The Potential Influence of the Microbiota and Probiotics on Women during Long Spaceflights

Abstract

Humans have been exploring space for almost 55 years but space travel comes with many psychological and physiological changes that astronauts have to adapt to, both during and post flight missions. Now, with the reality of such missions lasting years, maintaining proper health of the flight crew is a high priority. While conditions such as nausea, bone loss, renal calculi and depression have been recognized, and approaches to medical and surgical care in space considered, the influence of the microbiota could be of added significance in maintaining astronaut health. While probiotics have long been part of the Russian cosmonaut diet, their use for specific health concerns of women has not been assessed. In this article, we explore the ways in which the microbiome may influence the health of female astronauts during long space flights, and present a rationale for the use of probiotics.

Since the first human was flown into space in 1961, there have been 543 astronauts/cosmonauts, of which 11% have been female [1]. In 1963, Valentina Tereshkova was the first woman in space, flying aboard Vostok 6. In orbit and during preflight training, astronauts are placed in a multistressor environment where they have to physically and psychologically adapt to multiple adverse conditions such as restricted diets, lack of sleep, isolation and harsh environmental conditions. Microgravity creates an environment vastly different from what the human body was built for. Without the compression of gravity, the back vertebrae separate, increasing body height [2]. Elevated excretion of calcium and phosphorus from bone results in rapid bone loss, which on long missions can lead to renal calculi and fractures [3]. Anxiety increases as the spacecraft moves further away from earth, and poorer food quality and hygiene compound this effect. With a compromised immune system, infections occur [4], and emergence of latent viruses is a concern [5–7]. Allergy symptoms can occur due to immune changes, and while antiviral drugs and various medications are included in the cargo, the shelf life of active ingredients is shorter in microgravity [8].

Men and women differ in many ways, which includes the risk of acquiring certain diseases. For example, on earth, cardiovascular disease (CVD) develops 7–10 years later in females than males due to the protective effects of estrogen during the female reproductive years [9]. Urinary tract infections (UTIs) are more common in women [10], while men have higher rates of kidney stones [11–13]. The prevalence of osteoporosis is higher in females than males, but mortality after fracture is higher in men than women [14,15]. As on earth, men and women adapt differently to certain conditions in space [16] and the risk of disease can also differ between them.

Manned missions to Mars are estimated to take 2–3 years, making it very difficult to return to earth if health issues arise. Thus, a priority for the success of long-term space explorations is the ability to minimize disease onset and the complications associated with them. This paper will explore how microbiome studies can be an important component of health management for women in zero gravity.

Human microbiome & space travel

The term ‘human microbiome’, was coined in 2001 by Joshua Lederberg who defined it as the “ecological community of commensal, symbiotic and pathogenic microorganisms that literally share our body space” [17]. These microorganisms consist of bacteria, archaea, viruses and eukaryotes, but the majority making up the human microbiome are bacteria (99%) [18], albeit this may change with future virome studies. While the terms ‘human microbiome’ and ‘human microbiota’ are often used interchangeably, the latter refers to the microbial taxa associated with humans, while the former refers to the collection of microbial taxa and their genes [19].

These bacterial communities are important in promoting health as they synthesize vitamins the host cannot make, salvage energy from indigestible compounds, create a competitive environment to prevent pathogen colonization, promote maturation and regulation of the immune system, contribute to vascular development and angiogenesis and promote integrity of epithelial barriers [20–24]. It is these collective traits that make our microbiota targets for maintaining health.

The healthy human microbiota contains a collection of: symbionts, which are bacteria that actively promote health; commensals, which are neither advantageous nor detrimental to the host; and pathobionts, which can promote pathology when conditions are altered in the host [25]. When there is microbial disruption, either by reduction of symbionts and/or an overgrowth of pathobionts, a breakdown in homeostasis will occur, leading to disease.

It has been observed that gut, nasal and oral bacterial profiles of astronauts change during both short- and long-term space missions [26–28]. These changes are associated with a decrease in the relative abundance of putative beneficial microorganisms from the genera Bifidobacterium and Lactobacillus and an increase in opportunistic pathogens such as Staphylococcus aureus, Escherichia coli, Clostridium spp., Pseudomonas aeruginosa and Fusobacterium nucleatum [29,26]. It is still unknown what aspects of space travel cause these changes but animal studies under stimulated microgravity have mimicked what was found in humans [30]. Diet could also be a contributing factor, as microbial profiles change in isolated ground crew members fed the same diet as those in space [31]. This could be a consequence of food sterilization that kills lactobacilli and bifidobacteria. If this is the case, strong consideration should be made in favor of supplementing the diet of astronauts with probiotics to make up for the loss of these beneficial microbes.

One limitation of the above microbiota studies is that they were conducted on male astronauts, with no data available on how space travel affects the microbiota in females. A North American study showed that diet impacts the gut microbiota differently in males and females [32]. Thus, conditions in space that shape microbial profiles, whether it be diet, hormones, microgravity or radiation, could impact male and female astronauts differently. Some conditions that are a concern for women astronauts, with a role of bacteria, are addressed below and summarized in Figure 1.

Figure 1.

Summary of the potential effects of the female microbiota and probiotic interventions in modulating health and disease during long-term space missions. The human microbiota plays an important role in modulating the risks of various health conditions. Growing evidence suggests that probiotic interventions, when microbial profiles are distorted, may help to reduce the risk of breast cancer, UTIs, bacterial vaginosis and osteoporosis; as well as promoting reproductive and digestive health, robust immune response and managing anxiety.

UTIs

UTIs are recurrent problems during spaceflight [3] with an increased incidence in female astronauts compared with males [16]. An estimated 95% of all UTIs are caused by the uropathogens E. coli and Staphylococcus saprophyticus [33] due to the ability to bind to uroepithelial cells via adhesion molecules [34,35]. A possibility of why UTIs are a common problem during spaceflight could be the increase in virulence factors in response to microgravity [36,37]. For example, both pathogenic and nonpathogenic strains of E. coli exhibit enhanced adherence and invasion in vitro in response to microgravity. This increased adherence, coupled with the enhanced growth kinetics of E. coli during spaceflight, could be responsible for promoting disease development [38]. While studies to date have focused on the effects of space conditions on known pathogens, work should also be done to assess which normal constituents of the female urogenital tract are affected by microgravity and how this impacts host health.

Standard practice to treat UTIs on earth and in space is with antibiotics, but studies have shown that some pathogens become less susceptible to these drugs under microgravity, leading to higher minimum inhibitory concentration (MIC) needed for eradication [39–41]. For example, the MIC of colistin and kanamycin for E. coli isolates aboard Salyut 7, increased from 4 mg/l to >16 mg/l [39]. If the antibiotic doses given to female astronauts in space to treat UTIs are the same as those on earth, the women may actually be receiving subinhibitory concentrations, which could be problematic. Such concentrations have been shown to induce increased expression of adhesins in S. saprophyticus and E. coli coinciding with promoting enhanced colonization of bladder and kidney cells, potentially leading to more severe and recurrent infections [33]. The idea of interfering with uropathogen ascension from the vagina and urethra to the bladder, by administering probiotic Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 that produce anti-infective properties, has been tested in elderly women and shown to prevent UTIs to a similar extent to long-term, low-dose antibiotics, without the side effects [42]. So, this is worthy of consideration for female astronauts.

Vaginal & reproductive health

Based upon a small sample size of females who were in space for an average of 9 days, there was no evidence of adverse reproductive outcomes upon return to earth [3]. However, this study failed to address the ability to conceive and deliver a healthy infant after extended space travel. If the loss of lactobacilli reported in the gut also occurs in the vagina, the chances of conception significantly decrease, according to studies performed on earth [43] and the risk of bacterial vaginosis (BV) may also increase, along with its recurrence, with potential adverse effects on quality of life. The ability of probiotic lactobacilli to reduce recurrences of BV in women who are immune suppressed [44], and even to potentially treat the condition [45], is worthy of consideration. Given the importance of reproduction for humanity, it seems short-sighted to have not acquired more information on the female vaginal microbiome during space flight, and to have considered how best to manage common infections using probiotics.

Breast cancer

Radiation is a major hazard for space travel leading to various types of cancers in both female and male astronauts. Female astronauts, however, have a 20% higher risk of cancer development, largely driven by breast and ovarian cancers [46]. In addition to radiation exposure, another risk factor for breast cancer development in female astronauts could be due to changes in their circadian rhythm as a result of altered sleeping patterns during spaceflight. It has been reported that females with rotating work schedules, such as flight attendants and nurses, have a higher risk of breast cancer development [47–50], prompting the International Agency for the Research on Cancer (IARC) to classify circadian rhythm disruptions (CRD) as a ‘probable carcinogen’ [51].

Transcriptome profiling studies have shown that up to 10% of our genes are under circadian control [52,53], however our ‘second genome’, those of the trillions of microbes inhabiting our body, is also under control of this master clock [54,55]. Changes in these bacterial profiles and their function as a result of CRD are linked to metabolic diseases [56,55]. While no work has yet been done examining the effects between circadian disrupted microbiota and breast cancer development, evidence suggests there could be a link. In mice, Lactobacillus levels increase during their ‘sleeping’ phase [55] and those with circadian disruptions have lower levels of gut Lactobacillus compared with controls, with differences occurring as early as 4 weeks after repeated dysregulation [55,54]. These effects could be detrimental to the host, as Lactobacillus has been shown in vitro to inhibit breast cancer cell growth [57] and in vivo to protect against breast cancer development in mice [58].

There is some basis for considering probiotics to reduce the risk of breast cancer development in women, caused by either radiation or changes in one's microbiome as a result of CRD. Epidemiological studies have shown that women who drink fermented milk products have a lower incidence of breast cancer [59].

Other probiotic applications for space flight

Bone loss is a key concern during long-term space missions. A study on earth found that L. reuteri strain 6475 had the ability to increase bone density and prevent osteoporosis in ovariectomized mice, which mimics the postmenopausal state in humans [60]. Hormones, however, may play a role in how effective probiotics are in this condition, as another study, using the same strain, saw effects in males but not premenopausal female mice [61].

Probiotics could be a promising tool to treat inflammatory or stress-induced gastrointestinal discomfort as numerous clinical and animal studies have shown an improvement in pain associated with irritable bowel syndrome [62–64], a condition more common in women. One mechanism could be that certain probiotic strains regulate analgesic receptors. Lactobacillus acidophilus NCFM has been shown to increase the expression of opioid and cannabinoid receptors on murine intestinal epithelial cells, leading to 20% better pain tolerance than controls [65].

The inclusion of fermented foods, even perhaps prepared fresh during flight, in the diet of astronauts may play a beneficial role in managing anxiety [66], enhancing immunity [67], promoting viral clearance after the re-emergence of latent viruses [68,69] and maintaining digestive health [70]. Such approaches are worthy of further investigation in the International Space Station, as a prelude to longer flights.

Conclusion & future perspective

With the increased interest in the role of the human microbiome in modulating health and disease here on earth, more efforts should be undertaken to study the effect of microgravity on gut, oral, breast, urinary and reproductive tract microbiota patterns in women. Transcriptomic and metabolomic analyses would provide the best understanding of how different microbes react during space flight. Future studies should examine how probiotics in dried and liquid forms are affected by microgravity and radiation; whether different strains might function better in space compared with on earth; appropriate dose for maximal health benefit; and recovery back to ‘normal’ upon re-entry to earth's atmosphere.

Executive summary

• As more women become part of space travel, and as duration of flights significantly increases, consideration should be given to diseases that affect their well-being.

• Even when ailments occur equally frequently in male and female astronauts, future studies need to include women as participants.

• The commercial space flight industry that is being developed, provides an opportunity, along with the existing International Space Station, to acquire microbiota samples and study functional and abundance changes induced by microgravity.

• The addition of fermented foods and probiotics should be considered as a staple in the astronaut diet to promote feminine health and potentially reduce urinary tract infection, bacterial vaginosis, anxiety, osteoporosis and breast cancer development.