Composition and Interactions of the Oral–Gastrointestinal Microbiome Populations During Health, Disease, and Long-Duration Space Missions: A Narrative Review

Abstract

All forms of life on Earth are dependent on microbes. In vertebrates, the oral cavity and the gastrointestinal tract are colonized by large numbers of microorganisms, which includes species from many life forms: bacteria, fungi, archaea, and protozoa; this collection of microorganisms are commonly referred to as the microbiome. This article reviews the literature, providing a summary of oral and gastrointestinal microbial composition in health and during various disease states. Interactions are explored between microbes in the oral cavity and gastrointestinal tract. This study explores the influence of changed diet, lifestyle, and living conditions in order to examine the link between the oral and gastrointestinal microbiome and changes in their composition, and how this may affect human health. This study also investigates potential microbiome dysbiosis and disease causation in the space environment. The role of prebiotics, probiotics and postbiotics in oral health is discussed, with extension into the unexplored territory of probable oral and gastrointestinal bacterial population changes during long-duration (exportation class) space missions (ECSM).

1. Introduction

The human body houses roughly the same quantity of microbial cells as it does human cells. However, the microbiome complement contributes an estimated 150 times more genetic information than that of the entire human genome [1,2]. The term microbiome refers to the collection of microorganisms with their genetic complement. These microorganisms reside in two main habitat zones on our bodies: skin and hair, and the oral–gastrointestinal tract. It should be noted that both of these habitat zones are technically outside the human body [3]. In 1988, Whipps et al. [4] described the term “microbiome” as a combination of microbe and biome, the microbial ecosystem, the collection of microbes and their activities within a given environment. They state: “A convenient ecological framework in which to examine bio-control systems is that of the microbiome. This may be defined as a characteristic microbial community occupying a reasonably well-defined habitat which has distinct physio-chemical properties. This term thus not only refers to the microorganisms involved but also encompasses their theatre of activity [4].” This concept has been revisited and updated by Berg et al., in 2020. Moreover, Joshua Lederberg, 2001, described the microbiota “the assortment of commensal, symbiotic, and pathogenic microorganisms residing in our bodies that play a significant role in our health and diseases” [1,5,6].

The human microbiome is integrated into the physiological functioning of the body. For certain physiological processes, the body depends on the microbiome to provide specific enzymes required for chemical reactions, including the breakdown of nutrients prior to absorption—indicating a long-standing biological association between the human body and its resident microbiome [7]. It is notable that up to one-third of the metabolites found in human fluids, including blood, encompass various molecules and originate from the human resident microorganisms [8].

The gastrointestinal tract and oral cavity have the most extensive range of microorganisms, and these microbial communities are essential for regulating blood pressure, extracting energy from indigestible food substances, synthesizing vitamins, regulating the immune system via direct or indirect pathways, and defending against harmful pathogens [3,7]. The evolution of the human—microorganism symbiosis has taken place over a large period of time [9]. Further classification into the functional categories includes the core and variable microbiome.

The core microbiome is shared amongst various human populations, reflective of their diet, culture, and location (i.e., urban vs. rural), whilst the variable microbiome is a dynamic microbe complement, reflecting changes in living conditions, diet, nutritional value of food, and urban vs. industrialized environments [2,10]. Recent research has highlighted the poorly understood but crucial influence that the interactive and collaborative contribution of these microorganism communities makes to the overall homeostasis and health of the human body [11,12].

The aim of the current review was to summarize and present the current knowledge on the composition and functional interactions of oral and gastrointestinal (GI) microbiome populations across states of health, disease, and long-duration space missions, as well as to assess the bidirectional interactions between the oral and GI microbiomes and their role in maintaining systemic health or contributing to disease progression. This will help in identifying the current knowledge gaps and future research needs in understanding the oral–GI microbiome axis, particularly in environments like space.

The above-mentioned aims were achieved through describing the baseline composition of oral and gastrointestinal microbiota in healthy individuals, highlighting common microbial taxa and their functions, reviewing evidence of dysbiosis (microbial imbalance) in the oral–GI microbiome across common diseases, reviewing the current research findings on the influence of microgravity, altered diet, stress, and radiation on microbiome changes during space missions, evaluating countermeasures and interventions (e.g., probiotics, prebiotics, dietary strategies) proposed to maintain or restore microbiome balance during spaceflights and proposing a conceptual framework for future research into oral–GI microbiome interactions in both terrestrial and extraterrestrial environments.

2. Methodology

A narrative approach was selected to allow for a broad, integrative exploration of the topic, encompassing diverse study designs and thematic domains, including microbiology, immunology, human physiology, and space medicine. The relevant literature was identified through searches in PubMed, Scopus, and Web of Science, supplemented by targeted searches in Google Scholar for gray literature and recent reviews. The search included a combination of keywords and Boolean operators such as

• “oral microbiome” OR “gut microbiome” OR “gastrointestinal microbiota”;
• AND “health” OR “homeostasis”;
• AND “disease” OR “dysbiosis”;
• AND “prebiotics” OR “probiotics” OR “postbiotics”;
• AND “spaceflight” OR “microgravity” OR “long-duration space missions”.

The literature search was limited to articles published in English between 2000 and 2025 to reflect the most current evidence. Seminal older studies were included when highly relevant to foundational microbiome mechanisms or early space microbiology research. Studies were included if they examined the oral and/or GI microbiome composition or function in humans or relevant animal models, explored host-microbe or microbe-microbe interactions in health, disease, or spaceflight environments, or addressed space-related microbiome alterations, especially under microgravity or isolation conditions. Furthermore, studies were excluded if they were unrelated to microbiome research, for example, general gastrointestinal physiology without microbial focus, or lacking peer review, such as commentaries or opinion papers, except for key technical reports from NASA or other space agencies.

Titles and abstracts were screened for relevance by the first two authors. Full texts of selected articles were then further reviewed by two other authors to assess their suitability based on the inclusion criteria. Studies were chosen to represent a range of perspectives, including observational studies, experimental research, reviews, and insights from both terrestrial and spaceflight contexts. Key data were manually extracted and organized according to themes relevant to the review’s aims, which allowed integrating multidisciplinary perspectives to highlight gaps, patterns, and emerging hypotheses. This approach allows for a narrative-driven discussion of the interplay between microbiome systems and host physiology. The themes identified and discussed included microbial diversity and composition in the oral and GI tract during health, disease, inter-compartmental interactions between oral and gut microbiomes, environmental and physiological factors influencing microbiome dynamics, and microbiome-mediated impacts on immune function and systemic health in earth-bound and space-based conditions. Figure 1 summarizes the methodology and the decision-making process involved in the selection of articles in the review.

3. Oral and Gastrointestinal Microbiome

3.1. Oral Microbiome Composition

Antonie van Leeuwenhoek, using his self-made microscope in 1670, was the first to describe human oral bacteria [13]. This was a significant turning point in understanding the oral microbiota. van Leeuwenhoek visually observed and recorded the different shapes of microorganisms in his notes and intuited the complex nature of the oral microbial community. Contemporary examination of the human oral microbiome has begun to define its crucial role in human health and wellness, while highlighting that oral microbiome imbalance often leads to the development of oral disease and contributes to physiological dysregulation and systemic diseases [14,15].

The acquisition of the oral microbiome follows a structured pattern, in the first instance, maternal transmission (with impact on brain development and immunity) and environmental factors (diet, living conditions, and location) [16,17,18]. A C-sections fetus is first exposed to maternal skin commensals, such as Staphylococcus species, Propionibacterium species, and Corynebacterium species, and the components of breast milk [19]. Babies born vaginally are seeded with commensals of the maternal vagina, such as Lactobacillus, Prevotella, and Sneathia [20,21].

Within a few hours after birth, the sterile oral cavity becomes exposed to environmental microorganisms through breathing, breastfeeding, and environmental contact. Within 24 h, pioneer colonizers, mainly Streptococcus and Staphylococcus bacteria, are established in the baby’s oral cavity, anchored to the epithelial cells in preparation for the eruption of teeth. These bacteria use sucrose to create extracellular polymers (biofilm) that other bacteria cling to, such as Actinomycetota spp. [22]. After the gastrointestinal tract, the oral cavity is the second most significant microbial habitat, providing a unique environmental niche for certain adapted microorganisms. The oral cavity consists of the gingiva, oral mucous membrane, unerupted teeth surfaces, the tongue, and palate, and the emergence of teeth in human infants introduces a new habitat, leading to increased microbial diversity [20]. It hosts a wide range of species and exhibits the highest alpha diversity, characterized by both species’ richness and evenness [22]. When microbiota is sampled from the same locations in the oral cavity and compared between individuals, the oral bacterial communities share more similarities than bacterial communities from other body sites, which is referred to as beta diversity, which is the variation in species composition among different communities or ecosystems [22].

The oral microbiome is dynamic and evolves as the baby grows and interacts with the environment. Anaerobic bacteria begin to appear around five months of age, and the oral cavity normally contains six phyla: Bacillota, Actinomycetota, Pseudomonadota, Bacteroidota, Fusobacteriota, and Spirochaetota, with the most common genera being Streptococcus, Haemophilus, Veillonella, and Neisseria [23]. Studies have shown that Streptoccoccus mutants (S. mutans), which are known for their cariogenic potential, can be present in the mouth of some children even before tooth eruption [23,24]. The oral mucosa can harbor oral pathogenic germs; Caufield et al. (1993) described this stage as “The window of infectivity” [24].

The oral cavity develops a complex anatomical structure that facilitates microbial colonization, creates diverse microhabitats, and serves as a gateway to the gastrointestinal tract. The oral cavity is in constant interaction with the external environment and is far from static—emerging research suggests that its diverse microbiome may contribute to modulating the immune system and enhancing immune responses [25]. The microbiome communities in the mouth continue to be influenced by various factors throughout a person’s life, including cigarette smoking, oral hygiene, dietary habits, stress, medications, and genetics [26,27,28]. The human mouth is home to more than 700 species of unicellular microorganisms, grouped into 185 genera and 12 major bacterial phyla. Of this microbial population, about 54% have been fully described, 14% have been cultivated but not yet officially named, and 32% exist only as DNA-based “phylotypes” that have not yet been grown in the lab or fully understood [29]. The major bacterial phyla in the human oral cavity are listed in

Table 1. The table below summarizes the 12 major bacterial phyla identified in the human oral cavity, highlighting their characteristics and relevance to oral or systemic health [29].

Phylum	Main Characteristics
Bacillota	Common in the mouth and include many Gram-positive bacteria
Fusobacteriota	Linked to periodontal disease
Pseudomonadota	Diverse group; some species associated with inflammation
Actinomycetota	Include beneficial and pathogenic species
Bacteroidota	Abundant in the gut and oral microbiome
Chlamydiota	Less common; intracellular pathogens
Chloroflexota	Rare in the oral cavity
Spirochaetota	Includes some pathogens like Treponema species
Synergistota	Anaerobic bacteria; some linked to periodontitis
Saccharibacteria	Part of the TM7 group; difficult to culture
Gracilibacteria	Uncultivated; found in various environments
Candidate division SR1	Uncultivated; detected via sequencing in oral and marine settings

.

Understanding the diversity and classification of these bacteria is important because different groups may play distinct roles in maintaining oral health or contributing to disease. Some belong to well-known groups like Bacillota and Pseudomonadota, while others—such as Gracilibacteria and candidate division SR1—remain uncultivated and poorly understood yet are consistently found in the oral cavity and other environments, including oceans and animal intestines [8,30,31].

3.2. Survival of Microorganisms in the Oral Cavity

Microorganisms are able to use their adhesins to bind to complementary receptors on the oral mucosa or teeth, creating preferential surfaces for colonization within the oral cavity [28,32]. Our understanding of geographical variation in the human oral microbiome remains limited. Some studies suggest that people from different parts of the world have distinct oral microbiomes, while others report that microbial communities are remarkably similar across populations. In contrast, within the mouth itself, microbial species tend to show strong site specificity—meaning the same types of bacteria consistently colonize the same oral regions, such as the tongue, cheeks, or teeth, regardless of a person’s geographical location in the world [20]. Arweiler & Netuschil in 2016 have used this data to categorize the oral microbiome into three groups, based on their environmental preference in the oral cavity [17]. Salivary bacteria thrive in the fluid environment of saliva, which promotes the growth of mostly aerobic species. Saliva maintains a stable pH of 6.5–7.0, maintains moistness, and has an average temperature of 37 °C—conditions that are favorable for microbial growth [33]. Bacteria that thrive in the mucosal zone are also aerobes, excepting the stable communities of the tongue, which are predominantly anaerobes. The non-mucosal bacteria are those bacteria that reside on the teeth or artificial hard services (tooth fillings, implants, orthodontic appliances, etc.), usually a population of aerobes or facultative anaerobes [17].

3.3. Healthy Oral Microbiota

A healthy oral cavity harbors a diverse microbiota, comprising both Gram-positive and Gram-negative bacteria. Gram-positive genera include Streptococcus, Actinomycetota, and Lactobacillus, while Gram-negative groups include Neisseria, Fusobacteriota, and Prevotella [6]. In addition to bacteria, the oral microbiota contains non-bacterial members such as protozoa (Entamoeba gingivalis, Trichomonas tenax), fungi, and viruses. Culture-independent studies have identified over 85 fungal genera, with Candida spp. being the most prevalent [34,35].

3.4. Oral Viral Microbiota

Oral viruses are typically bacteriophages, as they parasitize a bacterium by infecting it and reproducing inside it. They display genetic and behavioral deviations when compared to viromes observed in other body regions. Most viruses in the oral virome included herpes viruses 74%, and mostly primarily human herpes virus 66%, followed by retroviruses 24%, then papillomaviruses 1.2%, with the occasional presence of pox viruses and other viruses <1% [36].

Saliva is a potential reservoir for coronaviruses, including the new coronavirus (SARS-CoV-2) first detected in 2019 (COVID-19) [12,37]. The SARS-CoV-2 global pandemic saw the development of culture-independent methods such as gel-based techniques, DNA microarrays, and refinement of polymerase chain reaction (PCR) with next-generation sequencing (NGS) [38]. These newer techniques allow for the identification and quantification of microbial communities without the need for culturing them in a laboratory, revolutionizing microbe identification [39,40]. In some countries, utilizing saliva as a diagnostic tool provides a convenient and easily accessible point-of-care platform for early COVID-19 diagnosis (as an alternative to traditional swab methods from the nose and pharynx) for detecting SARS-CoV-2 [12,41,42].

3.5. Oral and Other Microbiomes in the Human Body

Many internal and external factors influence the composition of the oral microbiota, including diet, lifestyle, socio-economic status, antibiotic use, pregnancy, smoking, immune responses, saliva production and the overall condition of the oral tissues [43]. Recent research trends have shifted towards exploring the role of host factors and their combined impact on the host-oral microbiome, not only in developing a healthy, balanced oral ecosystem, but also in understanding systemic and oral diseases [44].

The oral cavity is an ideal model for studying the relationship between the host and microorganisms as it is easily accessible, and the oral microbial community is relatively consistent over time. Microorganisms coexist in our bodies through symbiosis (mutually advantageous relationship), dysbiosis (loss of balance within bacterial communities and over-growth of harmful bacteria), and pathological interactions; the human host offers an environment conducive to the growth of these microorganisms [45]. The consistent stability state of symbiosis is referred to as “resilience,” including two important aspects: resistance, which is the ability to withstand stress factors, and recovery from disturbances. When the delicate balance between the host and their oral microbiota is upset, the symbiotic relationship can become a pathogenic dysbiotic one. Local environmental disturbances can disrupt the relationship between various microbiomes, which can upset the balance between the host and the microbes and increase the likelihood of developing disease [46].

Alterations in the oral microbiome, specifically the shift from a healthy (normal) to an imbalanced (dysbiotic) microbial community, have been proposed as potential biomarkers for the early detection of pre-cancerous and cancerous lesions [47]. In pre-cancerous oral lesions, Actinomycetota, Clostridium, Enterobacteriacea, Fusobacteriota, Hemophilus, Porphyromonus, Prevotella, Streptococcus, and Veilonella have been detected. Moreover, P. gingivalis and F. nucleatum were discovered to be 600 times more abundant in cancerous areas than in pre-cancerous and normal tissues [48,49].

3.6. Impacts on Oral Microbiota

Dietary intake plays a crucial role in influencing the oral microbiome. Bacteria convert dietary carbohydrates into acids through fermentation. Acid production in the mouth can dissolve tooth tissues, leading to tooth decay. This shift in pH also alters the oral environment, favoring the growth of specific bacterial populations. For instance, although P. gingivalis thrives best at a slightly alkaline pH of around 7.5, changes in the subgingival environment—such as reduced oxygen levels and inflammation—can create conditions that support its growth. These shifts do not cause direct genetic mutations in bacteria but rather promote ecological changes that favor certain species.

Nutrition plays a major role in the development of periodontitis, a serious inflammatory disease that affects the gums and supporting structures of the teeth, potentially leading to tooth loss. Since diet is a modifiable factor, improving nutritional habits can significantly reduce the risk or severity of periodontitis. Moreover, there is an association between periodontitis and dental caries (tooth decay) with low socio-economic status. It has been noted in the literature that alcohol consumption and socio-economic status can impact the composition of the oral microbiome. Furthermore, changes or impairments in the host’s immune system—such as inflammation, immune suppression, or chronic disease—can reduce the body’s ability to control harmful bacteria. This weakened immune surveillance allows certain bacteria to increase the expression of virulence factors (e.g., toxins, enzymes, or adhesion molecules), helping them evade immune responses and out-compete beneficial microbes. As a result, the balance of the oral microbiome shifts, favoring the overgrowth of pathogenic species and contributing to disease progression [50].

Antibiotics have been proposed as a significant factor in changing the composition of the oral microbiome. It was reported by Almeida et al. in 2020, that the composition of salivary microbiota did not fully recover after antibiotic treatment, specifically the abundance of Actinomycetota was significantly reduced by amoxicillin during the 10-day treatment period but recovered to pre-treatment levels three weeks post-treatment. On the other hand, the prevalence of Pseudomonadota in saliva exhibited a notable rise around three weeks following the administration of amoxicillin, in comparison to its levels prior to therapy [51].

Pregnancy and the hormonal fluctuations of pregnancy impact on the composition of the oral microbiome, with increased risk of periodontal disease development. Premature labor has been linked to microbial invasion of the amniotic cavity, which can occur when P. gingivalis is present in periodontal pockets, which are the abnormal spaces or gaps that form between the teeth and gums, indicating gum disease. Specifically, bacteria such as Neisseria, Porphyromonas, and Treponema become common during pregnancy, while Streptococcus and Veillonella are less prevalent [52,53].

Smoking notably impacts the composition of the oral microbiota and the patho-physiology of oral and dental conditions. Harmful substances found in cigarettes can lead to the depletion of beneficial oral bacteria and colonization by harmful pathogens. Smokers often harbor diminished levels of beneficial bacteria. For instance, S. parasanguinis and Streptococcus sanguinis are affected, and an increased abundance of anaerobic microbes like Fusobacteriota nucleatum and F. naviforme can be found. Research has shown variations in the formation of marginal and sub-gingival biofilms, smokers’ biofilms showed a higher level of taxonomic diversity associated with oral disease, even in individuals who appear clinically healthy [54]. In smokers, the initial stages of dental plaque formation—known as early biofilm development—are rapidly colonized by periodontal pathogens such as Fusobacteriota, Synergistota, Cardiobacterium, and Selenomonas, as well as respiratory pathogens like Haemophilus and Pseudomonadota. This altered microbial composition is thought to be influenced by the smoking-induced changes in the oral environment, such as reduced oxygen levels, impaired immune responses, and altered saliva composition [26].

Gingivitis and periodontitis are conditions marked by inflammation spreading to the tissues supporting the teeth, leading to bone loss and attachment loss, and are significantly influenced by the presence of certain bacteria. Disease progression can result from various factors, including local, systemic, or environmental factors, and can result in inflammatory immune responses that are either hypo- or hyper-responsive [55].

Recent advancements in molecular technologies have provided a deeper comprehension of the varied microbial population present in the mouth. These methods have allowed for estimating about 500 species in the sub-gingival plaque. In a healthy microbiome below the gum level (sub-gingival), dominant Gram-positive cocci and rods, including Actinomycetota and Streptococcus spp., act as early colonizers by attaching to their binding sites on the tooth surface’s protective salivary layer known as the acquired enamel pellicle [56]. The second most common species in dental plaque is Fusobacteriota nucleatum [57,58]. Socransky et al. were the first to propose the idea of the red complex, a group of three Gram-negative anaerobic species (P. gingivalis, Treponema denticola, and Tannerella forsythia) that work together to cause periodontal disease [59]. Other types of Gram-negative bacteria, such as Veillonella spp. and Capnocytophaga spp., are also essential components of dental biofilms. As gingivitis develops and the oxygen levels in the biofilm decrease, the balance of bacteria in the sub-gingival microbiome shifts to include more Gram-negative bacteria that thrive in anaerobic conditions, leading to increased gingival inflammation and higher levels of inflammatory cytokines in the gingival crevicular fluid (GCF), which is an inflammatory exudate that seeps into the space between the gums and the teeth.

Dental caries occurs when the dental hard tissues are demineralized by acidic by-products of bacterial carbohydrate metabolism. The plaque on healthy tooth surfaces usually contains around 500–600 species, while dentine (the tissue forming the bulk of a tooth, beneath the external enamel layer) caries has fewer species, at around 200. Streptococcus mutans, the initial colonizers of the supra-gingival (above the gum level) biofilm, make up less than 1% of the total bacterial count, and are recognized as pathogenic bacteria owing to their significant acidogenic (acid-producing) and aciduric (acid-tolerant) properties [60]. Dental caries develops when an imbalance (dysbiosis) occurs in the oral microbial community. As the biofilm matures, acid-producing bacteria become dominant, and the oral microbiota adapts to the increasingly acidic environment. Over time, cavities form and act as advanced ecological niches that further support the growth of acid-tolerant and pathogenic species [61,62]. The presence of Lactobacillus and Scardovia wiggsiae is strongly linked to dental caries. A complex community associated with caries encompasses other prominent species, such as non-mutans streptococci, Atopobium, Corynebacterium, Veillonella, Prevotella, and Capnocytophaga [63]. These species ferment dietary sugars, producing mild organic acids. These acids lower the pH of the local environment, which causes the demineralization of tooth tissues [64]. Differences in how quickly saliva flows and clears from various areas of the mouth can affect which bacteria are able to grow on specific tooth surfaces. These variations create distinct microenvironments, influencing the distribution (biogeography) of the oral microbiome. In areas where saliva clearance is slower, acidic conditions may persist longer, making those regions more susceptible to bacterial colonization and tooth demineralization, which includes the loss of calcium and phosphorus from dental hard tissues [61,65].

Lichen planus is a chronic inflammatory condition primarily affecting the oral mucosa; various factors, including auto-immune diseases, allergic reactions to dental restorative materials, viral and bacterial infections, vaccinations, and certain medications, can trigger it. Oral lichen planus (OLP) is associated with higher levels of certain bacteria, like Aggregatibacter actinomycetemcomitans (Aa), P. gingivalis, P. intermedia, T. forsythia, and T. denticola, with a reduction in Streptococcus bacteria [57,66,67].

Pre-malignancy and oral cancers refer to cancer affecting the mouth, lips, or oropharynx, and it is proposed that chronic inflammatory mediators released during bacterial infections promote cell proliferation, mutagenesis, and may contribute to the development and/or the progression of oral cancer [43,68]. Anaerobic oral bacteria cause chronic inflammation in the periodontal (tooth-supporting) tissue, primarily through increasing levels of interleukin-1, a pro-inflammatory cytokine, which is a signaling protein produced by certain cells of the immune system to regulate immune and inflammatory responses. Additional research is needed to fully understand the link between oral cancer and the oral microbiota. However, evidence suggests a connection, as areas affected by oral cancer have noticeably more aerobic and anaerobic bacteria than healthy mucosal surfaces [69].

Diabetes mellitus patients notably exhibit dry mouth (xerostomia) and higher glucose levels in their blood, tissues, and gingival crevicular fluid, and a correspondingly higher prevalence of saccharolytic bacteria that break down sugars, including Streptococci and Lactobacilli. Both type I and type II diabetes contribute to systemic inflammation, with the accumulation of advanced glycation end products, which are a group of compounds formed when sugars react non-enzymatically with proteins, lipids, or nucleic acids, triggering intracellular signaling pathways, and resulting in the production of cytokines that promote systemic inflammation. This, in turn, exacerbates an inappropriate host response to periodontal bacteria. Reflecting the intimate connection between the oral care of diabetic patients and systemic health, proper plaque control and periodontal treatment lead to better control of the diabetic condition [70,71].

3.7. The Gastrointestinal Microbiome Composition

The gastrointestinal (GI) microbiome, often referred to as the gut microbiota or gut flora, consists of a diverse and dynamic community of microorganisms that inhabit the human digestive tract. These microorganisms play an essential role in human health, contributing to digestion, immune regulation, metabolism, and even neurobehavioral processes. Disruptions in the microbiome can lead to or exacerbate various diseases, both within and beyond the GI system [47]. The gut microbiome is home to trillions of microorganisms, with bacteria making up the vast majority. Other residents include archaea, viruses (including bacteriophages), fungi, and protozoa. This ecosystem begins forming at birth and evolves throughout life in response to factors such as diet, environment, genetics, medications, and health status [72].

Each individual’s microbiome is unique, resembling a microbial fingerprint, yet certain “core” microbiota are commonly shared among healthy individuals [73]. The predominant bacterial phyla in the adult gut microbiome include Bacillota with genera such as Clostridium, Lactobacillus, and Faecalibacterium for fermentation of dietary fibers, Bacteroidota for degradation of complex polysaccharides, Actinomycetota such as Bifidobacterium, which are important in early infancy and for maintaining gut barrier function, Pseudomonadota including some opportunistic pathogens such as Escherichia coli, Verrucomicrobiota especially Akkermansia muciniphila, which plays a role in mucin degradation and has been linked to metabolic health [73,74].

3.8. The Gastrointestinal Microbiome in Health and Disease

The gastrointestinal (GI) microbiome plays a fundamental role in maintaining host health through a range of metabolic, immunological, and protective functions [72]. Metabolically, gut microbes break down otherwise indigestible dietary fibers into short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, which provide energy to colonocytes and regulate systemic metabolism. The microbiome also contributes to the synthesis of essential vitamins (e.g., vitamin K and B-group vitamins) and modulates bile acid metabolism [75]. Microbial signals help maintain the integrity of the intestinal epithelial barrier and stimulate the production of mucus and antimicrobial peptides [76]. Immunologically, the microbiome educates and regulates the host’s immune system by promoting immune tolerance, stimulating the development of gut-associated lymphoid tissue, and producing microbial metabolites that dampen inflammation [77]. Ecologically, it protects against pathogens by occupying ecological niches, competing for nutrients, and producing antimicrobial compounds, thereby conferring colonization resistance [78]. Additionally, the microbiome interacts with the gut–brain axis, influencing neural signaling, stress responses, and behavior [79]. Collectively, these functions highlight the microbiome as a key determinant of health, maintaining homeostasis and resilience against disease.

When the balance of microbial communities is disrupted, the protective functions of the microbiome may be compromised, and disease processes can be initiated or exacerbated. This includes gastrointestinal diseases such as inflammatory bowel disease (IBD) with the variants of Crohn’s disease and ulcerative colitis. Dysbiosis in IBD is characterized by reduced diversity, loss of beneficial microbes like Faecalibacterium prausnitzii, and enrichment of pro-inflammatory species such as Enterobacteriaceae [80]. Other forms of GI microbiome dysbiosis are irritable bowel syndrome (IBS) that contribute to symptoms such as bloating and abdominal pain, and Clostridioides difficile infection (CDI). This often occurs after antibiotic use disrupts normal flora, allowing C. difficile to proliferate and produce toxins, leading to severe diarrhea and colitis [81].

Furthermore, dysbiosis in the GI microbiome can contribute to metabolic and systemic diseases such as obesity and type 2 diabetes through alterations in the Bacillota/Bacteroidota ratio, and low microbial diversity are associated with metabolic dysfunction [82,83]. Also, certain gut bacteria metabolize dietary choline and carnitine into trimethylamine (TMA), which is converted in the liver to TMAO, a compound linked to atherosclerosis and cardiovascular disease [84]. In addition to the above, GI microbiome dysbiosis contributes to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) via gut–liver axis mechanisms involving increased intestinal permeability and endotoxin translocation [85]. Finally, emerging research suggests gut microbiota communicates with the central nervous system via neural, endocrine, and immune pathways. Dysbiosis has been implicated in depression, anxiety, autism spectrum disorders, and Parkinson’s disease [86,87].

The gastrointestinal microbiome is a cornerstone of human health. Its diverse microbial communities perform essential functions that go far beyond digestion, influencing immunity, metabolism, and neurological function. As research advances, microbiomes hold promise not only for understanding disease mechanisms but also for revolutionizing how we approach health and medicine.

4. Interactions Between Oral and Gastrointestinal Microbiomes

Evidence has been found that the similarities between the bacterial communities in the oral cavity and gut result from oral microbiome bacteria being passively transferred to the gut through saliva, allowing for downstream manipulation of the gastrointestinal microbiome [88]. Studies have indicated that bacteria derived from the oral cavity can colonize and persist in the intestines, leading to the activation of the intestinal immune system and contributing to chronic inflammation [89].

In order to answer the question of how oral microbiota reaches the organs of the digestive system, we need to explore three possible pathways/mechanisms. The oral microbiota can directly invade the intestinal tract via the esophagus, disturbing the balance of microorganisms in the intestines and affecting the digestive system [88,90]. Pathogenic bacteria linked to periodontitis, found in the oral cavity, can also enter the systemic circulation via the blood vessels of the tissues supporting the teeth, which are known as the periodontium, thus impacting the entire body [91]. Fusobacteriota nucleatum, commonly found in dental plaque, has been associated with colorectal cancer. Research suggests that it may reach and colonize the colorectal tract by entering the bloodstream, especially during episodes of gum inflammation or periodontal disease, and then localize in tumor tissues, where it may promote cancer progression through inflammatory and immune-modulating mechanisms [92]. The oral microbiota produces metabolites that enter the bloodstream and cause a state of low-grade inflammation. This inflammation contributes to the development of chronic digestive diseases [93]. Prebiotics, probiotics, and postbiotics have been suggested to boost the positive effects of the body’s microflora [94,95].

Table 2. Possible interactions between oral and gastrointestinal bacteria.

Type of Interaction	Oral Bacteria	Gut Bacteria	Description
Mutualism	Lactobacillus spp.	Bifidobacterium spp.	Symbiosis in which both bacteria are beneficial to each other.
Antagonism	Streptococcus mutans	Lactobacillus rhamnosus	Beneficial gut bacteria can be hostile to oral bacteria.
Immune Modulation	Veillonella	Bacteroidota fragilis	Oral and gut bacteria can change immune responses in the body.
Dysbiosis	Treponema denticola	Clostridium difficile	Bacteria are out of balance.
Translocation	Enterococcus faecalis	E. coli	Oral bacteria can change the location to the gut and vice versa, affecting gut flora.
Metabolite Exchange	Actinomycetota spp.	Bifidobacterium longum	Exchange of molecular factors produced by gut bacteria can influence oral bacteria and vice versa.
Competition for Nutrients	Porphyromonas gingivalis	Faecalibacterium prausnitzii	Both compete for nutrient supplies, thus can affect overall health.

provides a summary of the possible interactions between the oral and gastrointestinal bacteria.

5. Effect of Systemic Diseases on the Oral Microbiome

The oral microbiome and inflammatory particles enter other body organs via two primary pathways: the bloodstream or the digestive system. The periodontal pockets’ proximity to the bloodstream allows for easy microbial invasion of the blood, whilst the oral microbiome can also spread through the digestive system [96,97]. The oral microbiome contributes to the development of systemic diseases, resulting in mutual interaction between the oral microbial community and systemic disorders, influencing each other [98]. A reported relation between microbiota and carcinogenesis has demonstrated the importance of diverse and healthy microbiomes. Fusobacteriota nucleatum is found in higher abundance in colorectal cancer (CRC) tissues compared to healthy controls or colorectal adenomas. This suggests that it may play a role in the later stages of colorectal cancer pathogenesis [92]. Increased Lactobacillus and Rothia in the oral cavities are implicated with CRC, that is associated with poor oral hygiene [99,100].

A decrease in the Neisseria elongata population, combined with a reduction in Streptococcus mitis, has been linked to pancreatic cancer, and individuals with higher levels of antibodies for P. gingivalis have been found to have an increased risk of developing pancreatic cancer [101].

5.1. Auto-Immune Diseases

The connection between the oral microbiome and auto-immune diseases has been extensively studied, with rheumatoid arthritis (RA) being the most researched. Various auto-immune conditions are reflected as a dysfunction of the oral microbiome: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjogren’s syndrome [22,102]. Individuals with RA have been found to have higher levels of antibodies against P. gingivalis, and multiple studies have demonstrated a link between RA and periodontitis [43,102,103,104].

5.2. Cognitive Decline

Recent research has highlighted the impact of dental disease and its association with cognitive decline, an important issue for world aging populations in general, and for future aging astronauts on exploration class space missions [105,106,107]. Although there appear to be no genetic risk factors, suffering from periodontitis, which is related to increased oral microbiome diversity, is believed to trigger systemic inflammation, and this in turn affects cognitive function [107,108]. Suggestions regarding the mechanism include a systemic inflammatory response found in patients suffering from cognitive decline with pre-existing severe periodontitis [108,109,110]. A review of various oral health issues, independent of age (gingival inflammation, attachment loss, probing depth, bleeding on probing, and alveolar bone loss) has been correlated with associated cognitive impairment [106,107,111].

Chronic oral inflammation—such as that seen in periodontal disease—may contribute to mitochondrial dysfunction in the body. This cellular damage can, in turn, promote neurodegenerative processes that lead to cognitive decline, potentially independent of an individual’s genetic risk factors [108,110]. Several studies, including a comprehensive review by Ayten and Bilici (2024), have reported that individuals with periodontal disease may experience an earlier onset of Alzheimer’s disease. This association is thought to be mediated by systemic inflammation and the translocation of oral pathogens or their toxins to the brain, contributing to neuroinflammatory processes involved in Alzheimer’s pathogenesis. It should be noted that this correlation does not necessarily mean causation, and there could be other factors influencing the relationship. Further analysis and investigations are needed to establish a causal link between both conditions [109].

A question remains as to when periodontal disease, not linked to other co-morbidities such as hygiene and depression, might have its impact remediated, and what may be the best way of identifying risk factors. Countermeasures thus far implemented demonstrate results in entrenched disease as opposed to early disease and are yet to consider the full spectrum of oral–gastrointestinal interactions and cognitive disease states [106,109].

5.3. COVID-19

Microbiomes play a management part in viral diseases. Reduction in diversity of microbes was strongly associated with reduced severity of symptoms [112,113]; a surge in the prevalence of bacterial genera, associated with inadequate oral hygiene and periodontal disease in individuals with COVID-19, provided an environment of increased viral load [114].

In individuals with COVID-19, the bacterial genera include Lactobacillus, Prevotella, Capnocytophaga, Aggregatibacter porphyromonas, Abiotrophia, and Atopobium. COVID-19 cases showed an abundance of fungi compared to the control group. Genera such as Aspergillus, Nakaseomyces, and Malassezia were found exclusively in COVID-19 subjects, along with commonly detected Candida and Saccharomyces genera [115]. The presence of Enterococcus and Enterobacter genera in COVID-19 cases indicates that these bacteria could be used as a marker to identify individuals who may be more susceptible to SARS-CoV-2 infection [116]. Epstein–Barr virus co-infection was found in around 30% of COVID-19 cases, compared to only 5% of control cases. This suggests that dysbiosis in the oral cavity contributes to the activation or reactivation of oral viruses, as EBV infection was identified in COVID-19 cases and was linked to a higher risk of severe symptoms and death [117].

6. The Role of Prebiotics, Probiotics, and Postbiotics in Oral and Gastrointestinal Health

6.1. Prebiotics and Probiotics

The term “prebiotics” refers to substances that can be found in food and either help the growth of probiotic organisms within the host or increase the activity of those organisms [105]. The majority of these prebiotics are composed of fibrous molecules that are indigestible. One therapeutic strategy for improving gut and oral health is the use of probiotics—living, non-pathogenic microorganisms that are administered to the host to help restore or maintain a healthy microbial balance. Probiotics may work by introducing beneficial bacteria into the gastrointestinal tract or by enhancing the activity of existing beneficial microbial communities. The goal is to support the growth and function of “good” bacteria while suppressing potentially harmful microbes, thereby contributing to better overall health. Probiotics can influence the composition and function of microbial communities through several mechanisms, such as competing with other microbes for nutrients, producing compounds that either support or inhibit microbial growth, and modulating the host’s immune responses in the gut [88,108].

The use of probiotics has included the oral cavity, female urogenital tract, and respiratory tract [118]. Probiotics may have the capacity to restore the composition of the gut microbiome and bring about beneficial outcomes for the communities of microbes that live in the gut, particularly Bifidobacterium and Lactobacillus sp., resulting in improvement or prevention of inflammation in the gut [109,118,119]. Certain prebiotic carbohydrates whose molecules are composed of a relatively small number of monosaccharide units, known as oligosaccharides, have been demonstrated to stimulate the growth of probiotic microorganisms in the oral cavity [65,118,120,121]. By promoting the growth of lactobacilli, a favorable environment is created, resulting in a decrease in the abundance of pathogenic bacteria like S. mutans due to the resulting low pH conditions [122,123]. Certain indigestible carbohydrates have been found to increase levels of immunoglobulin-A (IgA) in saliva; this is important for maintaining the balanced state of the oral mucous membrane lining [124]. Overall, these processes contribute to the overall improvement of oral health, promote immune response, and wound healing [125].

Probiotic bacteria commonly belong to genera such as Bifidobacterium and Lactobacillus, but other genera like Enterococcus, Bacillus, Streptococcus, and yeast Saccharomyces have also been considered probiotics [126]. When prebiotics are combined with probiotics, they complement each other. As symbiotics, the presence of prebiotics can enhance the survival of the microbes mentioned above [118,127,128]. Lactobacilli also exhibit antagonistic action against periodontal pathogens such as Aa., P. intermedia, and P. gingivalis by inhibiting their growth, and have a significant impact on preserving microbial stability and balance within the mouth cavity [129,130].

6.2. Prebiotics, Probiotics, and Their Applications in Oral Health

Studies have shown that short-term probiotic interventions can lead to a temporary reduction in the salivary counts of Streptococcus mutans, a bacterium closely linked to dental caries. Additionally, these interventions may have delayed effects on the overall composition and counts of salivary streptococci, potentially promoting a shift toward a more balanced and less cariogenic oral microbiota [129]. Saliva samples were collected after each phase, and the results showed a significant decrease in salivary streptococci counts after consuming milk containing L. rhamnosus HCT 70, suggesting that it may have a beneficial influence in preventing dental caries [131]. A commercial probiotic drink containing Lactobacillus casei strain significantly lowered the risk of dental caries in children. The administering of lozenges for four weeks containing Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. Lactis BB-12 led to reductions in the Plaque Index (which measures plaque buildup on teeth) and the Gingival Index (which evaluates gum inflammation), without significantly disrupting the overall composition of the oral microbiota [131,132]. It has been demonstrated that four strains of lactobacilli were able to inhibit the growth of Streptococcus mutans and had effects on the composition of bacterial biofilms in vitro [114]. Furthermore, probiotic Lactobacillus plantarum inhibited the growth of S. mutans and C. albicans through an inhibitory impact on the expression of their virulent genes and virulent structure, which could lead to a new paradigm shift in dental caries prevention [133]. Exploring the underlying mechanisms involved in the above correlation revealed that an isolated metabolite impedes S. mutans biofilms by modulating gene expression of several essential genes involved in biofilm establishment [134]. Indirectly, probiotics have various effects on the host immune system, such as increasing the production of Ig A, triggering non-immunological defense mechanisms, including the biological barriers of the normal flora, and maintaining a balanced oral environment [132,135]. Figure 2 summarizes the effects of probiotics on oral health.

6.3. Prebiotics and Probiotics and Their Applications in Gastrointestinal Health

The clinical applications of prebiotics in gastrointestinal health cover irritable bowel syndrome (IBS) to improve bloating and stool regularity, inflammatory bowel disease (IBD) to enhance butyrate-producing bacteria and reduce mucosal inflammation, and colorectal cancer by protecting against tumorigenesis through epigenetic regulation of gene expression [119,136]. The mechanisms of action involved range between improvement of colonic health and anti-inflammatory signaling through fermentation reactions, enhancement of beneficial bacteria such as Bifidobacterium and Lactobacillus, modulation of bile acid metabolism and cholesterol absorption, as well as immune regulation through increased regulatory T-cell activity and decreased pro-inflammatory cytokines [136,137].

The clinical applications of probiotics in gastrointestinal health involve IBD using Escherichia coli Nissle 1917 in maintaining ulcerative colitis remission [138]. Furthermore, multi-strain probiotics reduce abdominal pain and bloating in IBS, and combining probiotics with antibiotics reduces the recurrence of C. difficile infection [139]. Finally, probiotics enhance eradication rates of Heliobacter pylori and reduce therapy-related side effects [140]. The mechanisms of action include competitive exclusion of pathogens via adhesion site occupation and nutrient competition, production of antimicrobial substances, enhancement of epithelial barrier integrity by upregulating tight junction proteins, modulation of innate and adaptive immunity, and neuroimmune modulation via the gut–brain axis [119,137]. Figure 3 summarizes the effects of probiotics on gut health.

6.4. Prebiotics and Probiotics in Commercial Oral Health Products

These prebiotic and probiotic products, such as toothpaste, gums, lozenges, and chewable tablets, are designed to combat caries, gingivitis, and halitosis, and are also formulated to target S. mutans and other bacteria contributing to tooth decay and plaque around orthodontic brackets and wires that are used to align teeth. Ensuring that the desired effects of these products are retained in the oral environment presents challenges, particularly for probiotic-containing products [141]. Unlike probiotics, prebiotics can maintain their effectiveness within a formulation, making prebiotic application potentially more beneficial for promoting oral health [123].

6.5. Postbiotics and Their Applications in Oral and Gastrointestinal Health

Postbiotic-producing strains include various bacterial and fungal species such as Lactobacillus, Bifidobacterium, Streptococcus, Akkermansia muciniphila, Saccharomyces boulardii, Eubacterium hallii, and Faecalibacterium, many of which are naturally present in fermented foods. Postbiotics refer to bioactive compounds generated by these microorganisms, either during their growth (e.g., in culture media or food) or upon cell lysis. Studied postbiotic substances include microbial cell fragments, bacteriocins, short-chain fatty acids (SCFAs), extracellular polysaccharides, enzymes, culture supernatants, vitamins (such as vitamin K, vitamin B12, and folic acid), teichoic acids, and cell lysates [142]. These compounds are typically produced during anaerobic fermentation of prebiotic substrates derived from organic sources.

The main source of postbiotic compounds is anaerobic fermentation—a process in which beneficial microbes such as Lactobacillus and Bifidobacterium break down dietary fibers and other prebiotic substances in the absence of oxygen, which allowed for anti-inflammatory, anti-mutagenic (preventing mutation), anti-proliferative, immunomodulatory, antioxidant, and anti-adiposity (reducing or preventing the buildup of body fat) effects in several in vitro and in vivo studies [143]. Postbiotics can aid in oral health, inflammatory bowel disease, irritable bowel syndrome, and the prevention of respiratory tract infections. Additionally, the stability of postbiotics is retained when provided in food and pharmaceutical products, as their viability is not necessary. Thus, they can be employed in food items that are detrimental to probiotics, for instance, postbiotics derived from the clear liquid (supernatant) that settles above the culture from Lactobacillus rhamnosus GG have been documented to effectively restrain the growth of Porphyromonas gingivalis, Candida albicans, and Streptococcus mutans [133,144]. Furthermore, Aghazadeh et al. (2017) reported that the anti-cancer characteristics of Acidobacteriota syzygii postbiotics involve the induction of apoptosis (pre-programmed cell death) [145].

Clinical applications of postbiotics in gastrointestinal diseases include the reduction in incidence of necrotizing enterocolitis (NEC) in preterm infants in experimental models, the improvement of mucosal healing in ulcerative colitis [146]. The mechanisms of action involved vary between direct anti-inflammatory effects, induction of mucin production, tight junction reinforcement, immunomodulation, antimicrobial activity, and metabolic regulation by influencing host energy balance and lipid metabolism [147].

Postbiotics have some advantages over probiotics as their components cannot cause bacteremia or fungaemia, and because they do not contain viable cells that can multiply, they are also considered safer for immuno-compromised patients and present an alternative that would not undergo bacterial resistance [145,148]. All of the above characteristics highlight the importance of customizing the choice of the most effective probiotic treatment for each individual. The oral microbiome is affected by lifestyle habits, including diet, as described by Ryu et al. 2024 [2]. However, given the fact that the food consumed by astronauts during long-duration space missions is mainly processed and sterile in nature, there are other factors that affect the oral microbiome in space, which are discussed later in this review.

7. Changes in Oral and Gut Microbiota During Long-Duration Space Missions

7.1. The Effect of Microgravity on the Oral–Gastrointestinal Microbiome

The space environment affects human physiology in different ways, and the accompanying microbiome is increasingly being examined. New studies are elucidating the role that the gastrointestinal flora has in human nutrition, health, and general welfare [127,149]. Gastrointestinal microbiome changes are experienced in the space environment, and in some cases recorded loss of diversity has occurred during short 2-week spaceflights [2,6]. Maintenance of an individual ‘normal’ microbiome attuned to an individual’s metabolism for optimum health and wellbeing in space, is a subject that has not been addressed. Precision medicine in space may be the ideal, but this will be subject to resource availability and limitations [88,150]. It is known that many bodily functions, from gut defense mechanisms, immune responses, and nutritional uptake, affect the general wellbeing, mental health status, and functioning of individuals, and that these seemingly unrelated systems are linked via the composition of an individual’s oral–gastrointestinal microbiome [105]. Modified nutrient intake, such as the sterile nature of space provisions, will have a separate effect on microbiome health and distribution in different parts of the gut, and though the food is packaged for long-term provisioning, it may not provide the best health outcome for astronauts [151,152,153].

Oral and gastrointestinal microbiome dysbiosis has been recorded during relatively short time periods in the enclosed environment of spacecraft and microgravity. It is known that microbial replication rate and growth parameters change under microgravity conditions, where the force of gravity is extremely small, almost negligible in Low Earth Orbit (LEO). Exploration class space missions will create conditions of extended microgravity exposures and are predicted to have additional effects on the microbiome [154,155,156]. Recent studies unveiling the effect of lifestyle and geography on oral microbial composition bring into question how the various stages of human growth and development, with their differing nutritional requirements, could be supported in space [3,133,152,157].

Specific ecological niches within the intestine, combined with a reduction in gut microbiome diversity, can allow oral microbes to colonize parts of the gastrointestinal tract. This relocation may disrupt the natural balance of the gut microbiome and interfere with normal nutrient absorption [2,154,158]. Additional challenges faced by astronauts in the space environment include immuno-suppression, increased stress, cardiac, skeletal, and physiological changes, compounded with the additive effect of prolonged physical confinement and psychological isolation [104,159,160,161].

Immune dysregulation, a condition in which the immune system functions abnormally, either by over-reacting or failing to respond adequately, combined with microbiome dysbiosis, can promote opportunistic oral infections. This increases the risk of dental caries and periodontal diseases. Additionally, microgravity has been shown to influence microbial replication, growth parameters, and biofilm formation, potentially exacerbating these oral health risks in space environments [122,162]. Astronauts demonstrate elevated salivary cortisol levels during space missions, contributing to disordered insulin because of reduced insulin sensitivity, which altered insulin signaling pathways and changed how insulin communicates with cells, a state that is similar to early-stage type 2 diabetes [71]. Further alterations in the microbiome, including increased Streptococcus, Pseudomonadota, and Fusobacteriota and decreased populations of Actinomycetota, Catonella, Megasphera, and Actinobacillus [6,152,153,162]. Studies have found a significant positive correlation between microbiome richness, or the lack thereof, and increased EBV viral load [117,120,162].

Exposure to ionizing radiation in space presents a unique risk to astronaut health, particularly through its disruptive effects on the oral microbiome and gut microbiota. Unlike Earth, space environments expose the body to chronic low-dose radiation from galactic cosmic rays and solar particles, which can disturb the delicate balance of microbial communities. There is evidence that space radiation, ionizing and Galactic Cosmic Radiation (GCR), combined with microgravity exposure, alters the gut microbiota replication rate, with changed microbial species behavior being observed. This, coupled with decreased diversity, increases the known risk for disease, including cancer, inflammatory bowel disorders, and accompanying nutritional deficiencies [88,160,163,164]. Oral microbial species would be expected to be affected in the same way. However, disease pathogenesis in oral disease and cancer is linked with increased rather than decreased diversity of the oral microbiome, and it should be remembered that oral microbiome species can adapt to newly created habitat zones in the bowel [88,132,135,163,165,166].

In the oral cavity, ionizing radiation may reduce microbial diversity and favor pathogenic species, potentially increasing the risk of dental caries, oral inflammation, and mucosal damage, especially in the absence of normal gravity-driven saliva flow, which warrants the need for a multidisciplinary approach to ensure the optimum oral health for astronauts [167]. Post-spaceflight data demonstrated increased levels of gingival inflammation and calculus that was related to the increase in anaerobic microbiota such as Bacteroidota spp., Veillonella spp., Fusobacteriota spp., aerobic/facultative species as Neisseria spp., and facultative species as S. mutans. in dental plaque, and increased populations of anaerobes as a result of changes in bacterial metabolites were attributed to the effect of microgravity [158,168,169]. Latent viruses, such as herpes virus, varicella-zoster virus, cytomegalovirus, and Epstein–Barr viruses, have been found to be reactivated in astronauts during both short and long space missions [170].

Similarly, the gut microbiota, which plays a crucial role in immune regulation, metabolism, and gut barrier maintenance, can be significantly altered [171,172]. Studies in animal models have shown that space-relevant radiation can lead to a reduction in beneficial bacteria like Lactobacillus and Bifidobacterium, while promoting the overgrowth of pro-inflammatory or opportunistic pathogens. For example, Casero et al. in 2017 studied the composition and functional potential of the gut microbiota using a mouse model exposed to high doses of radiation and concluded that ionizing radiation is an under-appreciated hazard of space travel that requires further investigations and validation due to its potential chronic effects on human health [173]. The changes in gut microbiota may impair intestinal barrier function, enhance systemic inflammation, and weaken immune responses, which is concerning especially concerning during long-duration missions. Furthermore, it has been reported that the effects of space radiation and circadian rhythm disruptions on the microbiome result in a complex interplay between the gut microbiota, immune responses, and mental health outcomes [174]. This is illustrated by understanding how space radiation affects microbial ecosystems is essential for developing countermeasures, such as probiotics, dietary interventions, or shielding technologies, to protect astronaut health during deep space exploration.

Studying the effects of microgravity and radiation on microorganism growth and activity is necessary for predicting the host–microbe interactions as well as the possible contamination of spacecraft [175]. The spacecraft microbiome, which comprises the microbial communities present on surfaces, air, water systems, and equipment within space habitats, plays a dynamic and interactive role with the human microbiome during space missions [176]. Despite the strict infection control procedures, stringent decontamination, and controlled environmental conditions, it has been shown by Schultz et al. in 2025 that novel and rare microbial species were isolated from clean rooms where spacecrafts are assembled and tested [177]. The spacecraft’s microbiome is believed to be facilitated by moisture levels and the absence of microbial diversity and competition [177,178]. In the closed, confined environment of a spacecraft, humans are both sources and recipients of microbial exchange. Over time, the spacecraft’s internal environment becomes colonized by microbes shed from crew members’ skin, mouth, gut, and respiratory tract, which is an artificial microbial ecosystem, which can influence the crew members’ microbiomes [176]. Changes in microgravity, radiation, altered hygiene practices, and stress can amplify these interactions, potentially leading to a reduction in microbial diversity, resistance, adaptability, and function [179,180]. Furthermore, a study investigating the International Space Station showed the uniqueness of the microbiology and chemistry of the area [181]. It is important to consider that astronauts are deprived of the replenishment that Earth inhabitants attain from environmental exposure to microbes, as they are limited to exposure to the microbiomes of the spacecraft itself and fellow crew members [182]. Strategies like fecal microbiota transplantation in astronauts, through manufacturing probiotic capsules from the astronauts’ own stool prior to space travel when their microbiome was healthy on Earth, may help to restore and diversify their gut microbiota [179,183]. Therefore, understanding the bidirectional relationship between the spacecraft microbiome and the human microbiome is essential for developing microbial management strategies that maintain crew health and prevent microbial-related hazards in space.

Strong evidence is developing that appropriate use of prebiotics and probiotics in aiming to modify and sustain astronauts’ oral and gut microbiomes can modify and regulate the interactions between the different habitat zones, as well as between the microbiome and human body [184,185]. Probiotics play an important role in the prevention of gastrointestinal diseases such as acute infectious and antibiotic-associated diarrhea, Helicobacter pylori infection, irritable bowel syndrome, ulcerative colitis, and constipation, as well as improve gut barrier functions in the form of strengthening the protective lining of the intestines so that it works better at keeping harmful substances out and letting nutrients in [120]. This proactive methodology may help to manage increased diversity in the oral habitat and decreasing diversity in the gastrointestinal habitat when occurring as a response to the space environment [167,186,187,188]. Probiotics, prebiotics, and other methods of microbiota modulation could be effective during short space missions but might not be sufficient to overcome the unique challenges faced in long-duration space travel [182]. It should be noted that methodological challenges contribute to the slow progression of the evidence base in the literature related to this topic due to the difficulties in simulating the connections between the trifecta of spaceflight, the host, and the microbiome [172]. Furthermore, the need for advanced tools such as metagenomic analysis and longitudinal tracking of astronaut health, as well as data integration across different sites of the body and missions, facilitated by resources like the Space Omics and Medical Atlas (SOMA), remain obstacles that prevent rapid exploration of consistent microbial changes induced by the unique occupational conditions of spaceflight, and shedding more light on the potential uses of prebiotics and postbiotics in space science [184,189].

The challenges associated with the study of the exact mechanisms and metabolic pathways that affect the microbiome, as well as the conduction of human trials under long-term simulated space environments, should be noted. This requires longer-term studies to develop a deeper understanding of the molecular biology and biomarkers responsible for the dental dilemma caused by microgravity [190]. Interestingly, it has been demonstrated that spaceflights redefine the correlation between aging and microbiota, for example, in the gut, two bacteria negatively correlated with aging were upregulated after spaceflight, whereas two bacteria positively correlated with aging were downregulated after spaceflight, and aging-associated microbiota in the oral cavity and skin exhibited significant changes after spaceflight [191]. A recent review revealed that the specific mechanism of the effect of microgravity on gastrointestinal function and the possible drugs or therapeutic technologies for the protection of the gastrointestinal tract in the space environment are potential research directions in the future [192]. However, more light is being shed on the specific mechanisms involved in microgravity-induced intestinal microbiome dysbiosis. A recent study showed that valeric acid, a metabolite of gut microbiota, is most likely the key factor leading to microgravity-induced gut microbiota abnormalities, disorders of amino acid and lipid metabolism, and further induced metabolic or functional disorders in the liver and brain [193]. Furthermore, modulating the gut microbiota in microgravity conditions has a correlation with cardiovascular and musculoskeletal diseases, which could also apply to periods of prolonged bed rest on Earth [194].

Attempts are being made to specify purpose-based drugs for spaceflight, establishing a foundation for the development of targeted therapies for astronauts [195]. Also, artificial intelligence and machine learning, along with other cutting-edge health technologies in space sciences research, allow a visionary approach for monitoring, prevention, and treatment of spaceflight-induced disorders [196]. The debate about the effect of microgravity extends beyond the oral cavity and the gastrointestinal tract to women’s health and hormones [197]. Despite the rapid developments in space environment simulation and analog studies [198,199], findings from such innovative studies need validation in real space conditions to explore potential side effects and biological impacts.

Table 3. Summarizes the differences between healthy Earth-based oral and GI microbiome versus dysbiotic space oral and GI microbiome, and demonstrates the changes in diversity, dominant taxa, biofilm, key functions, host effects, and drivers/systemic effects.

Feature	Healthy Earth Oral Microbiome	Dysbiotic Space Oral Microbiome	Healthy Earth GI Microbiome	Dysbiotic Space GI Microbiome
Diversity	High and balanced	Reduced and pathogen-dominated	High and balanced	Reduced and pathogen-dominated
Dominant taxa	Streptococcus Actinomycetota Veillonella	P. gingivalis F. nucleatum Candida overgrowth	Faecalibacterium Bifidobacterium Akkermansia	Enterobacteriaceae Clostridioides Opportunistic E. coli
Biofilm	Stable and protective	Unstable and pathogenic	N/A	N/A
Key functions	pH balance Metabolism Immune tolerance	Acid production Inflammation Immune resistance	Short-Chain Fatty Acids Vitamin synthesis Immune tolerance	Reduced Short Chain Fatty Acids Increased pro-inflammatory metabolites Immune resistance
Host effects	Oral health maintenance Systemic benefits	Caries Periodontal disease Systemic inflammation	Intact mucus Strong epithelial integrity	Leaky gut syndrome Impaired gut barrier
Drivers/systemic effects	Salivary flow Diet Immune system	Microgravity Radiation Immune suppression Altered diet	Metabolic balance Immune regulation Gut–brain signaling	Inflammation Malabsorption Metabolic and immune dysfunction

summarizes the differences between the healthy Earth-based oral and GI microbiome versus the dysbiotic space oral and GI microbiome.

7.2. The Link Between the Oral and Gastrointestinal Microbiome

On Earth, the symbiosis of the oral–gastrointestinal microbiome is poorly understood, but it has become obvious that it is a complex, dynamic, and inter-dependent relationship. Many insults to the oral microbiome can affect the gastrointestinal microbiome, with the additional ability of the oral microbes to be able to inhabit other areas of the gastrointestinal tract, impacting the function of the native flora [88,200]. After stool samples, the oral environment exhibits the greatest alpha diversity. The skin and vagina display lower alpha diversity levels. Interestingly, oral sites show the least microbial variations among individuals (so-called beta diversity). People within a specific population share organisms that are more similar in their oral cavities than in other body parts.

In space or enclosed environments, the gastrointestinal microbiome (compared to the oral microbiome) conversely reduces in diversity, leading to gastrointestinal tract (GIT) upset, nutritional interruption due to altered eating habits during space missions, cognitive decline, immuno-suppression, and disease pathogenesis like diabetes mellitus as an example [69,119,134,144,188]. Long-duration exploration class space missions, or colonization of other celestial bodies, present particular challenges due to the microgravity effect on the replication rate of the microbiome and the exposure to ionizing space radiation, leading to possible genetic alterations in the microbiome [159,161,187,201]. The growth curves of certain bacterial species were shown to increase under simulated microgravity conditions due to the upregulation of certain genes that are related to certain physiological characteristics [202]. Similarly, viral replication rate increases under microgravity due to pro-inflammatory cytokine gene expression [203]. A recent review by Bakr et al. in 2024 has summarized the effects of microgravity and spaceflight on different oral tissues, including salivary glands, and the composition of saliva, and explains the mechanisms behind the changes [167]. Studies have shown that the composition of saliva changes under simulated microgravity conditions [188]. Additionally, alterations in the size of salivary glands, a decrease in masticatory activity, and changes in the expression of salivary proteins have also been observed [204]. Specifically, it has been found that simulated microgravity leads to a shift in the salivary microbiome, from bacteria associated with oral health to those linked to oral diseases, accompanied by a trend toward a reduction in salivary pH, although it remains alkaline [188]. Another study also indicated that changes in the salivary microbiome during space missions are linked to the reactivation of certain viral conditions that affect the oral mucosa [162].

As the oral and gastrointestinal microbiomes are linked, dysbiosis in one may invoke dysbiosis in the other. The normal parameters of the oral microbiome can be disturbed by lifestyle, antibiotics, diet, pregnancy, and other modifying factors, leading to increased diversity [27,122,159]. Oral health can therefore affect gastrointestinal and overall health, because, as mentioned, in the right biological circumstances, the oral microbiome can also inhabit the gastrointestinal zones [46,89,135,165,205].

In contrast to the gastrointestinal increase in diversity with disease states, poor oral health has correlations to a number of disease states, including local (e.g., gingivitis, caries) [63], and distant (e.g., Alzheimer’s, urinary tract infections, cardiac) as well as cancers (e.g., bowel, pancreatic) [64,88,187,206,207,208,209]. The links and biological mechanisms related to poor oral health and Alzheimer’s disease [210,211], as well as cardiac disease [212], still require further large-scale studies so as to be fully understood in order to develop targeted interventions that would help in prevention and management strategies.

The relationship between oral microbiome diversity and oral health remains a topic of ongoing debate, with seemingly contradictory findings in the literature. Traditionally, reduced microbial diversity has been associated with dysbiosis and disease in many body sites, including the gut [213,214]; however, in the oral cavity, increased microbial diversity has paradoxically been linked to oral diseases such as periodontitis and dental caries [55]. This is thought to occur because the breakdown of ecological balance allows for the overgrowth of opportunistic pathogens, leading to a more complex but pathogenic microbial community. Conversely, other studies suggest that low oral microbiome diversity, often seen with poor diet, antibiotic use, or compromised immune systems can also impair the resilience of the microbiota, making the oral environment more vulnerable to infection and inflammation [215,216]. These conflicting observations highlight the importance of microbial community composition and functional interactions, rather than diversity alone, in maintaining oral health. As such, understanding not just how diverse the oral microbiome is, but which microbes are present and how they interact, is critical for clarifying its role in disease development.

Oral cavity health and hygiene have a holistic impact on human health, and other conditions such as the pregnancy stage (trimester) and birthing method influence the oral microbiome as well as that in the GIT [58,217,218,219,220]. Whilst pregnant, women greatly increase their gastrointestinal flora, vaginal birth will expose the infant to a different range of microbes than a C-section, thus seeding vastly different populations of microbes in the naked oral–gastrointestinal habitat of the newborn [17,23,53,221]. This has health consequences for the child in later life.

Associations are found between microbial exposure linked to the type of birth (delivery) and physiological issues such as asthma, obesity, and later development of diabetes [35,38,43,53,205,207]. Although no children or infants have yet flown to space, consideration of the development of future space colonies on other worlds raises concerns regarding the nature of infant microbiome exposure, and the effect of an altered oral and GIT microbiome being associated with physiological dysfunction and disease [200,222,223]. The importance of a dynamic microbiome for the healthy growth and development of future infants, children, and teenagers during habitation in the space environment cannot be ignored [95,122,128,164,224].

7.3. Innovative Approaches for Maintaining a Healthy Oral–Gastrointestinal Microbiome in Space Missions

Current commercial probiotic products are often generic, require refrigeration, or lack validation in microgravity environments due to limited studies and small sample sizes [185]. Innovative approaches that can overcome the current limitations of the current products in the market include designing synbiotic formulations that combine astronaut-tolerant probiotic strains with robust prebiotics tailored to enhance survival and functionality in microgravity. Furthermore, developing recipes for onboard yogurt production, or similar fermented food systems enriched with probiotics [182,225], formulation of long-duration single-use capsules that are heat-resistant, light-proof, and compact to integrate into space missions, and developing oral probiotic lozenges or mouth rinses containing species tailored to maintain oral microbial balance amid altered salivary flow, pH shifts, and limited hygiene contexts in space would be beneficial for regulating the oral–gastrointestinal microbiome in space missions. In addition to the above, developing smart nutrition systems that dynamically adjust probiotic/prebiotic delivery based on individual microbiome monitoring and the space mission duration would allow for the implementation of an adaptive nutritional platform that addresses any microbiome imbalance that occurs in space.

These innovations and future research directions offer greater resilience, personalization, and practicality for maintaining astronaut health over extended missions. They provide advantages over the current available products through custom selection of strains that are proven viable in microgravity, their non-refrigerated delivery method that is optimized for long missions, their synergistic nature through the combined prebiotic–probiotic strategies, and the possibility of dietary integration as part of nutritious, morale-boosting food items like onboard manufactured fermented yogurt. Finally, the dual-target nature of these interventions addresses both microbiomes (Oral and GI microbiome) rather than the current products focusing only on gut health.

Humans, their microbiome, and human health are intimately related concepts. To maximize human health in space, increased understanding of the oral–gastrointestinal axis is needed, and novel management tools, which work together to maintain a healthy and functional microbiome, in all habitat regions of the gastrointestinal tract, will be required [89,164,200]. With the rapid development of space missions and missions back to the Moon being likely to become more common, more investigation and tailoring of the microbiome to maximize human health in altered gravity environments is required, given that the Moon gravity is approximately 1/6 of Earth’s gravity and Mars gravity is approximately 0.38 of Earth’s gravity, and taking into consideration the transitions between different gravitational fields, including the return to Earth.

8. Conclusions

Space exploration is not without challenges for human health. The oral and gastrointestinal microbiome inhabit different physical zones in the human body, and their constituent microorganisms are remarkably different. The oral cavity is prone to disease when there is increased diversity; conversely, the gastrointestinal tract is prone to disease with decreased diversity. Both microbiomes are complex, dynamic, and reactive, and reassemble their composition in response to dietary changes, geographical location, radiation, microgravity, and in response to physiological changes and disease pathogenesis. Newer diagnostic tools can be deployed for rapid identification of infections and imbalances of the oral microbiome; however, adequate stabilization and resilience of these tools have not yet been adequately tested nor approved for space missions. Conceptually, prebiotic, probiotic, and postbiotic supplementation is an attractive concept, and may provide solutions for maintaining the health of both microbiome habitat zones. Stabilization and protection of prebiotics, probiotics, and postbiotics during spaceflight and in the space environment will require sophisticated knowledge of growth, harvest, and maintenance procedures, with considerable focus needed on the appropriate protective packaging and storage required for spaceflight. It is important to keep in mind that probiotics are living microbes, and are prone to radiation and microgravity insult.

The space environment affects the constituents of the human microbiome, presenting the harsh reality of changed growth patterns, resident population disruption and distribution, as well as collective microbiome behavioral change; all with potential downstream health and welfare effects, including a potential impact on cognition. It is becoming increasingly obvious that both the oral and gastrointestinal microbiome, and their associated habitats, require careful selection and academic attention in order to maximize the ability of both humans and microbiomes to change traits or behavior in the space environment. The benefits of such a focus may establish a methodology for reducing the risk of disease morbidity and mortality, whilst providing a mechanism to increase health and wellbeing for astronauts during ECSM.

Despite the growing interest and advancements in understanding the oral and gastrointestinal microbiomes during long-duration space missions, significant limitations still constrain the scope and applicability of current research. One of the most critical challenges is the discrepancy between simulated space environments (such as ground-based microgravity models or analog missions) and actual spaceflight conditions. While these simulation models provide valuable insights, they often fail to fully replicate the complex interplay of factors present in space. As a result, findings from such models may not accurately reflect the physiological and microbial responses experienced during real missions, especially those of long duration.

Another major limitation is the inherently small sample size available for human studies in space. The limited number of astronauts participating in missions severely restricts the statistical power and generalizability of microbiome-related findings. Inter-individual variability in microbiome composition and immune responses further complicates efforts to draw definitive conclusions or develop standardized countermeasures. These constraints make it difficult to distinguish between changes caused by spaceflight-specific conditions and those arising from individual biological differences or other confounding variables.

Together, these limitations warrant the urgent need for more comprehensive, long-term, and interdisciplinary studies involving larger, more diverse astronaut groups and improved in-flight data collection tools. Improving our understanding in this area will be essential not only for safeguarding astronaut health during long-duration missions but also for translating space microbiome research into novel interventions for extreme or confined environments on Earth.