Modulation of neutrophil-to-lymphocyte ratio and gut microbiome balance in astronauts: potential benefits of novel beta-glucans during space missions

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Introduction:Among the multitudes of clinical experiments, human beings subjected to spaceflight travel stand apart because of their complexity owing to a microgravity environment. Before considering any pathological implications due to changes in the gravitational force, the fundamental physiological processes aided by the Earth’s gravity are disrupted and need to be evaluated. Therefore, maintaining physiological stability despite altered gravity is the utmost priority, followed by addressing the pathological implications and their management.Spaceflight, characterised by microgravity, circadian misalignment, isolation, confinement, stress, a semi-closed food system, and increased exposure to space radiation, has been shown to have detrimental effects on the human immune system [1,2]. The immune system dysregulations reported in astronauts include altered leukocyte distribution, changes in plasma cytokines, reduced T-cell function, and reactivation of latent herpesviruses. Persistent low-grade systemic inflammation characterised by increased TNF-α and IL-1RA, which can lead to various diseases, has been documented [3]. The clinical implications of such immune dysfunction include rashes, hypersensitivity, and atopic dermatitis, in addition to accelerated physiological aging, as evidenced by muscle wasting and loss of bone density [1,2].In this context, ongoing research has focused on identifying safe and easily evaluable in-flight biomarkers for monitoring the immune system of astronauts. The neutrophil-to-lymphocyte ratio (NLR) has been identified as a potential biomarker candidate to evaluate the immune status [1,3] because (i) leukocyte counts have been reported to be altered during spaceflight, and (ii) on Earth, elevated NLR is an extremely useful biomarker of chronic persistent subclinical inflammation, which can be a major pre-existing factor for disease development. Furthermore, an elevated NLR has been shown to predict poor prognosis in cancers and chronic conditions such as coronary heart disease, stroke, diabetes, obesity, psychiatric diagnosis, anaemia, and stress. A gradual increase in the NLR, apart from having a positive correlation with age, also serves as a biomarker to predict the overall mortality of a specific population [4]. Significance of NLR:Recent reports [1,3] have documented a gradual increase in the NLR in astronauts, which has been suggested to be an indicator of hastened inflammation. Moreover, compared to other biomarkers of inflammation and immune status, NLR is easy to measure and has been proven to be altered under simulated spaceflight conditions on Earth, as well as in spaceflight experiments, suggesting that it is a critical biomarker for monitoring the immune system and health of astronauts [3].The NLR can be considered a critical biomarker because it acts as a bridge between innate and adaptive immune systems [5]. The NLR in the peripheral blood, serves as a biomarker linking two key components of the immune system: the innate immunity mediated by neutrophils and adaptive immunity mediated by lymphocytes. Neutrophils constitute the frontline defence of the host immune system against pathogens by employing mechanisms such as chemotaxis, phagocytosis, reactive oxygen species (ROS) generation, granular protein release, and cytokine production. Beyond these functions, neutrophils considerably influence adaptive immunity and are pivotal effector cells in systemic inflammatory response syndrome. Acting as regulators of innate immunity, neutrophils recruit, activate, and modulate other immune cells by secreting diverse pro-inflammatory and immunomodulatory cytokines and chemokines, thereby enhancing the activity and recruitment of immune cells such as dendritic, B, natural killer (NK), CD4+, CD8+, γδ T, and mesenchymal stem cells [5].However, although the NLR has been identified as a critical biomarker for monitoring the immune system and prognosis of diseases both in routine clinical settings and in astronauts, safe, easily administrable dietary or nutritional interventions are still needed to beneficially modulate the NLR for maintaining health in astronauts. Even in a head-down tilt bed rest experiment, considered as the best and most integrated Earth-based analogue of the microgravity in spaceflight, the NLR was identified as a critical biomarker for astronauts and was found to increase in the study participants. However, dietary supplementation which was part of the experiment, did not produce any changes in NLR values [3].Interventions to modulate NLR:Some interventions have decreased the NLR in routine clinical settings. One such is Vitamin D, wherein high-dose supplementation of vitamin D reduced NLR distribution in a clinical study in adolescent girls [6]. Vitamin D supplementation has been suggested as a means to beneficially modulate NLR in astronauts, and despite daily vitamin D supplementation, crew members on the Russian space station Mir had serum 25(OH)-D3 concentrations that were 32%–36% less during and after long-duration (3- to 4-mo) missions than before the missions [7]. In another study, an oral food supplement containing Echinacea angustifolia, rosehip, propolis, royal jelly, and zinc, was shown to decrease NLR inpatients with COVID [8]. Other nutritional supplements reported to influence NLR include omega-3 fatty acids [9] and synbiotic supplements [10]. However, the search continues for a dietary intervention that is safe, easy to administer, and can work on immunity as well as other aspects contributing to optimal health, including the gut microbiome.Gut microbiome and NLR:Regarding the relevance of gut microbiome to NLR and health, it is well established that 70% of the immune cells in our body are found in the gastrointestinal (GI) tract, where their development and maturation are influenced by their interactions with the gut microbiota. When gut dysbiosis occurs, a clinically “maladaptive” immune response can arise [11]. Changes in NLR have already been found to be directly correlated with gut dysbiosis, and gut microbiome abundance has been reported to differ considerably between patients with normal NLR and those with increased NLR [12]. Thus, NLR can be considered a critical indicator along with the correlation of the gut microbiome for monitoring health status and disease prognosis [12-14]. On spaceflight and in the gut microbiome, notable changes in 44 microbiome species, including relative reductions in bile acid and butyrate-metabolising bacteria such as Extibacter muris and Dysosmobacter welbionis, have been reported [15]. Increases in the genera Clostridium, Romboutsia, Ruminiclostridium, and Shuttleworthia, along with the decreases in Hungatella and significant enrichment of Dorea sp. and Lactobacillus murinus have also been reported [16].Beta-glucans beneficially modulate NLR:Given the above background of several known and unknown factors that affect the health of astronauts and the critical nature of maintaining NLR and gut homeostasis, a major solace is the result of our work on the safe and beneficial modulation of NLR in pre-clinical and clinical studies using the biological response modifier (BRM) Beta-1,3-1,6-glucans produced as an exo-polysaccharide by the AFO-202 and N-163 strains of a black polyextremotolerant yeast, Aureobasidium pullulans. Beta-glucans are naturally occurring polysaccharides found in the cell walls of yeast, fungi (including mushrooms), certain bacteria, seaweed, and cereals such as oats and barley. These bioactive compounds possess multiple functional properties including hypocholesterolaemic, hypoglycaemic, immunomodulatory, antitumour, antioxidant, and anti-inflammatory activities. The structural and functional properties of Beta-glucans vary depending on their source. Among the various types, yeast-derived Beta-1,3-1,6-glucans have demonstrated superior BRM effects compared to those derived from cereal sources such as oats or barley. Clinical app

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