What is engineered probiotics? Engineered probiotics are microorganisms with optimized metabolic processes, typically achieved using synthetic biology and omics technologies.
In recent years, genome sequencing has become more affordable and some of the tools for editing and modifying microbial genomes have become more powerful, enable us to engineer probiotics according to our own ideas.
By means of gene editing, probiotics can have a variety of beneficial properties, and can treat specific diseases, which is beneficial to human health. Engineered probiotics is a promising research which may become new methods to solve some problems.
Scientists have also developed engineered microorganisms that are relevant to industrial applications. Microbe bioengineering has the potential to improve the nutritional value and health benefits of food products. However, the application of engineered probiotics still faces a series of challenges.
Gut microbiota is closely related to the host’s health. Pathogenesis of Colorectal Cancer is often
accompanied by intestinal microbial dysbiosis. It has been demonstrated that increased abundances of some gut bacteria, including Fusobacterium nucleatum and Peptostreptococcus anaerobius, promotes colorectal carcinogenesis. Now a day, the prevention or treatment of Colorectal Cancer using probiotics has become a potential strategy. (Use of Engineered Probiotics for Colorectal Cancer Therapy)
Engineering Clinically Relevant Probiotics for Precision Colorectal Cancer Therapy
Probiotics have the potential as bio-therapeutic agents for cancer management in preclinical models
and human trials by secreting antineoplastic or immune-regulatory agents in the tumor microenvironment (TME).
However, current probiotics lack the ability to dynamically respond to unique tumor microenvironment characteristics, leading to limited therapeutic accuracy and efficacy. Although progress has been made in customizing controllable probiotics through synthetic biology, the engineering process is complex and the predictability of production is relatively low. Use of engineered probiotics shows promise in subcutaneous, orthotropic, and colitis-associated colorectal cancer tumors, offering a new methodology for modulating probiotic metabolism in a pathological environment.
The Beneficial Mechanisms of Biology and Biomedical Engineering
With great advancements in synthetic biology and biomedical engineering, the therapeutic benefits of wild-type bacteria have been enhanced via directional genetic modifications.
Genetically modified bacteria can be employed as live vectors to deliver various therapeutic payloads, including cytotoxic proteins, prodrug-converting enzymes, angiogenesis regulation proteins, RNA interference (RNAi) molecules, and immunoregulatory factors.
In addition, the targeting of genetically modified bacteria is further optimized for precise intervention at tumor lesion sites. One strategy involves enhancing the capacity of bacteria to bind to tumor cells.
Another strategy involves the precise control of therapeutic payload expression and release. Several Gram-negative bacteria continuously release vesicles called outer membrane vesicles (OMVs) to the outside.
Instead of delivering therapeutic proteins by constructing recombinant plasmids, another strategy is to reprogram bacteria via the design of metabolic pathways for synthesizing therapeutic molecules.
Engineered Bacteria via Therapeutic Protein Delivery
۱. Cytotoxic Proteins
Killing colorectal cancer cells via cytotoxins is a feasible method of CRC treatment. However,
because of a lack of selectivity for protein toxins, normal cells may be accidentally injured. Bacteria
can specifically colonize tumor sites, which provides an opportunity for toxic proteins to directly
contact tumor cells and exert their toxic effects.
A study described that engineered E. Coli K-12- expressing ClyA could significantly decrease tumor growth rates, and a combination of therapy and radiation was effective in suppressing tumor growth and metastasis in a CT26 mouse model.
Another approach involved using an engineered attenuated S. typhimurium ∆ppGpp strain as a
bacteria chassis to express ClyA. This strategy could significantly suppress both primary and
metastatic tumors and prolong survival in CT26 tumor-bearing mice.
۲. Prodrug-Converting Enzymes
The targeted delivery of prodrug-converting enzymes with engineered bacteria is a therapeutic
strategy for converting prodrugs into cytotoxic products at the tumor site.(Use of Engineered Probiotics for Colorectal Cancer Therapy)
It aims to yield effective concentrations of anticancer drugs in the tumor microenvironment (TME) along with minimized adverse effects on organisms. Cytosine deaminase, produced by bacteria and fungi, is a kind of representative prodrug-converting enzyme.
۳. RNA Interference (RNAi) Molecules
RNAi is an efficient gene-silencing mechanism, and the expression of various genes of interest can
be effectively suppressed via RNAi. This makes it a potential tumor gene therapy tool via the
silencing of particular genes associated with cancer induction.
۴. Angiogenesis Regulation Proteins
Based on targeting tumor blood vessels to treat CRC using engineered bacteria, both ant
angiogenesis and vascular destruction are widely researched vessel-targeting therapies.
۵. Immunoregulatory Factors
Immune cells can be induced by cytokines to clear tumors by modulating innate and adaptive
immune response.
Conclusions and Future Perspectives
The genetic instability of engineered bacteria arises from the potential loss and mutation of the
recombinant plasmid carried within the bacterial host over successive generations, particularly in
the absence of antibiotic pressure. The oral administration of bacteria without affecting efficacy may
be an optimal approach.
Provided by: Dr. Nazila Kassaian
References:
۱. Cao F, Jin L, Zhang C, Gao Y, Qian Z, Wen H, Yang S, Ye Z, Hong L, Yang H, Tong Z. Engineering
Clinically Relevant Probiotics with Switchable “Nano‐Promoter” and “Nano‐Effector” for
Precision Tumor Therapy. Advanced Materials. 2024 Feb;36(5):2304257.
۲. Han H, Zhang Y, Tang H, Zhou T, Khan A. A Review of the Use of Native and Engineered
Probiotics for Colorectal Cancer Therapy. International Journal of Molecular Sciences. 2024
Mar 31;25(7):3896.
Key words: Engineered bacteria, Engineered Probiotics, Colorectal Cancer Therapy, Tumor, Dr.
Peyman Adibi, Dr. Babak Tamizifar, Dr. Nazila Kassaian
The gut microbiota plays a pivotal role in thyroid disorders, including Hashimoto thyroiditis, Graves’ disease and thyroid cancer.
Recent data have suggested that microbes influence thyroid hormone levels through the regulation of iodine uptake, degradation, and enterohepatic cycling.
Studies have been shown that Lactobacillaceae and Bifidobacteriaceae are often reduced in hypothyroidism and hyperthyroidism.
In Graves’ disease patients, the composition of the gut microbiota differs from that of healthy individuals, with a significant decrease in the relative abundance of Faecalibacterium prausnitzii, Butyricimonas faecalis, Bifidobacterium adolescentis and Akkermansia muciniphila compared to the control.
Furthermore, a diagnostic model was developed using metagenome-assembled genomes of the gut microbiome, which may serve as a valuable predictor for Graves’ disease.
The gut microbiota has the capacity to produce various neurotransmitters, such as dopamine, which can regulate the hypothalamus-pituitary axis and inhibit thyroid-stimulating hormone (TSH).
The Effects of Probiotics and prebiotics on thyroid function
Numerous studies have been conducted to investigate the modulation of gut microbiota in order to restore dysbiosis in patients with thyroid disorders.
Probiotics and prebiotics have demonstrated beneficial effects on thyroid diseases.
Probiotics including bifidobacterium longum supplied with methimazole was implemented in nine patients with Graves’ disease for six months.
The results showed a significant reduction in clinical thyroid indexes, including free T3, free T4, and thyrotropin receptor antibody (TRAb), while TSH levels increased compared to baseline.
Another study explored the effects of a four-week treatment with a complex probiotics preparation consisting of Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis and Bacillus cereus in patients post-thyroid hormone withdrawal (THW) following thyroid cancer surgery.
The treatment led to a decreased occurrence of complications such as dyslipidemia and constipation. However, the serum levels of free T4, free T3 and TSH showed no change between groups.
Synbiotics, which are a mixture of probiotics and prebiotics, have also been examined.
They have shown potential in reducing TSH and increasing freeT3 in patients with hypothyroidism.
A strategy based on microbiome-directed therapies, involving supplementation with probiotics, prebiotics and synbiotics holds promise as a therapeutic approach for thyroid disorders.
Conclusion
There is a growing interest in investigating the potential role of probiotics or prebiotics supplementation to improve thyroid function in humans.
A recent meta-analysis indicates that supplementation with probiotics/prebiotics has no significant effect on thyroid hormone levels, while showing a modest decrease in TRAb levels. However, the results have been inconsistent, and the probiotics or prebiotics are various in each randomized clinical trial, leading a mixed effect.
References:
Shu Q, Kang C, Li J, Hou Z, Xiong M, Wang X, and Peng H. Effect of probiotics or prebiotics on thyroid function: A meta-analysis of eight randomized controlled trials. Plos one. 2024 Jan 11; 19(1):e0296733.
Lin B, Zhao F, Liu Y, Wu X, Feng J, Jin X, et al. Randomized Clinical Trial: Probiotics Alleviated Oral-Gut Microbiota Dysbiosis and Thyroid Hormone Withdrawal-Related Complications in Thyroid Cancer Patients Before Radioiodine Therapy Following Thyroidectomy. Frontiers in endocrinology. 2022; 13:834674.
Talebi S, Karimifar M, Heidari Z, Mohammadi H, Askari G. The effects of synbiotic supplementation on thyroid function and inflammation in hypothyroid patients: A randomized, doubleblind, placebocontrolled trial. Complement Ther Med. 2020; 48:102234.
The gut-liver axis is a bidirectional connection through the biliary tract, portal vein, and systemic circulation. This unique interaction between the liver and the gastrointestinal tract allows the transport of nutrients from the intestines directly to the liver, whereas the liver provides feedback via bile secretion into the digestive tract. NAFLD is associated with changes in the composition and function of the gut microbiota, known dysbiosis.
GUT MICROBIOTA TARGETTING: NAFLD THERAPY STRATEGY
The most recommended therapy for NAFLD patients is still limited to lifestyle changes that include exercise, diet, and weight loss to prevent worsening risk factors such as obesity and diabetes.
Pharmacological therapy to improve insulin resistance, reduce oxidative stress and inflammation, or slow the mechanism of fibrosis has been widely used in NAFLD patients but has not been fully demonstrated.
Altering the gut microbiota is widely cited as having a potential role in treating NAFLD. Several approaches to changing the gut microbiota have been investigated in NAFLD patients, including antibiotics, probiotics, prebiotics, synbiotics, and fecal transplantation.
CONCLUSION
Pathogenicity is a complex mechanism involving many factors. Recent evidence reveals that the gut microbiota is one of the main factors in the pathogenesis and progression of NAFLD through several mechanisms, particularly dysbiosis. This significant role makes the gut microbiota a noninvasive biomarker for NAFLD examination and a more effective therapeutic target. However, further research is needed to evaluate the effectiveness of the gut microbiota as a biomarker or therapy.
Maimunah U, Soelistijo SA, Hadisuwarno W, Miftahussurur M. Gut Microbiota and Non-Alcoholic Fatty Liver Disease: Current Pathogenic Paradigm and Therapeutic Aspect. The Indonesian Journal of Gastroenterology, Hepatology, and Digestive Endoscopy. 2023 Nov 24; 24(2):154-62.
Ebrahimzadeh Leylabadlo H, Ghotaslou R, Samadi Kafil H, Feizabadi MM, Moaddab SY, Farajnia S, et al. Nonalcoholic fatty liver diseases: from role of gut microbiota to microbial-based therapies. Eur J Clin Microbiol Infect Dis. 2020;39:613–۲۷
The use of antibiotics to fight microbial infections is a cornerstone of modern medicine. However, antibiotics can also disrupt the delicate balance of our gut microbiome, leading to side effects like antibiotic-associated diarrhea (AAD) and potentially contributing to antibiotic resistance. This is where probiotics come in, raising the question: can co-prescribing antibiotics with probiotics be an efficient strategy?
The Potential Benefits:
Reduced AAD: Studies suggest probiotics can help prevent AAD, a common side effect affecting up to 30% of antibiotic users. They may achieve this by:
Competing with harmful bacteria: Probiotics occupy space and resources, hindering the growth of pathogens.
Boosting immune function: Probiotics can stimulate the immune system to fight off infections more effectively.
Restoring gut barrier function: Probiotics may help maintain the integrity of the gut lining, reducing inflammation and preventing the invasion of harmful bacteria.
Improved treatment outcomes: Some studies suggest co-prescribing probiotics might enhance the effectiveness of antibiotics against certain infections. This may be due to their ability to modulate the gut microbiome, creating an environment less favorable for pathogens.
Reduced risk of antibiotic resistance: By promoting a healthy gut microbiome, probiotics may indirectly reduce the selection pressure for antibiotic-resistant bacteria.
However, the picture is not entirely clear:
Limited evidence: While promising, the research on coprescribing antibiotics with probiotics is still evolving. More high-quality studies are needed to confirm the benefits and identify the most effective probiotic strains for specific infections.
Strain specificity: Different probiotic strains have varying effects. Choosing the right strain for the specific infection and individual patient is crucial for optimal results.
Timing and dosage: The timing and dosage of both antibiotics and probiotics are critical for their effectiveness. Further research is needed to determine the optimal regimen.
Safety concerns: While generally safe, there are potential risks associated with probiotics, especially in immunocompromised individuals. Consulting a healthcare professional before using probiotics is essential.
Conclusion
Overall, co-prescribing antibiotics with probiotics holds promise for managing microbial infections while minimizing side effects. However, more research is needed to optimize this approach and ensure its safety and efficacy for various infections and patient populations. Always consult your doctor before starting any new treatment, including probiotics.
Dysbiosis in IBD Patients: A Deep Dive for Experts
Dysbiosis, a disruption in the delicate balance of gut microbiota, is increasingly recognized as a key player in the pathogenesis and progression of inflammatory bowel disease (IBD).
Understanding its complexities and potential therapeutic interventions requires an in-depth exploration beyond basic explanations.
Pathogenic Role of Dysbiosis in IBD:
Compositional Shifts: IBD patients exhibit decreased diversity and altered composition compared to healthy individuals. Key changes include:
Reduced: Firmicutes, Bacteroidetes, butyrate-producing bacteria
Increased: Proteobacteria (including adherent-invasive Escherichia coli, or AIEC, pro-inflammatory bacteria
Functional Alterations: Dysbiosis disrupts essential functions like:
Barrier integrity: Reduced production of short-chain fatty acids (SCFAs) weakens intestinal barrier, increasing permeability and inflammation.
Immune regulation: Altered microbiota-immune interactions trigger Th1/Th17 pro-inflammatory responses.
Nutrient metabolism: Dysbiosis can impair nutrient absorption and exacerbate malnutrition in IBD patients.
Factors Contributing to Dysbiosis in IBD:
Genetic Susceptibility: Mutations in genes like NOD2 can predispose individuals to dysbiosis and IBD.
Environmental Factors: Diet, smoking, antibiotic use, and stress can all impact gut microbiota composition.
Disease Activity: Active inflammation further disrupts the gut microbiome, creating a vicious cycle.
Correcting Dysbiosis in IBD: Therapeutic Approaches:
Dietary Interventions:
Prebiotics: Promote growth of beneficial bacteria (e.g., Bifidobacteria, Lactobacilli)
Probiotics: Introduce live bacterial strains with potential health benefits
Fecal microbiota transplantation (FMT): Transfer of healthy donor stool microbiome
Targeted Therapies:
Antibiotics: Eliminate specific pathogenic bacteria (e.g., AIEC)
Anti-inflammatory agents: Reduce inflammation and promote microbiota recovery
Phage therapy: Viruses targeting specific pathogenic bacteria
Emerging Strategies:
Metabolomics: Tailoring interventions based on individual metabolic profiles
Microbiome engineering: Developing personalized probiotic formulations
Challenges and Future Directions:
Individual Variability: Microbial composition and responses to interventions vary significantly between patients.
Long-Term Efficacy: Maintaining microbiota balance and achieving sustained clinical improvement requires long-term strategies.
Safety and Regulatory Considerations: Novel therapies like FMT and phage therapy require careful evaluation and regulatory frameworks.
Expert Insights and Considerations:
Multimodal Approach: Combining dietary, pharmacological, and potentially personalized interventions is crucial for optimal outcomes.
Monitoring and Adjustment: Regular monitoring of microbiota composition and disease activity is essential to tailor interventions over time.
Collaboration: Interdisciplinary collaboration between gastroenterologists, microbiologists, and dieticians is key for optimal management.
Conclusion:
Understanding the complex interplay between dysbiosis and IBD is crucial for developing effective therapeutic strategies. By staying abreast of the latest research, experts can provide their patients with personalized and evidence-based approaches to manage this challenging condition.
The gut microbiota plays a pivotal role in thyroid disorders, including Hashimoto thyroiditis, Graves’ disease and thyroid cancer. Recent data have suggested that microbes influence thyroid hormone levels through the regulation of iodine uptake, degradation, and enterohepatic cycling.
Studies have been shown that Lactobacillaceae and Bifidobacteriaceae are often reduced in hypothyroidism and hyperthyroidism. In Graves’ disease patients, the composition of the gut microbiota differs from that of healthy individuals, with a significant decrease in the relative abundance of Faecalibacterium prausnitzii, Butyricimonas faecalis, Bifidobacterium adolescentis and Akkermansia muciniphila compared to the control. Furthermore, a diagnostic model was developed using metagenome-assembled genomes of the gut microbiome, which may serve as a valuable predictor for Graves’ disease. The gut microbiota has the capacity to produce various neurotransmitters, such as dopamine, which can regulate the hypothalamus-pituitary axis and inhibit thyroid-stimulating hormone (TSH).
The Effects of Probiotics and prebiotics on thyroid function
Numerous studies have been conducted to investigate the modulation of gut microbiota in order to restore dysbiosis in patients with thyroid disorders. Probiotics and prebiotics have demonstrated beneficial effects on thyroid diseases. Probiotics including bifidobacterium longum supplied with methimazole was implemented in nine patients with Graves’ disease for six months. The results showed a significant reduction in clinical thyroid indexes, including free T3, free T4, and thyrotropin receptor antibody (TRAb), while TSH levels increased compared to baseline. Another study explored the effects of a four-week treatment with a complex probiotics preparation consisting of Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis and Bacillus cereus in patients post-thyroid hormone withdrawal (THW) following thyroid cancer surgery. The treatment led to a decreased occurrence of complications such as dyslipidemia and constipation. However, the serum levels of free T4, free T3 and TSH showed no change between groups. Synbiotics, which are a mixture of probiotics and prebiotics, have also been examined. They have shown potential in reducing TSH and increasing freeT3 in patients with hypothyroidism. A strategy based on microbiome-directed therapies, involving supplementation with probiotics, prebiotics and synbiotics holds promise as a therapeutic approach for thyroid disorders.
Conclusion
There is a growing interest in investigating the potential role of probiotics or prebiotics supplementation to improve thyroid function in humans. A recent meta-analysis indicates that supplementation with probiotics/prebiotics has no significant effect on thyroid hormone levels, while showing a modest decrease in TRAb levels. However, the results have been inconsistent, and the probiotics or prebiotics are various in each randomized clinical trial, leading a mixed effect.
The human intestinal flora is closely related to human health. Gut microbiota dysbiosis is involved in the occurrence and development of various diseases, including coronary heart disease, hypertension, diabetes, inflammatory bowel diseases, and a wide range of inflammatory, metabolic, and neurological disorders. Studies in the last decade have proved that gut microbiota dysbiosis plays a crucial part in host inflammation and the formation of atherosclerosis and hypertension.
Challenges and future perspectives
It is difficult to apply what is known about microbiome composition and function in therapeutic settings. The dynamic nature of the microbiome, particularly it changes throughout illness development and in response to numerous variables such as nutrition, lifestyle, and pharmaceutical therapies, must be understood in order to address this, which calls for longitudinal investigations. Deeper research projects employing cutting-edge approaches like next-generation sequencing, metatranscriptomics, metaproteomics, and metabolomics, as well as computational methodologies, are currently of the utmost importance.۴ We can now investigate the complex interactions of the Heart–Gut axis thanks to these instruments. We will be able to identify the processes by which the gut microbiota affects medication metabolism and response by merging functional analysis, simultaneous profiling of the gut microbiome, metabolomics, and other omics data. These multifaceted techniques have a great deal of promise for unravelling the complex mechanisms by which the gut microbiota interacts with the host, ultimately revealing insightful information for enhancing medication, therapy and enhancing patient outcomes.
Targeting gut microbiota as a therapeutic option
There is interest in employing microbiome-based therapeutics as a possible therapeutic option for CVDs given the potential impact of the gut microbiota on cardiovascular health. Probiotics, which are living bacteria that provide health advantages when taken in sufficient quantities, are one strategy. Numerous beneficial bacterial strains like bifidum, L. casei, L. Acidophilus, L. zisttakhmir, L. reuteri, L.fermentum, C. butyricum, B.breve,have been tested for the treatment of CVDs both in animal models and humans.
Prebiotics and CVDs study is still in its infancy, but there is mounting evidence that they may have beneficial effects on several risk factors for cardiovascular disease like-blood pressure, cholesterol management, chronic inflammation, oxidative stress, glucose metabolism, and weight management. However, further studies are required to evaluate the effectiveness of these probiotics and the best dosage.
Another method is fecal microbiota transplantation (FMT), which involves inserting healthy donor’s feces into the recipient’s gut. Although research is still being done to determine FMT’s potential therapeutic function in CVDs, it has historically been utilized largely to treat illnesses like Clostridium difficile Following FMT, preliminary research in animal models has demonstrated encouraging improvements in cardiovascular parameters and atherosclerotic reduction. The use of gut microbiota-based therapeutics for CVDs is still in its infancy, and more study is required to completely comprehend the intricate relationships between the gut and the heart and to assess the efficacy and safety of these strategies. Individual differences in gut microbial makeup and responsiveness to therapies may also provide challenges in developing personalized therapy modules and regimen.
Research has shown AST-120, an oral charcoal adsorbent to have beneficial effect in the treatment of CVDs. However, it is unclear how adsorbents may affect the gut microbiota’s composition and its associated metabolites in people with CVDs.
Reference
Majumder S, Kirtikumar RM, Shetty V, Mukherjee S, Narayan P. Cardiovascular diseases and the heart–gut cross talk. Indian Heart Journal. 2023 Dec 7.
The gut microbiome has been identified as a potential factor in weight regulation. Thirty-nine percent of the adults are overweight (25–۲۹.۹ kg/m2) and 13% are obese (BMI≥۳۰kg/m2) worldwide. Recently, it has been found that obesity may affect brain function and structure, as it is associated with impaired cognition and alterations in gray matter (GM) and white matter (WM). Moreover, a higher BMI and waist-to-hip ratio (WHR) have been associated with lower fractional anisotropy (FA) values. Moreover, it is proposed that obesity increases the risk of developing dementia later in life by 60–۹۰%, versus healthy weight individuals. A growing of evidence reveals that obesity is related with alterations in neuroendocrine production and secretion, including ghrelin, insulin, GLP-1 and PYY.
Bariatric surgery for obesity treatment
Bariatric surgery is an effective treatment for obesity leading to rapid and sustainable weight loss. Bariatric surgery decreases body weight not only due to physical effects such as reduced food intake and malabsorption but also due to the various neuroendocrine changes which affect energy homeostasis and hunger/satiety. Moreover, Bariatric surgery might improve the gut microbiota diversity and restore white adipose tissue function, which can improve obesity-related immunological and cognitive impairments. The gut-brain axis consists of a bidirectional communication system, connected through the vague nerve, spinal fibers and sympathetic and parasympathetic fibers which are directly innervating the gastrointestinal tract. These elements communicate through endocrine messengers, neuro-immune mediators and neuroactive metabolites.
Conclusion
To summarize, Bariatric surgery is a good procedure to treat obesity and its related pathologies, however long-term effects remain unsolved. Future research should focus on the long-term effects of Bariatric surgery, to be able to investigate the neuroendocrine, microbiota and white adipose tissue changes and to potentially determine the new “normal” after homeostatic adjustments. Various studies have focused on neuroendocrine alterations already after six months. Six months post-surgery patients lose weight rapidly and generally still follow their post-operative diet. Therefore, the observed effects 6 months post-surgery might differ at longer follow-ups, when patients achieve a stable weight, or regain weight.
The mutual relationships and metabolic activities among microorganisms have a significant impact on modulate hormone levels, especially estrogens in women. The gut microbiota mainly controls estrogen levels through the secretion of β-glucuronidase, which is encoded by several microbiome genera, including Bacteroides, Bifidobacterium, Escherichia, and Lactobacillus. β-glucuronidase enzyme converts conjugated estrogens to deconjugated forms in the gastrointestinal tract. These deconjugated and unbound “active” estrogens enter the bloodstream and subsequently act on estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), eliciting downstream activation of intracellular signaling cascades, gene transcription, and epigenetic effects. A decrease in β-glucuronidase activity due to an imbalance in the GM community (dysbiosis), there is less estrogen deconjugation, resulting in lower circulating estrogen levels. Conversely, increased β-glucuronidase activity can increase estrogen levels. Thus, maintaining optimal β-glucuronidase activity is critical for regulating estrogen levels in females. Estrogens contribute to epithelial proliferation throughout the female reproductive system and have been shown to drive proliferative diseases such as endometriosis and polycystic ovary syndrome (PCOS).
There is evidence of lower SCFAs concentrations in fecal samples from PCOS patients. Indeed, probiotics’ supplementation promoted the growth of Faecalibacterium prausnitzii, Bifidobacterium, and Akkermansia, which are SCFA-producing bacteria, and can lead to an increase in intestinal SCFAs. In turns, SCFAs bind to their receptors on enter endocrine cells and directly stimulate the release of gut–brain mediators that can influence sex hormone secretion by the pituitary gland and hypothalamus via the gut–brain axis.
Vaginal Microbiota Transplantation and Gynecological Disorders
Gynecological disorders that have been explored in relation to Vaginal Microbiota Transplantation (VMT) include bacterial vaginosis, vulvovaginal candidiasis (VVC), and specific cases of infertility. These conditions are often associated with an imbalance in the vaginal microbiota, characterized by a decrease in beneficial Lactobacillus species and an overgrowth of pathogenic bacteria or fungi. The use of microbiota transplantation from healthy women has been suggested as a potential therapy to address imbalances in the vaginal microbiota, known as vaginal dysbiosis. Studies in rat models of vaginal dysbiosis have demonstrated that VMT can be therapeutically effective in reducing inflammation and increasing the presence of Lactobacilli, as well as relieving endometritis-like symptoms (inflammation of the lining of the uterus). The benefits of therapeutic VMT have also been demonstrated in patients with symptomatic, intractable, and recurrent bacterial vaginosis, and this has opened a new avenue for such future studies.
Bacterial vaginosis (BV) refers to a condition in which there is a disturbance in the normal microbial community of the vagina. As well previously documented, usually, the vagina is predominantly inhabited by Lactobacillus species. However, in BV presence, there is a shift in the vaginal microbiome, leading to the emergence of anaerobic bacteria. BV may be associated with a risk of upper genital tract infections, pregnancy complications, and susceptibility to sexually transmitted infections. Currently, there are many limited treatment options in patients with persistent or recurrent BV despite multiple attempts at antibiotic treatment. In addition, probiotic treatment of symptomatic patients with oral and/or vaginal administration of bacterial strains of Lactobacillus has yielded conflicting results, suggesting that the microbiome as a whole, rather than a single bacterial species, may be effective for severe BV.
An experience presentation
Lev-Sagie et al. performed the first exploratory study testing the VMT approach from healthy donors as a therapeutic alternative for patients suffering from symptomatic, intractable, and recurrent bacterial vaginosis (Clinicaltrials.gov NCT02236429). Four out of five VMT recipients experienced a significant improvement in both clinical symptoms and the composition and function of the dysbiotic vaginal microbiome, which persisted over an extended follow-up period, while one recipient experienced partial remission. The authors reported no significant side effects and no serious adverse events. While the lack of adverse outcomes is reassuring, the small study size and lack of a placebo arm make it difficult to interpret whether VMT provided an additional benefit over antibiotics alone. Additional clinical trials are currently ongoing with the goal of further evaluating whether VMT could serve as a viable option in symptomatic and intractable BV
Other Microbiota-Changing Strategies and Future Perspectives
In addition to FM, there are other strategies such as diet, and the administration of prebiotics, probiotics , synbiotics, and postbiotics. Recent research has documented that more than 50% of the diversity in the microbiome can be attributed to food, while host genetics only slightly influence the composition of the microbiota. In detail, a diet high in fiber promotes a significant rise in species producing SCFAs. A high-protein, high-fat, low-fiber diet, on the other hand, is linked to decreased biodiversity and an increase in species that could cause inflammation. A brief food change may cause a change in the gut’s population, but these modifications seem to be temporary. Diet may increase the success of FMT by fostering a favorable environment for the engraftment of donor microbiota and by exerting its own anti-inflammatory effects.
However, these natural approaches lack a direct-targeting action for gut microbiota shaping. For this purpose, researchers have developed the use of engineered bacterial (EB) strains to influence and manipulate the composition and behavior of the microbiota in a promising targeted manner. EB strains can be designed to produce specific metabolites or molecules that, interacting with the microbiota, can influence its composition or activity, showing beneficial effects on human health. EBs are rightly considered the next-generation microbiota therapeutics. In addition, they can be designed to express functions that address monogenic inborn errors of metabolism or to exert a tumor-killing activity.
However, although FMT is a valid therapeutic approach for certain diseases, it shows some procedural limitations. The preparation of fresh or frozen fecal suspensions requires the constant and periodic presence of healthy donors which must be negative in a series of serological and microbiological screening tests. Moreover, the stool samples have to be processed within six hours after collection for preserving anaerobes.
Furthermore, it is essential to know in detail the bacterial composition of the suspension to be infused into the recipient, in order to increase FMT efficacy and especially safety. For these reasons, the therapeutic efficacy of a synthetic bacterial preparation called “Bacterial Consortium” is now under development. This approach involves the isolation from healthy donors’ stool samples of several bacterial species normally present in the human intestinal microbiota, and thus the use of this “Bacterial Consortium”, composed by 13 microbial species, as a safe and valid alternative to donor stools. In conclusion, understanding the mechanisms by which the human microbiota can influence the progression of diseases, including gynecological disorders, can lead to the development of personalized approaches to shape the microbiota composition (and so its function), improving the symptoms and patients’ prognosis.
