodent quadriceps, there are potentially certain mitigation strategies in effect, again vital information, namely the initiation time of these biofunctions, remained obscure.…”

Section: Discussionmentioning

confidence: 99%

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Gene-Metabolite Network Linked to Inhibited Bioenergetics in Association With Spaceflight-Induced Loss of Male Mouse Quadriceps Muscle

Chakraborty

Waning

Gautam

et al. 2020

Journal of Bone and Mineral Research

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Prolonged residence of mice in spaceflight is a scientifically robust and ethically ratified model of muscle atrophy caused by continued unloading. Under the Rodent Research Program of the National Aeronautics and Space Administration (NASA), we assayed the large-scale mRNA and metabolomic perturbations in the quadriceps of C57BL/6j male mice that lived in spaceflight (FLT) or on the ground (control or CTR) for approximately 4 weeks. The wet weights of the quadriceps were significantly reduced in FLT mice. Next-generation sequencing and untargeted mass spectroscopic assays interrogated the gene-metabolite landscape of the quadriceps. A majority of top-ranked differentially suppressed genes in FLT encoded proteins from the myosin or troponin families, suggesting sarcomere alterations in space. Significantly enriched gene-metabolite networks were found linked to sarcomeric integrity, immune fitness, and oxidative stress response; all inhibited in space as per in silico prediction. A significant loss of mitochondrial DNA copy numbers in FLT mice underlined the energy deprivation associated with spaceflight-induced stress. This hypothesis was reinforced by the transcriptomic sequencing-metabolomics integrative analysis that showed inhibited networks related to protein, lipid, and carbohydrate metabolism, and adenosine triphosphate (ATP) synthesis and hydrolysis. Finally, we discovered important upstream regulators, which could be targeted for next-generation therapeutic intervention for chronic disuse of the musculoskeletal system.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gene-Metabolite Network Linked to Inhibited Bioenergetics in Association With Spaceflight-Induced Loss of Male Mouse Quadriceps Muscle

Chakraborty

Waning

Gautam

et al. 2020

Journal of Bone and Mineral Research

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“…The host immune defense system is vulnerable to spaceflight-induced stress. 1 Given that microgravity can simultaneously aggravate pathogenicity 2 , 3 and suppress host defenses, 1 we posit that the host–pathogen dynamics assume novel characteristics in space. Comprehensive characterization of host–pathogen relationships is critical in developing mitigation strategies for the many challenges continuously faced by astronauts, such as delayed wound healing 4 and musculoskeletal atrophy.…”

Section: Introductionmentioning

confidence: 99%

Gene-metabolite profile integration to understand the cause of spaceflight induced immunodeficiency

et al. 2018

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Spaceflight presents a spectrum of stresses very different from those associated with terrestrial conditions. Our previous study (BMC Genom. 15: 659, 2014) integrated the expressions of mRNAs, microRNAs, and proteins and results indicated that microgravity induces an immunosuppressive state that can facilitate opportunistic pathogenic attack. However, the existing data are not sufficient for elucidating the molecular drivers of the given immunosuppressed state. To meet this knowledge gap, we focused on the metabolite profile of spaceflown human cells. Independent studies have attributed cellular energy deficiency as a major cause of compromised immunity of the host, and metabolites that are closely associated with energy production could be a robust signature of atypical energy fluctuation. Our protocol involved inoculation of human endothelial cells in cell culture modules in spaceflight and on the ground concurrently. Ten days later, the cells in space and on the ground were exposed to lipopolysaccharide (LPS), a ubiquitous membrane endotoxin of Gram-negative bacteria. Nucleic acids, proteins, and metabolites were collected 4 and 8 h post-LPS exposure. Untargeted profiling of metabolites was followed by targeted identification of amino acids and knowledge integration with gene expression profiles. Consistent with the past reports associating microgravity with increased energy expenditure, we identified several markers linked to energy deficiency, including various amino acids such as tryptophan, creatinine, dopamine, and glycine, and cofactors such as lactate and pyruvate. The present study revealed a molecular architecture linking energy metabolism and immunodeficiency in microgravity. The energy-deficient condition potentially cascaded into dysregulation of protein metabolism and impairment of host immunity. This project is limited by a small sample size. Although a strict statistical screening was carefully implemented, the present results further emphasize the need for additional studies with larger sample sizes. Validating this hypothesis using an in vivo model is essential to extend the knowledge towards identifying markers of diagnostic and therapeutic value.

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“…SPACEFLIGHT, IN PARTICULAR MICROGRAVITY, CHANGES the innate and adpative immune system in many aspects (1)(2)(3). For example, astronauts returning from spaceflights have neutrophilia and eosinopenia (4)(5)(6).…”

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Simulated microgravity disrupts intestinal homeostasis and increases colitis susceptibility

Li¹,

Shi²,

Zhang³

et al. 2015

The FASEB Journal

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The immune systems can be altered by spaceflight in many aspects, but microgravity-related mucosal immune changes and its clinical significance have not been well studied. The purpose of this study was to investigate whether simulated microgravity influences the intestinal homeostasis and increases the susceptibility to colon inflammation. The hindlimb unloading (HU) mouse model was used to simulate the microgravity condition. Three percent dextran sulfate sodium (DSS) was given to mice to induce colitis. Compared to ground control (Ctrl) mice, the HU ones revealed an impaired intestinal homeostasis and increased susceptibility to DSS-induced colitis. This includes an early-onset, 4-fold expansion of segmented filamentous bacteria (SFB), more than 2-fold decrease in regulatory T (Treg) cell numbers and IL-10 production, ∼2-fold increase in colonic IL-1β expression, 2-fold increase in circulating neutrophils, and colonic neutrophil infiltration. The application of antibiotics ameliorated the Treg and IL-10 reductions but did not significantly dampen neutrophilia and elevated expression of colonic IL-1β. These results indicate that the intestinal microflora and innate immune system both respond to simulated microgravity and together, contribute to the proinflammatory shift in the gut microenvironment. The data also emphasize the necessity for evaluating the susceptibility to inflammatory bowel diseases (IBDs) in distant space travels.

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An integrated omics analysis: impact of microgravity on host response to lipopolysaccharide in vitro

Cited by 22 publications

References 58 publications

Gene-Metabolite Network Linked to Inhibited Bioenergetics in Association With Spaceflight-Induced Loss of Male Mouse Quadriceps Muscle

Gene-Metabolite Network Linked to Inhibited Bioenergetics in Association With Spaceflight-Induced Loss of Male Mouse Quadriceps Muscle

Gene-metabolite profile integration to understand the cause of spaceflight induced immunodeficiency

Simulated microgravity disrupts intestinal homeostasis and increases colitis susceptibility

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