Recent advances in molecular biology, metagenomics, and microbiology have revolutionized our understanding of the skin microbiome, showing that its composition and functions are far from passive. Alterations in the skin microbial community — a condition known as dysbiosis — have been associated with numerous dermatological diseases, including acne, atopic dermatitis, psoriasis, rosacea, and more. At the same time, novel therapeutic strategies that aim to restore a balanced skin microbiome are being explored, ranging from probiotics and prebiotics to bacteriophage therapy and microbial transplants.

This article explores the core components of the skin microbiome, its essential functions in maintaining health, the mechanisms by which its disturbance can contribute to disease, and the future of skin microbiome-based diagnostics and therapies.

The composition of the skin microbiome

Microorganisms on the skin can be divided into two main categories:

• Resident microbiota: these are long-term inhabitants of the skin, acquired during birth and early life. They are stable, adapted to specific niches, and contribute to host homeostasis.

• Transient microbiota: these organisms are acquired from the environment and may not establish permanent residence unless conditions (e.g., immune suppression or barrier disruption) allow them to persist.

Each individual’s skin microbiome is as unique as a fingerprint, influenced by genetics, age, environment, diet, hygiene practices, and anatomical site.

Main bacterial phyla

The most common bacterial phyla on the human skin are:

• Actinobacteria (51%) – including Cutibacterium and Corynebacterium species
• Firmicutes (24%) – including Staphylococcus species
• Proteobacteria (16.5%)
• Bacteroidetes (6.8%)

Key genera and species

• Staphylococcus epidermidis. A dominant and typically beneficial commensal, S. epidermidis plays a protective role by producing antimicrobial peptides (AMPs) and enhancing the host’s innate immune responses. However, under certain conditions, it can form biofilms and become pathogenic, especially in immunocompromised individuals or those with indwelling medical devices.
• Staphylococcus aureus. Though often part of the normal flora, S. aureus is a known opportunistic pathogen, particularly in patients with atopic dermatitis. It can exacerbate inflammation, compromise the skin barrier, and develop resistance to antibiotics.
• Cutibacterium acnes (formerly Propionibacterium acnes). A key resident in sebaceous areas, C. acnes is involved in skin homeostasis but also in acne pathogenesis. Specific strains are associated with disease, whereas others are linked to healthy skin.
• Corynebacterium species. These bacteria thrive in moist areas and contribute to body odor production. They also interact with immune cells, though their role in health and disease is still being elucidated.

Non-bacterial components

• Fungi: malassezia species dominate the skin mycobiome, especially in oily regions. Some species are implicated in seborrheic dermatitis and dandruff.
• Viruses: including bacteriophages that infect skin-residing bacteria and human viruses such as HPV.
• Archaea and mites: less studied, but emerging evidence suggests they contribute to skin health and disease.

The role of the skin microbiome in health

Barrier function

The microbiome reinforces the skin’s physical barrier by:

• Occupying niches that could otherwise be colonized by pathogens.
• Producing antimicrobial substances (e.g., bacteriocins, fatty acids, peptides).
• Modulating the host’s pH and hydration.

Immune regulation

Microbial metabolites (e.g., short-chain fatty acids, tryptophan derivatives) influence the innate and adaptive immune systems. Commensals promote immune tolerance, while pathogens can trigger inflammation.

S. epidermidis, for example, induces the expression of AMPs via Toll-like receptors (TLRs) and supports wound healing.

Sensory and metabolic functions

Recent studies suggest that the microbiome may affect the skin’s sensory responses and metabolome. Microbes process skin lipids, release volatile compounds, and may even influence neuroimmune communication.

Dysbiosis and skin disease

When the microbial balance is disrupted — due to antibiotics, poor hygiene, immune dysfunction, or genetic factors — dysbiosis can lead to or exacerbate skin disorders.

Common dysbiosis-linked dermatological conditions

• Acne vulgaris. Involves overgrowth or pathogenic strain dominance of C. acnes. Inflammatory responses to its porphyrins and lipases contribute to lesion formation
• Atopic Dermatitis. Characterized by decreased microbial diversity and dominance of S. aureus. Linked to barrier dysfunction and heightened Th2 immune responses
• Psoriasis. Dysbiosis includes increased Streptococcus and Malassezia.     Immune activation via IL-17 and IL-23 pathways plays a key role
• Rosacea. Altered composition of facial skin microbiota and Demodex mite overgrowth
• Seborrheic dermatitis and dandruff. Overgrowth of Malassezia species in sebaceous areas
• Wound healing impairment. Biofilms of pathogens (e.g., Pseudomonas, Staphylococcus) delay repair.
• Vitiligo and autoimmune diseases. Altered microbial communities may modulate melanocyte-targeted autoimmunity

Therapeutic and diagnostic applications

Probiotics (topical and systemic)

Live microorganisms administered to improve microbial balance and skin health.

• Topical application of S. epidermidis or non-pathogenic C. acnes strains may reduce inflammation and pathogen load.
• Oral probiotics, including Lactobacillus and Bifidobacterium, show promise in atopic dermatitis.

Prebiotics

Substrates that nourish beneficial skin microbes.

• Examples: inulin, oligosaccharides, plant-derived sugars
• Found in some moisturizers and cleansers

Postbiotics and bacterial lysates

Non-viable microbial products that exert health benefits.

• Fermentation products, enzymes, and cell wall fragments modulate immunity and enhance barrier repair.

Phage therapy

Use of bacteriophages to selectively target and destroy pathogenic bacteria without harming commensals.

• Potential for acne and S. aureus-driven conditions

Skin microbiome transplants

Still experimental, involves transferring skin microbiota from healthy donors to restore balance.

• Considered for chronic wounds and inflammatory skin diseases

Cosmetic and environmental modulation

• Use of functional textiles that influence skin microflora
• Application of thermal water rich in beneficial microbes
• Development of skincare lines tailored to individual microbiome profiles

Diagnostic advances

Modern tools to study the skin microbiome include:

• 16S rRNA and shotgun metagenomic sequencing. Identify microbial composition and strain-level variations

• Culturomics. High-throughput culture-based techniques to isolate fastidious microbes
• Metabolomics and transcriptomics. Assess microbial function and interaction with the host

These technologies enable personalized dermatology and open new frontiers in preventive and precision medicine.

Conclusion

The skin microbiome is an essential partner in the maintenance of cutaneous health and a key player in the pathogenesis of numerous dermatological disorders. Our expanding knowledge of its composition, function, and clinical relevance opens the door to a new era of microbiome-centered therapies and diagnostics.

Future dermatology will likely include microbiome profiling as part of standard skin assessments, and therapeutic approaches will increasingly target microbial communities rather than individual pathogens. In this evolving landscape, restoring and preserving microbial balance will be just as important as treating the visible symptoms of disease.

The vaginal microbiota is a complex ecosystem primarily composed of Lactobacillus species, which help regulate pH, prevent infections, and support fertility. However, various factors—such as hormonal changes, lifestyle, and external influences—can alter this balance, leading to conditions like bacterial vaginosis, recurrent infections, and even implications for fertility and pregnancy outcomes.

Understanding the vaginal microbiome is essential not only for treating gynecological conditions but also for preventing them and promoting overall well-being.

Composition of the vaginal microbiome

In healthy women, the vaginal microbiome is primarily dominated by Lactobacillus species. These beneficial bacteria play a protective role by producing lactic acid, which maintains an acidic vaginal pH (between 3.8 and 4.5). This acidity creates an environment that inhibits the growth of pathogenic bacteria and fungi.

The five vaginal Community State Types (CST)

Scientific studies have classified the vaginal microbiota into five distinct community types, known as Community State Types (CSTs):

• CST I – Dominated by Lactobacillus crispatus (associated with strong protection and stability)
• CST II – Dominated by Lactobacillus gasseri
• CST III – Dominated by Lactobacillus iners (less stable, can shift toward dysbiosis)
• CST IV – Low levels of lactobacilli, high presence of Gardnerella vaginalis and anaerobic bacteria (linked to bacterial vaginosis)
• CST V – Dominated by Lactobacillus jensenii

The presence or absence of lactobacilli significantly influences vaginal health. CST I and III are considered the most protective, while CST IV is associated with an increased risk of infections and gynecological disorders​.

Functions of Lactobacilli in the vaginal microbiome

Lactobacilli serve as the first line of defense against vaginal infections and play several critical roles:

• pH Regulation: By producing lactic acid, they maintain an acidic vaginal environment, which prevents the overgrowth of harmful bacteria.
• Production of Hydrogen Peroxide (H₂O₂): Some lactobacilli, such as Lactobacillus crispatus, synthesize H₂O₂, which has antimicrobial properties against pathogens like Gardnerella vaginalis and Escherichia coli.
• Production of Bacteriocins: These are proteins with antibacterial activity that help control the growth of harmful microorganisms.
• Biofilm Formation: Lactobacilli can form protective biofilms on vaginal epithelial cells, preventing the adhesion of pathogenic bacteria​.

The vaginal microbiome across life stages

The vaginal microbiome is not static; it evolves throughout a woman’s life in response to hormonal changes.

Childhood and adolescence

At birth, the vaginal microbiota is diverse and lacks dominant lactobacilli. However, with the onset of puberty and increased estrogen production, glycogen accumulates in vaginal epithelial cells, providing a substrate for lactobacilli to thrive.

Reproductive years

During the fertile years, the microbiome stabilizes, with Lactobacillus crispatus and Lactobacillus iners being the most common species. This stability is essential for:

• Preventing bacterial and yeast infections
• Supporting fertility and embryo implantation
• Reducing the risk of sexually transmitted infections (STIs)​

Pregnancy

Pregnancy triggers hormonal and immune changes that increase the dominance of lactobacilli. This stabilization serves to protect against preterm birth and infections that could harm the fetus​.

Menopause

After menopause, the decline in estrogen reduces vaginal glycogen levels, leading to a decrease in lactobacilli and an increase in anaerobic bacteria such as Gardnerella vaginalis and Mobiluncus spp.. This change can cause symptoms like vaginal dryness, infections, and increased risk of bacterial vaginosis​.

Dysbiosis: when the balance is lost

Dysbiosis refers to an imbalance in the vaginal microbiome, where harmful bacteria outnumber beneficial lactobacilli. This condition is linked to:

• Bacterial Vaginosis (BV): characterized by an overgrowth of anaerobic bacteria such as Gardnerella vaginalis, Atopobium vaginae, and Prevotella spp. Symptoms include unusual discharge, a fishy odor, and increased susceptibility to infections.
• Yeast infections (Candidiasis): overgrowth of Candida albicans, often due to antibiotic use, stress, or hormonal fluctuations.
• Urinary Tract Infections (UTIs): the vaginal and urinary microbiomes are closely linked, and dysbiosis can increase UTI risk​.

The Intestinal-Vaginal axis

The intestinal-vaginal axis refers to the intricate relationship between the gut and vaginal microbiomes. While these microbial ecosystems are distinct, they are closely connected through immune signaling, microbial translocation, and metabolic interactions. Increasing evidence suggests that gut health directly influences vaginal health, affecting susceptibility to infections, inflammation, and even reproductive outcomes.

Microbial migration: the gut as a reservoir for vaginal bacteria

One of the most significant links between the gut and vagina is the transfer of bacteria from the gastrointestinal (GI) tract to the vaginal and urinary tracts. This occurs primarily through:

• Fecal-Perineal-vaginal transmission: the proximity of the anus to the vaginal opening allows for the migration of gut bacteria to the vaginal area. While this process helps maintain a natural reservoir of beneficial lactobacilli, it also increases the risk of pathogenic bacteria like Escherichia coli, Enterococcus spp., and Clostridium spp. colonizing the vagina and urinary tract, potentially leading to infections such as bacterial vaginosis (BV), urinary tract infections (UTIs), and yeast infections.
• Oral probiotic influence: studies have shown that orally consumed probiotic strains, such as Lactobacillus rhamnosus and Lactobacillus reuteri, can colonize the gut and later migrate to the vagina, contributing to microbial balance​.

Gut dysbiosis and vaginal infections

When the gut microbiome is imbalanced (a state known as gut dysbiosis), it can negatively affect vaginal health. Several mechanisms explain this connection:

• Inflammation and immune crosstalk: a disrupted gut microbiome can lead to chronic low-grade inflammation, which affects the immune defenses of the vaginal mucosa. This can make the vaginal environment more susceptible to infections, particularly bacterial vaginosis, yeast infections, and sexually transmitted infections (STIs).
• Endotoxemia and vaginal health: dysbiosis in the gut can cause an increase in lipopolysaccharides (LPS), bacterial endotoxins that enter the bloodstream due to increased intestinal permeability (“leaky gut”). LPS-induced inflammation can alter vaginal immunity, reducing the protective effects of lactobacilli and making the vaginal microbiome more susceptible to pathogenic overgrowth.
• Estrobolome regulation: the estrobolome, a subset of gut bacteria responsible for metabolizing estrogens, plays a significant role in regulating estrogen levels. Since estrogen directly affects vaginal health by promoting glycogen production (the main energy source for lactobacilli), a disrupted gut microbiome may lead to reduced estrogen metabolism, causing vaginal dryness, increased vaginal pH, and a higher risk of infections​.

Diet, the gut microbiome, and vaginal health

What we eat has a profound impact on both gut and vaginal health. A diet rich in processed foods, sugars, and unhealthy fats can promote inflammatory gut bacteria, whereas a fiber-rich, plant-based diet supports beneficial microbes that indirectly benefit the vaginal microbiome. Some dietary influences include:

• Prebiotic-rich foods (fiber, polyphenols): support the growth of beneficial gut and vaginal lactobacilli.
• Fermented foods (Yogurt, Kefir, Kimchi, Sauerkraut): provide probiotic strains that can migrate from the gut to the vagina.
• High-Sugar diets: promote Candida overgrowth, increasing the risk of recurrent yeast infections.
• Omega-3 fatty acids: help reduce inflammation and maintain mucosal immunity, benefiting both the gut and vaginal microbiome​.

The role of probiotics and the intestinal-vaginal axis

Since the gut serves as a primary reservoir for Lactobacillus species, maintaining a healthy gut microbiome through probiotics and prebiotics can have a direct positive impact on vaginal health. Clinical studies suggest that probiotics:

• Restore vaginal lactobacilli levels: orally administered L. rhamnosus and L. reuteri can colonize the vagina and reduce the recurrence of BV and UTIs.
• Modulate inflammation: probiotics help reduce systemic inflammation, which can otherwise weaken vaginal defenses.
• Improve hormonal balance: by regulating estrogen metabolism via the estrobolome, probiotics can support vaginal health during menopause and pregnancy​.

Clinical implications: the gut as a therapeutic target for vaginal disorders

Given the strong connection between gut and vaginal health, treating gut dysbiosis could be a novel approach to managing recurrent vaginal infections. Some promising strategies include:

• Probiotic and prebiotic therapy: supporting both gut and vaginal microbiomes.
• Dietary interventions: reducing inflammatory foods and increasing gut-friendly nutrients.
• Fecal microbiota transplant (FMT): some studies are exploring whether FMT could restore balance in cases of severe gut dysbiosis and vaginal disorders​

Given the importance of lactobacilli in vaginal health, probiotics (live beneficial bacteria) have gained attention as a strategy to restore balance. 

For example, probiotic species such as L. rhamnosus and L. reuteri have been shown to help restore a healthy vaginal microbiota. Clinical studies suggest that oral and vaginal specific probiotics strains may reduce  the recurrence of BV and UTIs.

A balanced microbiome is also crucial for successful embryo implantation and pregnancy​.

Challenges and future research

Although probiotics hold promise, research is ongoing to determine:

• The most effective strains for specific conditions
• The ideal dosage and delivery method (oral vs. vaginal)
• The long-term impact on women’s health​

Conclusion

The vaginal microbiome is a dynamic and essential component of female health. It interacts with hormonal changes, immune function, and even gut bacteria. While the dominance of lactobacilli is a key factor in maintaining vaginal health, disruptions can lead to various infections and reproductive challenges. 

By understanding the complex interactions within this microbial ecosystem, we can develop better strategies—including probiotics, diet, and lifestyle interventions—to support women’s health across different life stages.

The gut microbiome influences digestion, immunity, metabolism, and even mental well-being. Despite its microscopic size, this vast ecosystem plays a fundamental role in maintaining overall health​.

Understanding the gut microbiome is essential because imbalances in this microbial community—known as dysbiosis—have been linked to a wide range of health conditions, from digestive disorders to metabolic diseases and even neurological conditions​.

The structure and composition of the gut microbiome

The human gut microbiome consists of thousands of microbial species, primarily residing in the colon. The most abundant bacterial phyla include:

• Firmicutes (e.g., Lactobacillus, Clostridium)
• Bacteroidetes (e.g., Bacteroides)
• Actinobacteria (e.g., Bifidobacterium)
• Proteobacteria (e.g., Escherichia coli)
• Verrucomicrobia (e.g., Akkermansia muciniphila)​

Each individual’s microbiome is unique, shaped by genetics, diet, lifestyle, and environmental factors. The balance of these microbes is critical for health, as certain bacteria contribute to digestion and immunity, while others, when overgrown, can promote inflammation and disease​.

Functions of the gut microbiome

The gut microbiome influences various bodily functions, many of which extend beyond digestion.

Digestion and nutrient absorption

One of the primary roles of gut bacteria is aiding in the breakdown of complex carbohydrates and fibers that the human body cannot digest on its own. These bacteria ferment dietary fibers, producing short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate, which serve as energy sources for gut cells and help maintain a healthy gut barrier​.

Additionally, gut microbes synthesize essential vitamins, including vitamin K and certain B vitamins (such as B12 and folate), which are crucial for metabolism and blood clotting​.

Immune system regulation

The gut is the largest immune organ in the body, housing nearly 80% of immune cells. Beneficial microbes help train the immune system to distinguish between harmful and non-harmful invaders. They also compete with pathogenic bacteria for space and nutrients, preventing infections like Clostridium difficile and Helicobacter pylori​.

Metabolism and weight regulation

The gut microbiome plays a significant role in metabolism and weight regulation. Certain bacteria influence fat storage, energy balance, and appetite hormones. For example:

• Bifidobacterium and Lactobacillus are associated with better metabolic health.
• Akkermansia muciniphila helps regulate the gut barrier and may protect against obesity and diabetes​.

An imbalance in gut bacteria has been linked to obesity, insulin resistance, and type 2 diabetes, partly due to its impact on energy extraction from food and inflammation​.

The Gut-Brain connection

The gut and brain communicate through the gut-brain axis, a bidirectional network involving the nervous system, immune system, and metabolic pathways. Some gut bacteria produce neurotransmitters like serotonin, dopamine, and GABA, which influence mood, stress responses, and even cognitive function​.

Studies suggest that probiotic supplementation can help alleviate anxiety and depression symptoms by modulating gut bacteria and reducing inflammation​.

Cardiovascular health

The gut microbiome is involved in heart health through its role in metabolizing dietary compounds like choline and L-carnitine, found in red meat and eggs. Certain bacteria convert these compounds into trimethylamine (TMA), which the liver processes into trimethylamine-N-oxide (TMAO)—a substance linked to atherosclerosis and heart disease​.

Dysbiosis: when the gut microbiome falls out of balance

An imbalance in gut bacteria, known as dysbiosis, can contribute to several health conditions, including:

• Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD)
• Metabolic disorders like obesity and diabetes
• Autoimmune diseases such as rheumatoid arthritis
• Mental health disorders, including depression and anxiety​

Factors contributing to dysbiosis include:

• Poor diet (high in processed foods, sugar, and unhealthy fats)
• Chronic stress
• Antibiotic overuse
• Lack of dietary fiber
• Disrupted sleep patterns​

Strategies for a healthy gut microbiome

Eat a diverse, fiber-rich diet. Diets rich in fruits, vegetables, whole grains, and legumes support microbial diversity and SCFA production, promoting gut health. Fiber acts as a prebiotic, feeding beneficial bacteria​.

Consume fermented foods. Fermented foods such as yogurt, kefir, sauerkraut, kimchi, and miso contain probiotics—live beneficial bacteria that can help restore gut balance​.

Limit processed foods and artificial sweeteners. Processed foods often contain emulsifiers and artificial sweeteners, which can negatively affect gut bacteria and increase inflammation​.

Use antibiotics wisely. While antibiotics are life-saving, overuse can wipe out beneficial gut bacteria, leading to long-term dysbiosis. When prescribed, consider probiotic supplementation to help restore microbial balance​.

Manage stress and get enough sleep. Chronic stress and poor sleep disrupt gut bacteria, increasing inflammation and promoting an imbalanced microbiome. Mindfulness practices, exercise, and maintaining a regular sleep schedule can benefit gut health​.

Stay active. Regular exercise is associated with a more diverse microbiome, benefiting digestion, metabolism, and immune function​.

Modulating the gut microbiome: strategies for optimal health

The gut microbiome is highly dynamic and can be modulated through various interventions to enhance health and prevent or manage disease. Diet is a primary factor influencing microbial composition, with fiber-rich foods serving as prebiotics—nutrients that promote the growth of beneficial bacteria. Probiotics, which are live microorganisms found in fermented foods or supplements, can help restore microbial balance, particularly after disruptions like antibiotic use. 

A newer approach involves postbiotics, which are bioactive compounds derived from probiotics, such as short-chain fatty acids (SCFAs) and antimicrobial peptides, that exert beneficial effects on gut health without the need for live microbes. Fecal microbiota transplantation (FMT), the transfer of stool from a healthy donor to a recipient, is an emerging therapy primarily used to treat recurrent Clostridioides difficile infections, but research is exploring its potential in conditions like IBD, obesity, and metabolic disorders.

Another frontier in microbiome modulation is live biotherapeutic products (LBPs), which are pharmaceutical-grade microbial formulations designed to target specific diseases by restoring microbial diversity or enhancing beneficial functions. 

Together, these strategies represent a growing arsenal of tools to harness the power of the gut microbiome for better health​.

Nurturing your gut microbiome for lifelong health

The gut microbiome is a dynamic and complex ecosystem that influences nearly every aspect of our health. By making informed lifestyle and dietary choices, we can support a balanced microbiome, reducing the risk of chronic diseases and promoting overall well-being.

Science continues to uncover new insights into how the gut microbiome affects our metabolism, immunity, mental health, and longevity. As research progresses, microbiome-targeted therapies, including probiotics, prebiotics, and personalized nutrition, will play a growing role in healthcare.

Taking care of your gut microbiome is not just about digestion—it is a foundation for whole-body health​.

The basics of fecal microbiota transplantation

FMT, also known as stool transplant, is the introduction of microbiota from a healthy donor’s stool into the gastrointestinal system of a patient. The process involves obtaining fecal matter from a carefully screened donor, mixing it with a sterile solution, and then administering it into the patient’s colon, typically through colonoscopy or enema. In some cases, the transplant can be delivered via capsules or through upper gastrointestinal routes such as nasogastric tubes. This procedure is especially useful in cases where the gut microbiota has been significantly disturbed, often due to factors like antibiotic use or disease, leading to an overgrowth of pathogenic bacteria like Clostridioides difficile.

History of fecal microbiota transplantation

The use of fecal matter as a treatment dates back to the fourth century in China, where it was used for gastrointestinal issues like diarrhea. However, it wasn’t until the 20th century that its scientific application began. In 1958, Dr. Ben Eiseman performed one of the first recorded instances of FMT to treat pseudomembranous colitis caused by Clostridium difficile (now Clostridioides difficile), observing dramatic improvements in patients. Interest in FMT waned until the early 2000s when an epidemic of C. difficile infection (CDI) renewed attention in this therapy, leading to significant advancements in its clinical application.

How Fecal Microbiota Transplantation works

Fecal Microbiota Transplantation (FMT) works by transferring a healthy and diverse community of gut bacteria from a donor into a recipient’s gastrointestinal system, with the goal of restoring the microbiome’s balance. T

he procedure typically begins by collecting stool from a carefully screened donor, who must meet specific health criteria to ensure the safety of the transplant. The stool is then processed—usually by mixing it with a saline solution—and administered to the recipient.

FMT can be delivered through several methods, including colonoscopy, enema, nasogastric tube, or more recently, oral capsules.

The transplant works by replenishing beneficial bacteria that may have been depleted due to factors like antibiotics, disease, or poor diet. This restoration of microbial diversity helps restore gut homeostasis, competing with harmful bacteria for resources, and supporting the immune system.

Moreover, the new bacteria can produce essential metabolites, such as short-chain fatty acids (SCFAs), which strengthen the gut lining and reduce inflammation. By re-establishing a healthy microbial environment, FMT can help improve digestive function, restore immune responses, and alleviate symptoms of diseases linked to microbiome imbalances​

Indications and potential indication for FMT

Clostridioides difficile infection

CDI is the most well-established indication for FMT. It occurs when the normal gut flora is disrupted by antibiotic use, allowing C. difficile to overgrow and produce toxins that damage the colon, causing symptoms like diarrhea, fever, and abdominal pain. In recurrent cases, standard treatments, including antibiotics, are often ineffective, and FMT has become the go-to therapy. Numerous studies have shown that FMT can cure recurrent CDI in up to 90% of patients by restoring microbial diversity and suppressing C. difficile growth​.

Inflammatory Bowel Disease (IBD)

Research into the use of FMT for IBD, which includes conditions like ulcerative colitis (UC) and Crohn’s disease (CD), has shown promising results. Studies have demonstrated that FMT can induce remission in patients with moderate to severe UC, although the results are more variable for CD. The key mechanisms believed to contribute to FMT’s success in IBD are the restoration of microbial diversity and the modulation of immune responses. However, the optimal treatment protocols are still under investigation, with some studies suggesting the need for pre-treatment with antibiotics to maximize engraftment of donor bacteria​.

Irritable Bowel Syndrome (IBS)

The link between gut microbiota and IBS has led researchers to investigate the potential of FMT in treating this condition, which is characterized by symptoms like abdominal pain, bloating, and changes in bowel habits. While early studies were inconclusive, more recent research suggests that a subset of IBS patients may benefit from FMT, particularly those with altered gut microbiota. However, results remain inconsistent, and further studies are required to clarify the role of FMT in IBS treatment​.

Metabolic syndrome

Metabolic syndrome, which includes conditions like obesity, insulin resistance, and high blood pressure, is associated with dysbiosis, or microbial imbalance. Preliminary studies have indicated that FMT could potentially improve insulin sensitivity and lipid profiles in patients with metabolic syndrome. However, more data is needed to confirm these benefits, as many studies have shown mixed results.​

Fecal microbiota transplantation in oncology

In oncology, Fecal Microbiota Transplantation (FMT) is emerging as a promising adjunctive therapy, particularly in the context of cancer immunotherapy. Recent studies have highlighted the critical role of the gut microbiome in modulating the response to immune checkpoint inhibitors (ICIs), which are widely used in the treatment of cancers like melanoma, lung cancer, and colorectal cancer.

The gut microbiota can influence the efficacy of ICIs by shaping the immune response and regulating tumor immunity. Research suggests that certain microbial populations can enhance the effectiveness of ICIs by promoting an anti-tumor immune response. Conversely, a disrupted microbiome may contribute to immune-related adverse events, such as colitis.

FMT has shown potential in alleviating these adverse effects and improving the response to ICIs by restoring a healthy microbiome. Small clinical trials have demonstrated that FMT from healthy donors can enrich the gut microbiota with beneficial bacteria, potentially boosting immune responses against cancer and enhancing the efficacy of immunotherapies.

However, further studies are needed to refine the protocols for FMT in oncology, particularly regarding donor selection, treatment timing, and long-term outcomes​

Mechanisms of action

FMT works through several proposed mechanisms to restore gut health.

Restoration of microbial diversity. One of the most significant outcomes of FMT is the re-establishment of a healthy, diverse microbiome. This is especially important in conditions like CDI, where the gut microbiota has been heavily disrupted. A healthy, diverse microbiota helps protect against the overgrowth of pathogenic organisms like C. difficile.

Engraftment of beneficial bacteria. The transplant introduces beneficial bacteria from the donor’s stool, which can outcompete harmful bacteria for nutrients and colonization sites, promoting a healthier gut environment. For instance, Bifidobacterium and Lactobacillus species have been shown to play crucial roles in gut health​.

Immune modulation. The gut microbiota plays a significant role in modulating the immune system. FMT has been shown to enhance the production of anti-inflammatory cytokines and promote the development of regulatory T-cells (Tregs), which help suppress excessive immune responses and inflammation. This is particularly relevant in conditions like IBD​.

Bile acid and Short-Chain Fatty Acid production. The bacteria introduced through FMT can restore the production of beneficial metabolites, such as short-chain fatty acids (SCFAs), which are vital for maintaining gut barrier integrity and regulating inflammation. SCFAs like butyrate are known to strengthen tight junctions in the gut lining, thus improving the gut barrier function​.

Virome modulation. The virome, which consists of viruses in the gut, is also influenced by FMT. Donor-derived bacteriophages can outcompete harmful viruses, contributing to the overall health of the microbiome. This aspect of FMT therapy is still under research but holds promise for further enhancing treatment outcomes​.

Challenges and future directions

Despite its potential, FMT faces several challenges that need to be addressed:

• Donor selection and screening: one of the critical aspects of FMT is selecting a healthy donor. Rigorous screening is required to ensure that the donor’s stool does not carry pathogens that could harm the recipient. Screening protocols vary, but they typically involve tests for infectious diseases like HIV, hepatitis, and gastrointestinal pathogens​.
• Standardization of the procedure: the lack of standardization in FMT procedures, including stool collection, processing, and administration methods, remains a challenge. Differences in donor microbiota composition, preparation methods, and delivery routes can lead to variability in treatment outcomes. Research is needed to establish standardized protocols that ensure consistent results across different settings​.
• Regulatory issues: in many countries, FMT is still considered an investigational therapy, and there are no FDA-approved FMT products. This poses regulatory hurdles for widespread clinical use and commercialization. However, the approval of microbiome-based therapeutics is on the horizon, with several biopharmaceutical companies developing microbiome restoration products​.
• Long-term effects and safety: while FMT has shown to be effective for recurrent CDI and other conditions, long-term studies are needed to assess the safety of FMT over extended periods. Potential risks include the transmission of undiagnosed pathogens, changes in microbial composition that may lead to adverse effects, and the long-term impact of altering the gut microbiome​.

Conclusion

FMT is a promising therapeutic modality with demonstrated efficacy in the treatment of recurrent C. difficile infections and potential applications in other conditions like IBD, IBS, and metabolic syndrome.

While challenges related to standardization, donor screening, and regulatory approval remain, ongoing research into the mechanisms of action and long-term safety of FMT will likely unlock its full therapeutic potential.

As microbiome science advances, FMT may become a cornerstone of treatments for a wide range of diseases associated with gut dysbiosis.

The findings, published in the European Heart Journal, suggest a new mechanism that could favor heart attacks. They also open up therapeutic avenues to treat this condition, the researchers say.

Most heart attacks result from the formation of a blood clot that obstructs one or more coronary arteries. Low levels of microbial molecules called endotoxins have been found in the blood of people whose coronary arteries are obstructed by blood clots, but the role of endotoxins in the formation of blood clots is still unclear.

To address this question, Francesco Violi at Umberto I University Hospital in Rome and his colleagues analyzed blood samples from 150 people, including 50 individuals affected by heart attack. From these individuals, the researchers also obtained samples of coronary blood clots.

Clotting activation

The analysis showed that endotoxins derived from Escherichia coli, a bacterium commonly found in the gut, circulate in the blood of people with heart attack. That’s likely because the intestine of these individuals is more permeable that the gut of healthy people, the researchers found.

The increased gut permeability observed in people with heart attacks could allow endotoxins as well as gut bacteria to enter the blood circulation. Indeed, the researchers found that 34% of samples from people with a heart attack contained E. coli DNA, compared to 4% of samples from healthy people.

The presence of low levels of endotoxins in the blood appears to trigger the formation of coronary blood clots through several mechanisms, the researchers found. These include the activation, adhesion, and aggregation of small cell fragments known as platelets, which help to turn blood from a liquid into a gel.

Therapeutic approach

To trigger the formation of blood clots, E. coli appears to bind to a specific cell-surface receptor called TLR4. The team also identified a molecule that inhibits the TLR4 receptor, hindering the formation of blood clots.

Mice injected with E. coli or treated with endotoxins developed more blood clots than untreated mice. But the detrimental effect of endotoxins disappeared when mice were given the TLR4 inhibitor.

The results could help to develop new therapeutic strategies that rely on TLR4 inhibition to counteract the formation of coronary clots in people with cardiovascular disease, the researchers say.

The findings, published in Science, could help to explain why immunotherapy, a type of cancer therapy that unleashes a person’s immune system against tumor cells, works in some cases but not in others.

“Recent studies have provided strong evidence that gut microbiota can positively affect anti-tumor immunity and improve the effectiveness of immunotherapy in treating certain cancers—yet, how the bacteria were able to do this remained elusive,” says study lead author Kathy McCoy at the University of Calgary. “We’ve been able to build on that work by showing how certain bacteria enhance the ability of T cells, the body’s immunity soldiers that attack and destroy cancerous cells.”

To find out which microbes can boost the activity of immunotherapy drugs, the researchers grew tumors from mice treated with immunotherapy and from mice that received no treatment.

Tumor bacteria

From the lab-grown tumors, the team was able to identify 21 bacterial species, seven of which were present only in immunotherapy-treated tumors.

Next, the researchers introduced the bacterial species present only in immunotherapy-treated tumors into mouse models for several types of cancer, including colorectal cancer, bladder cancer, and skin cancer. Three bacterial species—Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella—boosted the efficacy of immunotherapy drugs.

The team found that B. pseudolongum modulated the mice’s response to immunotherapy by producing a metabolite called inosine, which is known to modulate immune responses. Akkermansia muciniphila, a microbe that is known to enhance the efficacy of some immunotherapy treatments in lung and kidney cancers, was also found in immunotherapy-treated tumors and was able to produce inosine.

Attacking tumors

In mice with colorectal cancer, the combination of inosine and immunotherapy activated the anticancer response of T cells, leading to a reduction in size of the tumors. Similar results were obtained in mice with skin cancer and bladder cancer. “Inosine interacts directly with T cells and together with immunotherapy, it improves the effectiveness of that treatment, in some cases destroying all the colorectal cancer cells,” says study first author Lukas Mager.

Although it’s still unknown whether the findings apply to people, the beneficial bacteria associated with improved response to immunotherapy in mice have also been found in human cancer. This suggests that inosine could be exploited to develop microbial-based adjuvant treatments for immunotherapy, the researchers say.

“Identifying how microbes improve immunotherapy is crucial to designing therapies with anti-cancer properties,” says McCoy. “We are in the early stage of fully understanding how we can use this new knowledge to improve efficacy and safety of anti-cancer therapy and improve cancer patient survival and well-being,” she says.

The genus Lactobacillus, a group of Gram-positive bacteria, includes more than 200 species found in diverse ecosystems, including the human body and fermented dairy products.

Some lactobacilli species, including Lactobacillus rhamnosus, are potential probiotics as they can maintain gut homeostasis and relieve dysbiosis-related diseases.

Lactobacillus rhamnosus CRL 1505  was isolated from goat milk and its genome has been published by M.P. Taranto and colleagues in 2013.¹

CRL 1505 is one of the most studied and characterized probiotic strains as it can provide numerous beneficial effects, as seen in preclinical models and in humans with special regard to respiratory and intestinal infections.

Lactobacillus rhamnosus benefits to the immune system

Since one decade ago the benefits of L. rhamnosus administration have been studied in mouse models. Lactobacillus rhamnosus CRL 1505 was able to induce the immune response against the infection by an intestinal pathogen (Salmonella typhimurium) and a respiratory pathogen (Streptococcus pneumoniae).¹ Importantly, CRL 1505 significantly decreased the number of S. pneumoniae in the lung, prevented its dissemination into the blood, and induced a significant increase of anti-inflammatory mediators.²

Mice fed with a protein-free diet for 21 days as a model of immunosuppression and malnourishment, displayed normalization of leukocytes, neutrophils, and lymphocytes in blood after receiving  fermented goat milk containing L. rhamnosus CRL 1505. In this work, CRL 1505 was selected at the optimal dose able to improve protection against S. pneumoniae and S. typhimurium, showing that CRL1505 can bring benefits to the mucosal immune system and improve defenses against respiratory and intestinal infections.³

Salva S. and colleagues further investigated on the effect of probiotics on the recovery of immune system after a malnutrition state. They reported that impaired B cell development in the bone marrow, induced by protein malnutrition in mice, was reverted by supplement repletion diet with fermented goat milk containing Lactobacillus rhamnosus CRL 1505. These results added additional information on the ability of CRL 1505 to recover lymphopoiesis in immunocompromised-malnourished hosts4. However, the researchers pointed out that the effects of the repletion diet could depend not only on L. rhamnosus, but also on non-bacterial components such as bioactive peptides present in goat milk.⁴

L. rhamnosus and viral respiratory infections

An experimental mouse model of lung inflammation based on the nasal administration of a synthetic molecular pattern associated with viral infections poly(I:C), demonstrates that L. rhamnosus CRL 1505 could serve as a valuable prophylactic agent to control respiratory viral infection4. In particular, the preventive administration of CRL 1505 reduced lung injuries and regulated the production of antiviral cytokines. Moreover, L. rhamnosus CRL1505 induced the mobilization of dendritic cells to the lungs of mice challenged with the viral infection.⁵

Another study using the same animal model revealed that L. rhamnosus can modulate the production of proinflammatory and anti-inflammatory cytokines and reduce coagulation activation, downregulating the expression of tissue factor (TF) and thrombomodulin in the lung.⁶ These results also point out a crucial role for IL-10 in the immune protection mediated by L. rhamnosus CRL 1505 during respiratory viral infections and report how CRL 1505 can influence the lung immune-coagulative reaction triggered by Toll-like receptor 3 (TLR3) activation induced by intranasal administration of poly(I:C).

Moreover, in this work mice were orally treated with Lactobacillus rhamnosus CRL 1505, intraperitoneally injected with anti-IL-10 receptor (IL-10R) antibodies, and then challenged with respiratory syncytial virus (RSV) or influenza virus (IFV). The researchers showed that blocking IL-10R impaired the ability of CRL 1505 treatment to reduce activation of coagulation in mice infected with IFV or RSV, describing a crucial role for IL-10 in the immune protection mediated by CRL 1505.

In a review from 2014, the role of TLR3-mediated inflammatory damage in the lungs and the interplay with CRL 1505 have been discussed.⁷ Given that TLR3 is known to have a complex role in viral infections and in modulating the immune response to pathogens, the researchers pointed out their findings on how IL-10 was increased in L. rhamnosus CRL 1505-treated mice. They propose that IL-10 would be valuable for attenuating TLR3-mediated inflammatory damage in the lungs, therefore CRL1505 treatment could be used to beneficially modulate the balance between pro- and anti-inflammatory cytokines, allowing a reduction of lung tissue damage through effective regulation of the inflammatory response.

It has been shown that L. rhamnosus CRL 1505 significantly reduces lung viral loads and tissue injuries in mice after a challenge with respiratory syncytial virus (RSV), a pneumovirus in the family of the Paramyxoviridae that infects nearly all children within the first 3 years of life and can cause bronchiolitis and viral pneumonia. Moreover, CRL 1505 stimulated the secretion of anti-inflammatory cytokines (IFN-γ and IL-10) and the activation of dendritic cells (CD103+ CD11b^high) bringing protective effects against the damaging immune reactions associated with RSV infection.⁸

A study by Tomosada and colleagues further demonstrated that L. rhamnosus CRL 1505 can beneficially modulate the activation of the immune response triggered by RSV. Moreover, this work shows that heat-killed L. rhamnosus CRL 1505 was, as well as the viable bacteria, able to modulate the respiratory defenses against RSV.⁹

The benefits of L. rhamnosus have been also studied in a swine in vitro model, because of the similarities between the swine and human immune system.¹⁰ Villena and colleagues used porcine Peyer’s Patches (PPs), lymphoid follicles similar to lymph nodes located in the intestinal mucosa, to investigate how to prevent viral diarrhea episodes. They showed that two different strains of L. rhamnosus (including CRL 1505) are capable to induce antiviral defense responses in intestinal epithelial cells, modulating innate immunity and inducing antiviral IFNs, IFN-γ and anti-inflammatory IL-109, when stimulated with poly(I:C).

L. rhamnosus and aging

Investigations on the beneficial effects of Lactobacillus rhamnosus CRL 1505 have not been limited to infectious disease. The benefits of CRL 1505 administration have been also investigated in aged mice, subjected to natural immunological alterations occurring during aging.

In this work, CRL 1505 was able to improve peritoneal macrophages phagocytic activity, and the number of intestinal IgA⁺ cells, reaching values of those parameters similar to young adult mice. The immune modulation of aging-induced by CRL 1505 could be useful to tailor specific food supplements for the elderly population.¹¹

Beneficial effects of L. rhamnosus in humans

The effects of L. rhamnosus CRL 1505 in humans have been investigated in a randomized-controlled double-blind clinical trial involving 298 healthy children from 2 to 5 years old. Researchers have designed a Yogurt containing CRL 1505 that was administered to children for 6 months, for five times a week. The control group received a yogurt without probiotics. In this study, the researchers found that:

The yogurt containing L. rhamnosus CRL 1505 displayed the ability to stimulate the mucosal immune response, associated with increased levels of mucosal IgA antibodies ¹², and it was able to prevent and reduce respiratory infections, pharyngitis, tonsillitis and intestinal infections.¹³

In particular, the administration of CRL 1505 to young children reduced the incidence of infections: 66% of children in the placebo group presented symptoms of infection, while only 34% of cases were detected in the CRL 1505 group.

Also, there were significant differences in the incidence of intestinal infections, upper respiratory tract infections, and angina between placebo and CRL 1505 children group.

Moreover, children who received CRL 1505 experienced fewer fever and acute diarrhea episodes, and needed fewer antibiotics than those receiving the placebo.

Conclusions

Numerous in vivo and in vitro studies support the beneficial role of Lactobacillus rhamnosus CRL 1505 in counteracting and modulating inflammation mediated by common pathogens. CRL 1505 can modulate the immune system in immunocompromised mice, activating mucosal immunity and stimulating the secretion of anti-inflammatory cytokines. Benefits of L. rhamnosus were further confirmed in a swine in vitro model and in aged mice, broadening its usage to age-related immune dysfunctions.

Studies on humans describe and confirm a protective role of CRL 1505 in human infectious disease. As recent findings suggest that 21% of global deaths in children younger than 5 years of age are attributable to malnutrition and infectious diseases ^6,13, probiotics usage may help to prevent and to reduce the burden of common childhood morbidities12. Lactobacillus rhamnosus strain CRL 1505 has been included in the official Nutritional Programs in Argentina.

«Although trials testing CRL1505 on human adults have not been carried out yet, its mechanism of action has been well described. It is plausible to assume that anti-inflammatory properties and beneficial effects of CRL 1505 to the immune system, observed in children, could benefit humans at all ages» said Marco Caspani, CEO of Centro Sperimentale del Latte srl.

This project was made possible thanks to an unconditional grant of CSL Centro Sperimentale del Latte – A company of Sacco System.

References

1. Taranto MP, Villena J, Salva S, et al. Draft genome sequence of Lactobacillus rhamnosus CRL1505, an immunobiotic strain used in social food programs in Argentina. Genome Announc. 2013;1(4). doi:10.1128/genomeA.00627-13
2. Salva S, Villena J, Alvarez S. Immunomodulatory activity of Lactobacillus rhamnosus strains isolated from goat milk: Impact on intestinal and respiratory infections. Int J Food Microbiol. 2010;141(1-2):82-89. doi:10.1016/j.ijfoodmicro.2010.03.013
3. Salva S, Nuñez M, Villena J, Ramón A, Font G, Alvarez S. Development of a fermented goats’ milk containing Lactobacillus rhamnosus: In vivo study of health benefits. J Sci Food Agric. 2011;91(13):2355-2362. doi:10.1002/jsfa.4467
4. Salva S, Merino MC, Agüero G, Gruppi A, Alvarez S. Dietary Supplementation with Probiotics Improves Hematopoiesis in Malnourished Mice. Ansari AA, ed. PLoS One. 2012;7(2):e31171. doi:10.1371/journal.pone.0031171
5. Villena J, Chiba E, Tomosada Y, et al. Orally administered Lactobacillus rhamnosus modulates the respiratory immune response triggered by the viral pathogen-associated molecular pattern poly(I:C). BMC Immunol. 2012;13. doi:10.1186/1471-2172-13-53
6. Zelaya H, Tsukida K, Chiba E, et al. Immunobiotic lactobacilli reduce viral-associated pulmonary damage through the modulation of inflammation-coagulation interactions. Int Immunopharmacol. 2014;19(1):161-173. doi:10.1016/j.intimp.2013.12.020
7. Kitazawa H, Villena J. Modulation of respiratory TLR3-anti-viral response by probiotic microorganisms: Lessons learned from Lactobacillus rhamnosus CRL1505. Front Immunol. 2014;5(MAY). doi:10.3389/fimmu.2014.00201
8. Chiba E, Tomosada Y, Vizoso-Pinto MG, et al. Immunobiotic Lactobacillus rhamnosus improves resistance of infant mice against respiratory syncytial virus infection. Int Immunopharmacol. 2013;17(2):373-382. doi:10.1016/j.intimp.2013.06.024
9. Tomosada Y, Chiba E, Zelaya H, et al. Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection. BMC Immunol. 2013;14(1). doi:10.1186/1471-2172-14-40
10. Villena J, Chiba E, Vizoso-Pinto MG, et al. Immunobiotic Lactobacillus rhamnosus strains differentially modulate antiviral immune response in porcine intestinal epithelial and antigen presenting cells. BMC Microbiol. 2014;14(1). doi:10.1186/1471-2180-14-126
11. Molina V, Médici M, Villena J, Font G, Pía Taranto M. Dietary Supplementation with Probiotic Strain Improves Immune-Health in Aged Mice. Open J Immunol. 2016;06(03):73-78. doi:10.4236/oji.2016.63008
12. Villena J, Salva S, Núñez M, et al. Probiotics for everyone! The novel immunobiotic lactobacillus rhamnosus CRL1505 and the beginning of social probiotic programs in Argentina. International Journal of Biotechnology for Wellness Industries. doi:2012, 1, 189-198
13. Villena J, Salva S, Núñez M, et al. Beneficial lactobacilli for improving respiratory defenses: The case of lactobacillus rhamnosus CRL1505. chapter.
    
    

John Cryan at the University College Cork in Ireland and his colleagues reviewed current knowledge on the microbiota-gut-brain relationship, and how gut bacteria and circadian rhythms act together to influence health and disease. Their work is published in Cell Metabolism.

Gut clock

Many gut bacteria exhibit oscillatory behavior in response to the time of day and time of eating. For example, the bacterial load in mice peaks at 11 p.m. and reaches a trough at 7 a.m.; the peak is associated with a maximum in the Bacteriodetes population, whereas the trough corresponds with a maximum in the Firmicutes population. Bacteroidetes and Firmicutes represent more than 99% of the known gut microbiota.

Several studies have shown that germ-free and antibiotic-treated mice experience an alteration of their circadian clocks, and changes in the host’s circadian rhythm, including jet lag and shift work, can significantly affect microbial oscillations.

Both jet lag and shift work have been associated with an altered microbiota composition as well as with several metabolic, inflammatory, and stress-related diseases in people. Animals housed for 24 hours in either dark or light conditions lost all gut microbial diurnal rhythmicity when compared to mice housed under normal conditions, and they exhibited increased weight gain and glucose intolerance when fed a high-fat diet.

Microbiota-derived metabolites such as short-chain fatty acids (SCFAs) and bile acids can also alter circadian rhythms. Oral administration of SCFAs to antibiotic-treated mice changed the rhythms of two genes that play major role in the circadian clock. Microbiota-related bile acids can upregulate circadian rhythm genes in cells grown in a lab dish, and alter circadian clock gene expression in the mouse gut and liver.

Microbe-host interaction

The interplay between the host circadian clock and microbiota oscillations influences many physiological processes, including host metabolism, the regulation of the endocrine system, and immune system function.

The gut microbiota has been shown to regulate the expression of proteins that are linked to lipid absorption and obesity. And mice lacking a gene involved in the circadian clock had increased fat accumulation, increased glucose production, and increased blood levels of leptin—a hormone that helps to regulate energy balance by inhibiting hunger.

Hormones, which are secreted by the endocrine system, play a key role in circadian rhythmicity and influence the gut microbiota, which in turn affects the secretion of such hormones. Melatonin, for instance, is important for diurnal rhythms and can determine the circadian rhythms of some gut microbes. Hormones such as growth hormone, testosterone, and estradiol secretion are all altered in germ-free mice, and the levels of ghrelin, which controls appetite and thus the timing of food, are reduced in the presence of microbes such as Bifidobacterium and Lactobacillus, and increased in the presence of Bacteroides and Prevotella in rodents.

But the influence of the microbiota and circadian rhythms goes beyond the endocrine system. Gut microbes are involved in the development of several types of immune cells, and many immune molecules shown diurnal rhythmicity. Germ-free mice’s T cells, B cells, and neutrophils are less efficient than those of mice raised in normal conditions. What’s more, the immune system is less effective in response to infection in mice that lack microbes altogether.

Metabolic effects

Several studies suggest that metabolic disorders can arise from the interaction between diet and other environmental factors, including circadian rhythm disruption and changes in the composition of the gut microbiota. For example, gut microbes of people with cardiovascular disease, diabetes, and obesity are more likely to cause inflammation than the bacteria present in the microbiota of healthy individuals.

The lack of gut bacteria protects mice from the negative effects of a high-fat diet, and disrupting the circadian clock of rodents leads to metabolic conditions such as obesity and diabetes. Similarly, rodents that lack key circadian genes have decreased glucose tolerance and insulin secretion. People with diabetes also show differences in gut microbiota composition and altered oscillations of circadian clock genes compared to healthy individuals.

Finally, individuals with atherosclerosis show increased inflammation and higher levels of Enterobacteriaceae and Streptococcus bacteria than healthy people. And mouse models of cardiovascular disease recovered faster when raised on a regular 24-hour light-dark cycle compared to those on a disrupted circadian rhythm.

Microbes, circadian clock, and the brain

Alterations of circadian rhythms due to shift work or jet lag have all been associated with an increased prevalence or severity of depression, and individuals with depression or bipolar disorder exhibit significant differences in their microbiota compared to healthy people. Mouse models of schizophrenia show an altered circadian cycle in which melatonin is released earlier than normal.

However, little is known about how the interplay between the microbiota-gut-brain axis and circadian rhythms influences brain disorders. “More preclinical and clinical work needs to be done to examine how both systems may engage with one another to modulate psychiatric disorders, positively and negatively,” the researchers conclude.

Elderly people with dementia or Alzheimer’s disease (AD) exhibit increased confusion and agitation as the sun sets, and they have lower melatonin levels than healthy individuals. Also, AD patients have increased levels of pro-inflammatory Escherichia/Shigella bacteria and reduced levels of anti-inflammatory E. rectale compared to healthy people of the same age. Finally, the gut microbiota of people with Parkinson’s disease and those with sleep behavior disorder are very similar.

The connection between AD, circadian rhythms, and the microbiota-gut-brain axis calls for more research in this area, the researchers say. The team also cautions that so far, studies have mostly examined the effect of either circadian rhythms or gut microbes independently, but not together.

“More work needs to be done to examine not only how both the microbiota-gut-brain axis and circadian rhythms influence disease, but also how they interplay with one another in the context of disease,” the researchers say.

For a long time, scientists have known that the microbes that populate our gut and mouth are key modulators of health and disease. Many studies focused on what kind of bacterial species affect disease risk, but little is understood about the genes that make up these different microbial species.

To address this question, Braden Tierney at Harvard Medical School and his colleagues analyzed the DNA of 3,655 human microbiome samples, of which more than 1,400 were obtained from people’s mouths and 2,100 from people’s guts.

Staggering diversity

The researchers found nearly 46 million bacterial genes—about 24 million in the mouth microbiome and 22 million in the gut microbiome. The team estimated that the total number of genes in the collective human microbiome could be around 232 million.

More than 50%—or 23 million—of the mouth and gut bacterial genes occurred only once and were specific to the individual. Of these unique genes, 11.8 million came from mouth samples and 12.6 million came from gut samples.

Unique genes

Whereas commonly shared genes appeared to be involved in basic functions such as metabolism and breakdown of proteins, unique genes tended to have more specialized functions, like gaining resistance against antibiotics and helping to build microbial cell walls.

This finding suggests that unique genes are important in the evolutionary life of microbes, acting as reservoirs of genetic diversity that the microbe can pull from to adapt, the researchers say.

Targeted therapies

The study produced a large database that could help study genetic variation across multiple body sites and samples. The findings show that the genetic diversity of the human microbiome is immense, the researchers say.

Although the factors that fuel such genetic diversity are unknown, the team hopes that building a catalog of the human microbiome genes could help to develop targeted therapies based on the unique microbial genetic make-up of a person rather than on bacterial species alone.

Many of these hormones and neurotransmitters are made in the gastrointestinal tract by the gut microbiota. Short-chain fatty acids (SCFAs), for example, are the main metabolites produced by bacterial fermentation of dietary fiber.

Previous studies have revealed that SCFAs play an important role in the communication loop between the gut and brain. But the mechanisms through which these bacterial metabolites influence our emotions and ability to think are unclear.

So Boushra Dalile at KU Leuven and her colleagues reviewed and summarized existing data on how SCFAs regulate the gut–brain crosstalk, including how they affect the immune, endocrine and neural systems. Their review is published in Nature Reviews Gastroenterology & Hepatology.

SCFAs in health

Acetate, propionate, and butyrate are the most abundant SCFAs in the human body. In the gut, these metabolites have many effects on gut health: for example, they maintain intestinal barrier integrity, influence the production of mucus in the gastrointestinal tract, and protect from gut inflammation.

In addition to exerting local effects in the gut, SCFAs interact with receptors expressed mainly in endocrine and immune cells, kidneys, nervous system and blood vessels.

Both propionate and butyrate increase the intestinal production of glucose and inhibit the activity of enzymes that are involved in a range of neuropsychiatric disorders including depression, schizophrenia, and Alzheimer’s disease.

What’s more, SCFAs can modulate neuroinflammation and affect the immune system by regulating the differentiation, recruitment, and activation of immune cells such as neutrophils, macrophages, and T cells.

Several studies have shown that SCFAs in the gut stimulate the release of gut hormones that affected responses to food pictures in participants with obesity. These bacterial metabolites also trigger the production of other metabolic hormones involved in brain function, including insulin, which maintains stable blood sugar levels, and leptin, which is known for its regulatory role in energy balance.

SCFAs in disease

SCFAs have been implicated in several neuropsychiatric disorders, from Parkinson’s disease to autism. People with Parkinson’s disease have a lower abundance of SCFA-​producing bacteria in their gut than healthy individuals, while children with autism have altered levels of SCFAs in their feces.

In a mouse model of Alzheimer’s disease, butyrate administration rescued memory function and increased the expression of genes involved in learning. In animal models of mania, butyrate reversed behavioral hyperactivity.

Many studies have suggested that SCFAs may play a role in a range of neurological conditions, and that intervention with prebiotics, probiotics, or a Mediterranean diet could increase SCFA production in the gut.

However, it is too early to conclude whether the effects of SCFAs are favorable or unfavorable. More work is needed to quantify the concentrations of SCFAs in probiotic, prebiotic and dietary intervention studies as well as to determine the extent to which SCFAs affect brain function, the scientists say.