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There is an increasing amount of information available about the gut.  Here are a few informative articles you may find valuable.

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Probiotics Beyond Terrestrial Limits

The Microbiome: The Forgotten Organ of the Astronaut's Body — Probiotics Beyond Terrestrial Limits
Amir Ata Saei, Abolfazl Barzegari, Future Microbiol. 2012;7(9):1037-1046.

Abstract and Introduction
Abstract
Space medicine research has drawn immense attention toward provision of efficient life support systems during long-term missions into space. However, in extended missions, a wide range of diseases may affect astronauts. In space medicine research, the gastrointestinal microbiome and its role in maintaining astronauts' health has received little attention. We would like to draw researchers' attention to the significant role of microbiota. Because of the high number of microorganisms in the human body, man has been called a 'supra-organism' and gastrointestinal flora has been referred to as 'a virtual organ of the human body'. In space, the lifestyle, sterility of spaceship and environmental stresses can result in alterations in intestinal microbiota, which can lead to an impaired immunity and predispose astronauts to illness. This concern is heightened by increase in virulence of pathogens in microgravity. Thus, design of a personal probiotic kit is recommended to improve the health status of astronauts.

Introduction
Living in space has been a great desire for mankind, leading to the development of space stations for long-duration manned space missions. The design of a life support system is needed to maintain the minimum life requirements for humans in space by conserving a stable body temperature, a standard pressure on the body and by managing waste products. So far, the majority of research in this area has been devoted to the human primary requirements such as air, water and food. Furthermore, a life support system deals with astronauts' healthcare. Although health status of the astronauts such as immunological and physiological problems has been investigated, less attention has been paid to the intestinal microbiome and its significant role in the astronaut's health. Immunological and physiological health problems could occur when considering the identified increase in the virulence and antibiotic resistance of some infectious bacteria exposed to microgravity, along with possible weakening of the immune system during space flight.[1,2] Compensating for these alterations may not only enhance the health and immunity status of astronauts, but might have possible effects on enhancing the duration of space journeys.

For many years, the importance of intestinal flora in human health and disease has been known to man. Researchers have suggested a possible association between the changes in the balance of gut flora and several diseases.[3] At the end of the Human Genome Project, the aggregation of flora genes within the human genome was named the 'human metagenome', highlighting the crucial role of the microbiome in the maintenance of health.[4] This perspective highlights the crucial role of the microbiome in the health and/or disease status in astronauts. Considering astronauts' special health and nutrition needs in orbit, it could be advantageous to develop probiotics for each crew member. These healthy bacteria could then be consumed during long-duration missions to replenish the intestinal microbiome.

The Human Intestine & the Microbiome
Today 'gut health' is a term increasingly used in the medical literature to describe effective digestion and absorption, the absence of gastrointestinal lesions, presence of normal intestinal microflora and proper immune function.[5] However, from a scientific point of view, it is still extremely unclear what gut health is or how it can be defined and/or measured. The interactions between the gastrointestinal barrier and the microbiome appear to be a complex mechanism that assists in maintaining gut health. The gastrointestinal tract contributes to digestion and absorption of nutrients, minerals and fluids, osmoregulation, endocrine regulation and host metabolism, mucosal and systemic tolerance, immunoenhancement, defense against potential pathogens and harmful substances, signaling from the periphery to the brain, and detoxification of toxic molecules originating from the environment or the host.[6] Recognition of the importance of gastrointestinal health and microflora can be an important asset to astronauts' health.

Across the large surface of the digestive tract, healthy and pathogenic bacteria compete for dominance. With such a huge exposure area, the immune system has a hard task of hindering pathogens from entering the blood and lymph. The presence of a balance between beneficial and potentially harmful bacteria is considered normal and contributes to a dynamic and healthy human gut. One way to maintain this homeostasis is to introduce helpful bacteria or probiotics. After the first suggestion of the health benefits of probiotics in the early 20th century by Nobel Laureate Metchnikoff, many bacterial strains have been clinically tested as potential probiotics.[7] Probiotics are thought to play a health-promoting role by improving intestinal microbial infections.[8–10] The surface area, apparent balance of microflora and health impact of the human gut reminds us that this complex organ must not be forgotten as one factor in long-duration spaceflight health.

Stress & Gut Microbiome
The Human Genome Project revealed that the human body is the habitat of microbial symbionts ten-times more in number than Homo sapiens cells.[4] The recognition of the complex interactional environment between the human and our symbiotic microflora led researchers to name this the 'human microbiome'.[11] In the human gut, the microbiome directly influences biochemical, physiological and immunological pathways and is the first line of resistance to various diseases.[12]

Traveling can act as an environmental stress causing changes in the microbiome composition or its gene expression.[13] This may lead to the transient (as in travelers' diarrhea) or permanent dominance of pathogenic gut bacteria. Recently, it was shown that exposure to a social stressor altered the composition of the intestinal microbiome, indicating stressor-induced immunomodulation.[14] It was demonstrated that stressor exposure changes the stability of the microflora and leads to bacterial translocation.[14] Circulating levels of IL-6 and MCP-1 increased with stressor exposure and these increases were significantly and positively correlated to changes in three bacterial genera (i.e., Coprococcus, Pseudobutyrivibrio andDorea) in the cecum.[14] This suggested that the microbiome somehow contributed to stressor-induced immunoenhancement. To test the theory, in follow-up experiments, mice were treated with an antibiotic cocktail to determine whether reducing microflora would annul this stressor-induced increase in circulating cytokines. In the antibiotic-treated mice, exposure to the same stressor failed to increase IL-6 and MCP-1 confirming that intestinal microflora were necessary for the observed increase in circulating cytokines.[14]

Microgravity Stress Alters Bacterial Virulence

Studies have shown an increase in the virulence, changes in growth modulation and alterations in response to antibiotics in certain bacteria both in space and simulated microgravity.[15–19] Significant technological and logistical hurdles have hindered thorough genotypic and phenotypic analyses of bacterial response to actual space environment. In this line, Wilson et al.cultured Salmonella enterica Typhimurium aboard space shuttle mission STS-115 with identical cultures as ground controls.[15] Global microarray and proteomic analyses were carried out and 167 differentially expressed transcripts and 73 proteins were identified among which conserved RNA-binding protein Hfq was suggested as a likely global regulator involved in the response to spaceflight. Similar results were obtained with ground-based microgravity culture model. Furthermore, spaceflight-grown S. enterica Typhimurium had enhanced virulence in murine models and exhibited extracellular matrix accumulation consistent with a biofilm.[15]

S. Typhimurium grown in spaceflight analog exhibited increased virulence, increased resistance to environmental stresses (acid, osmotic and thermal stress), increased survival in macrophages and global changes in gene expression.[20–22] Low-shear modeled microgravity rendered adherent–invasive Escherichia coli more adherent to a mammalian gastrointestinal epithelial-like cell line, Caco-2.[23] Simulated microgravity conditions markedly increased production of the heat-labile enterotoxin from enterotoxigenic E. coli.[18] Upon a 12-day exposure to low-shear modeled microgravity, Candida albicans exhibited increased filamentation, formation of biofilm communities, phenotypic switching and more resistance to the antifungal agent amphotericin B.[24]

Only one virulence gene was found among 163 differentially expressed genes in simulated microgravity grown S. Typhimurium and actually, most virulence genes were expressed at a lower level (including genes involved in lipopolysaccharide production).[22] Furthermore, sigma factor (a transcription factor responsible for a general stress response) was not thought to be a cause, since a decreased level of its gene expression was observed in simulated microgravity.[25] The mechanism of enhanced virulence of S. Typhimurium grown in actual spaceflight and rotating wall vessel culture conditions does not involve an increased expression of traditional genes that regulate the virulence of this bacterium under normal gravity conditions; however, Hfq pathway is required for full virulence in S. Typhimurium.[26]

Biofilm formation is part of the normal growth cycle of most bacteria and this film is linked to chronic diseases that are difficult to treat such as endocarditis, cystitis and bacterial otitis media.[27] Bacterial biofilm creates superior resistance to oxidative, osmolarity, pH and antibiotic stresses.[28] Theoretically, bacterial biofilm production, which enhances bacterial survival by resistance to the immune system and antimicrobial agents, may increase the risk and/or severity of infection in long-term space missions. Diminished gravity has been shown to stimulate bacterial biofilm formation both in E. coli [29] and Pseudomonas aeruginosa.[30–32] In a study by Crabbe et al. in 2008, rotating wall vessel technology was exploited to study the effect of microgravity on growth behavior of P. aeruginosa PAO1.[31] Rotating wall vessel cultivation resulted in a self-aggregating phenotype which subsequently led to formation of biofilms.[31] In a second study in 2010, the same researchers employed microarrays to investigate the response of P. aeruginosa PAO1 to low-shear modeled microgravity both in rotating wall vessel and random position machine.[32] P. aeruginosa demonstrated increased alginate production and upregulation of AlgU-controlled transcripts (including those coding for stress-related proteins) in modeled microgravity.[32] Results of the study also implicated the involvement of Hfq in response of P. aeruginosa to simulated microgravity.[32] Involvement of Hfq in response of P. aeruginosa to actual spaceflight was later confirmed in another study.[30]

In addition, there is concern that antibiotic-resistance increases during short-term spaceflight.[33] The MIC of both colistin and kanamycin increased significantly in E. coli grown aboard the flight module compared with the MIC on the ground.[34] A similar increase in the MIC of oxacillin, erythromycin and chloramphenicol was reported in Staphylococcus aureus.[34,35] This has led to concerns that the efficacy of antibiotics may be diminished during even short orbital missions.[36,37]

It has been hypothesized that reduction in the natural, terrestrial diversity of the gastrointestinal bacterial microflora in spaceflight may give rise to an increase in the presence of the drug-resistant bacteria.[38] It has also been postulated that the emergence of such resistant clones could be facilitated by the administration of antibiotics either before or during the flight.[38]Emergence of drug resistance is also facilitated by bacterial mutation which occurs more frequently in long-term spaceflights.[39] Overall, there is the possibility that drug-resistant bacteria could colonize all crew members on a mission, giving rise to a difficult-to-treat healthcare problem.

Spaceflight & the Microbiome
In an attempt to protect astronauts from exposure to novel pathogens preflight, several guidelines are carried out. Prelaunch, crew members are limited both in travel and visitors to limit pathogen exposure.[201] Therefore, crew members tend to launch with normal gut microflora and with a reduced risk of gut infection. Items flown to the International Space Station (ISS) are cleaned before loading to limit introducing bacteria to the environment. Once in orbit, all areas in the ISS have ultra-high-efficiency bacterial filters in the air supply ducts to reduce the levels of bacteria and fungi. Finally, cleaning of the surfaces of the modules is a regular 'housekeeping' chore to limit bacterial and fungal growth.[201]

Still, microorganisms exist on the ISS. No matter how much cleaning is done, microorganisms are continuously shed from skin, mucous membranes, gastrointestinal and respiratory tracts or can be released by sneezing, coughing and talking.[40] Specimens were obtained for mycological examination from the skin, throat, urine and feces of the six astronauts who conducted the Apollo 14 and Apollo 15 lunar exploration missions both before and after flight.[41] Analysis of preflight data demonstrated that the process of severely restricting opportunities for colonization for 3 weeks before flight resulted in a 50% reduction in the number of isolated species.[41] Postflight data indicated that exposure to the spaceflight environment for up to 2 weeks resulted in an even greater reduction with a relative increase in the potential pathogen C. albicans.[41,42] The compositions of intestinal,[43] oral[44,45] and nasal[44] flora have been shown to change even during short spaceflights. In one study, a reduction in the number of nonpathogenic bacteria and an increase in the number of opportunistic pathogens has been reported in the nasal flora of cosmonauts.[46] A significant reduction in the number of bacterial species of the intestine has been seen after 2 weeks of spaceflight.[47] These observations were similar to changes seen in ground volunteers who were kept in isolation, in which volunteers were fed only sterilized, dehydrated foods. A significant decrease in the number of bifidobacteria, lactobacilli and other bacteria was seen.[38] In a Russian experiment, a decrease in lactobacilli (and replacement with pathogens) were seen in mouth and throat cavities in all mission members in inflight period.[48] Spaceflights and even the preparation phase before take-off can exert dysbiosis in the human microflora which results in reduction of the defense group of microorganisms (bifidobacteria and lactobacilli) and appearance of opportunistic pathogens such as E. coli, enterobacteria and clostridia.[49] Subsequently, this procedure can lead to accumulation of the potentially pathogenic species and their long-term persistence.[49–51] Colonization resistance is one of the factors that needs to be taken into account to stabilize the microflora of the cosmonauts during space flights. Indigenous microflora are vital for preservation of microecological homeostasis.[7] It has been hypothesized that a regular intake of probiotic foods might be helpful in correcting this change.[38,52,53]

Human microflora functions as a barrier against antigens from microorganisms and food.[54] Alterations in the microbiome composition have been reported in inflammatory bowel disease, inflammatory conditions, ulcerative colitis and more.[55–57] Healthy immunophysiologic regulation in the gut has been hypothesized to depend on the establishment of indigenous microflora that create specific immune responses at the gut and system levels.[58–61] Furthermore, gut microflora has a role in induction and maintenance of oral tolerance in experimental animal models.[62] Changes in the diversity and number of gut microflora have been linked to a deficient immune system[63] as well as immunological dysregulation which is associated with many human noninfectious diseases such as autoimmunity, allergy and cancer.[63] Reinforcing this concept of health symbiosis, studies of germ-free animal showed wide-ranging defects in the development and maturation of gut-associated lymphoid tissues.[54,63–66] Another way of viewing this health interaction comes from the data that ten Salmonella bacteria have been shown to induce infection in germ-free mice, while 109 bacteria are needed to induce infection in a conventional animal possessing intact intestinal microflora.[67] To maintain astronaut health on orbit, an awareness of the importance of a balanced gut microbiome to maintaining the immune homeostasis and resistance to infections is valuable.

Previous studies have shown that important immune parameters are decreased during spaceflight.[68] Reductions in the number and proportion of lymphocytes and their cytokine production, depression of dendritic cells function and T-cell activation, and finally reduction in numbers of monocytes and precursors of macrophages, have been noted.[68] In one study, stresses associated with spaceflight were shown to alter important functions of neutrophils and monocytes.[69] In another study, the astronauts' monocyte functions showed reductions in their ability to engulf E. coli, elicit an oxidative burst and degranulation.[70] Non-MHC-restricted (CD56) killer cell cytotoxicity tends to decrease after short-term spaceflight.[71] In the latter study, the authors examined the age, gender (nine men and one woman), flight experience, mission factors and mission role (e.g., pilot, scientist or crew) of the astronauts and found no correlation between these variables and individual non-MHC killer cell function levels.[71] Therefore, other factors may contribute to the compromised immune system in space. Decreased natural killer cell cytotoxicity in cosmonauts after short- and long-term spaceflights have also been reported.[72–75] Reductions in absolute numbers of lymphocytes, eosinophils and natural killer cells,[76] reduced lymphocyte mitogenic response,[76,77] diminished delayed-type hypersensitivity,[77] changes in CD4+:CD8+ ratios and reduced production of IL-2 and IFN-? have also been reported.[78]

The immune system changes of astronauts as well as environmental stress may have been a factor in known incidents of infectious illness in crew members. During the Apollo 8 preflight period for instance, all crew members suffered viral gastroenteritis.[42] During flight, the effects of mission duration on the neuroimmune responses in astronauts were studied and changes in plasma cortisol, epinephrine, norepinephrine, total IgE levels, number of white blood cells, polymorphonuclear leukocytes and CD4+ T cells were found at different times.[79] Upper respiratory problems, influenza, viral gastroenteritis, rhinitis, pharyngitis or mild dermatologic problems were among the illnesses that astronauts faced during Apollo spaceflights.[42]Reactivation of varicellas zoster virus,[71] herpes virus[80] and shedding of Epstein–Barr virus[81] was also found in space shuttle crew members. In astronauts of the Mir station, analyses demonstrated a significant number of episodes of microbial infections, including conjunctivitis, acute respiratory events and dental infections.[82]

Future Perspective: Considering Probiotics as a Countermeasure
On Earth, probiotics have been shown to improve both innate and adaptive immune responses.[83] Oral bacteriotherapy with probiotic bacterial strains is believed to improve the intestine's immunologic barrier, particularly through intestinal IgA responses and alleviation of inflammatory reactions.[83] A gut-stabilizing effect seems to occur through a balance between proinflammatory and anti-inflammatory cytokines. Lactobacillus rhamnosus GG has been shown to inhibit TNF-?-induced IL-8 secretion of human colon adenocarcinoma (HT29) cells and to reduce elevated fecal concentration of TNF-? in patients with atopic dermatitis and cow milk allergy.[84] On the other hand, ingestion of lactobacilli in fermented milk products or as live-attenuated bacteria potentiated the IFN-? production by peripheral blood mononuclear cells.[85,86] Oral administration of lactobacilli increased the systemic and mucosal IgA response to dietary antigens.[59,60,87] Oral supplementation with Bifidobacterium bifidum and Bifidobacterium breve enhanced the antibody response to ovalbumin[88] and stimulated the IgA response to cholera toxin in mice.[89] An increase in the humoral immune response including an increase in rotavirus-specific antibody-secreting cells in the IgA class was also detected in children[60] and individuals receiving L. rhamnosus GG.[90]
Isolauri et al. reported that infants receiving a reassortant live oral rotavirus vaccine in conjunction with L. rhamnosus GG had a higher frequency of rotavirus-specific IgM class antibody-secreting cells.[91] An increased incidence of rotavirus-specific IgA antibody class seroconversion compared with placebo subjects was also seen.[91] IgA+ cells and IL-6-producing cells increased in number after 7 days of Lactobacillus casei administration.[92] In another study, administration of lactic acid bacteria stimulated the gut immune cells to release inflammatory cytokines such as TNF-?, IFN-? and IL-12, and regulatory cytokines like IL-4 and IL- 10 in a dose- and strain-dependent manner.[93] Several lactobacilli strains have been shown to promote the immunopotentiator capacity of cells of the innate immune system, including macrophages.[94] Examples of probiotics that can modulate the gut immune system are abundant and have been reviewed extensively.[95–98]

Buckley et al. have suggested that consumption of soy-based fermented products (containing lactic acid bacteria) can prevent the health problems of astronauts associated with long-term space travel.[99] Assessment of soy-based fermented products by in vitro challenge system (using TNF-?) with human intestinal epithelial and macrophage cell lines has demonstrated the ability of the intervention to downregulate production of the proinflammatory cytokine IL-8.[99]

Considering the importance of the human gut in healthy digestion, nutrient absorption and exposure to pathogens across its large surface area, a healthy digestive tract is important to a healthy human. Diet, lifestyle, antibiotic therapy, different kinds of stressful conditions and so on, can exert alterations in an astronaut's gut microbiome in space (Figure 1). Considering potential immune system alterations from gut microflora changes, antibiotic use in orbit and changes of increased virulence and antibiotic resistance of bacteria in space, physicians who care for astronauts must remember the importance of the intestinal microbiome to their health status. From this perspective, an impaired digestive system might endanger the mission as well as the health of the astronaut. One countermeasure to be considered would be replenishing the astronaut's intestinal microflora by introducing immune-enhancing probiotic bacteria periodically during the mission.

Although single probiotics have sometimes been shown to promote health, the human microbiome is composed of more than 400 microbial species, most of which remain uncultured and have as yet unknown functions.[100] The Human Microbiome Project will certainly pave the way for us to increase our understanding of these microbial entities.[4] Thus, providing only a single probiotic might not be the answer. Contrary to numerous previous investigations and clinical trials in which only effects of single or a couple of probiotics have been studied, we think multiprobiotic therapy and/or designing individualized probiotic kits seems a more reasonable option. A series of experiments need to be launched to confirm the efficacy and safety of using probiotics in space. Safety studies are of equal importance as efficacy studies, since astronauts are immunocompromised (although as discussed above, much of this may return to washing out of microflora in space). These studies can be carried out initially in ground-based space analogs and further followed in actual space (first on animal models and then on humans). The lifestyle of astronauts can be simulated in these studies and after interventions, the composition of microbiota (including opportunistic pathogens) along with immunological markers should be determined. Both short- and long-term confinement and actual spaceflight studies can be designed. The administration and/or consumption of probiotics is supposed to have immune-enhancing effects, hinder alterations in the human microbiome to a large extent and prevent colonization of potential pathogens. Upon observation of possible benefits, probiotics can be incorporated into astronauts' food or supplied periodically as a probiotic kit. This line of research can be followed by NASA scientists and other space agencies to enhance the quality of life of astronauts and to contribute to human presence in space.

Surprisingly, this may bring a future where astronauts utilize probiotic bacteria to counteract the potential effect of pathogenic bacteria during spaceflight.

Sidebar
Executive Summary
Establishment of Efficient Life Support Systems in Space
• Designing an efficient life support system is needed to maintain the minimum life requirements for humans in space.
• Although the health status of astronauts has been extensively investigated, less attention has been paid to the intestinal microbiome and its significant role in the astronaut's health.
The Human Intestine & the Microbiome
• At the end of the Human Genome Project, the aggregation of flora genes within the human genome was named the 'human metagenome'.
• A healthy gut seems to require a natural combination of healthy and pathogenic microflora, such that the certain resident microflora strains are now being characterized as a microbiome: cells essential in the maintenance of human health.
• The human gut microbiome is implicated in human health and disease.
• The microbiome plays key roles in maintenance of a healthy immune system.
Stress & Gut Microbiome
• Spaceflight has several important disrupting events that could lead to astronaut intestinal changes: the sterility of space food, the changes in lifestyle, the possible use of antibiotics preflight and inflight, and changes in astronaut immune function.
Microgravity Stress Alters Bacterial Virulence
• Microgravity seems to alter the availability and virulence of some pathogens.
• A number of pathogens exhibit enhanced antibiotic resistance in microgravity.
• It has been hypothesized that reduction in the natural, terrestrial diversity of the gastrointestinal microflora in spaceflight may give rise to an increase in the presence of the drug-resistant bacteria.
• It has been postulated that the emergence of resistant clones could be facilitated by the administration of antibiotics, either before or during the flight.
• Emergence of drug resistance is also facilitated by bacterial mutations which occur more frequently in space.
Spaceflight & the Microbiome
• A reduction in the number and/or diversity of beneficial gut microbiota can lead to an increase in the relative number of potential pathogenic bacteria in space.
• The composition of intestinal, nasal and oral flora has been shown to change even during short spaceflights.
• Changes in the diversity and number of gut microflora have been linked to a deficient immune system as well as immunological dysregulation.
• To maintain astronaut health in orbit, an awareness of the importance of a balanced gut microbiome to maintaining immune homeostasis and resistance to infections is valuable.
• Studies have shown that important immune parameters are decreased during spaceflight.
• Reductions in the number and proportion of lymphocytes and their cytokine production, depression of dendritic cells function and T-cell activation, and finally reduction in numbers of monocytes and precursors of macrophages have been noted.
• Upper respiratory problems, influenza, viral gastroenteritis, rhinitis, pharyngitis and mild dermatologic problems are among the common illnesses observed in astronauts.
Future Perspective: Considering Probiotics as a Countermeasure
• On Earth, probiotics have been shown to improve both innate and adaptive immune responses.
• An impaired digestive system might endanger the mission as well as the health of the astronaut.
• One countermeasure to be considered would be replenishing the astronaut's intestinal microflora by introducing immune-enhancing probiotic bacteria periodically during the mission.
• A series of experiments need to be launched to confirm the efficacy and safety of using probiotics in space.
• There may be a future where astronauts utilize probiotics to counteract the potential effect of pathogenic bacteria during spaceflight.
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Website

201. Flight crew health stabilization program. http://lsda.jsc.nasa.gov/books/apollo/s2ch6.htm

Papers of special note have been highlighted as:

• of interest

•• of considerable interest

Acknowledgement

The authors are sincerely grateful to S Saei, who contributed in editing the manuscript.
Future Microbiol. 2012;7(9):1037-1046. © 2012 Future Medicine Ltd.

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