The role of the microbiome in preventing pregnancy loss

19 Dec

A continuously growing and evolving body of research highlights the significant role of the microbiome. Whilst research is ongoing and a definitive causal link hasn't been established, a growing body of evidence suggests that microbial dysbiosis—an imbalance in the microbial communities—is associated with repeat pregnancy loss (RPL).

There are many proposed mechanisms for how the reproductive microbiome drives RPL. Research suggests that microbial dysbiosis, especially in the vaginal and endometrial environments, can disrupt the delicate balance of the immune system during pregnancy, potentially leading to RPL. In a healthy pregnancy, the maternal immune system needs to tolerate the semi-allogeneic foetus while maintaining its ability to fight off infections. A balanced microbiome is thought to contribute to this immune tolerance by promoting an anti-inflammatory environment and regulating immune cell activity. Dysbiosis, on the other hand, can trigger a pro-inflammatory response that may disrupt crucial processes like implantation, angiogenesis, and placental development, ultimately increasing the risk of RPL.

When it comes to establishing how the reproductive microbiome can drive or prevent pregnancy loss, it’s important to understand the differences in the microbial colonies and how they each play a role in reproductive health and therefore pregnancy outcomes.

The vaginal microbiome plays a crucial role in reproductive health by influencing vaginal pH, immune responses, and susceptibility to infections. Ideally, a healthy vaginal microbiome is dominated by Lactobacillus species, which produce lactic acid, creating an acidic environment that inhibits the growth of other bacteria. Dysbiosis in the vaginal microbiome has been linked to adverse reproductive outcomes, including RPL. Studies have observed an increased prevalence of certain bacteria like Atopobium, Prevotella, Gardnerella vaginalis, Pseudomonas, and Streptococcus in RPL patients. Notably, bacterial vaginosis (BV), characterized by a depletion of Lactobacilli and an overgrowth of anaerobic bacteria, has been associated with a higher risk of various gynaecological conditions and adverse pregnancy outcomes. When it comes to vaginal dysbiosis and RPL, studies summarised that the main driving factors include:

Reduced Lactobacillus dominance: A healthy vaginal microbiome is typically dominated by Lactobacillus species. These bacteria produce lactic acid, maintaining an acidic vaginal environment that inhibits the growth of harmful bacteria. Dysbiosis often involves a decrease in Lactobacillus and an increase in other, potentially pathogenic bacteria, leading to a less acidic and more vulnerable vaginal environment.
Inflammation and immune dysregulation: This shift in the vaginal microbiome triggers an inflammatory response, which can damage tissues and disrupt normal immune function within the reproductive tract. This inflammation can interfere with implantation, placental development, and the overall maintenance of a pregnancy.
Increased risk of infections: The disrupted vaginal ecosystem becomes more susceptible to infections, including sexually transmitted infections (STIs). These infections can further exacerbate inflammation and increase the risk of pregnancy complications, including miscarriage.

Overall, research suggests that an imbalance in the vaginal microbiome, particularly a shift away from Lactobacillus dominance, could be a contributing factor to RPL. Several studies also noted increased diversity in the vaginal microbiome of women experiencing miscarriage, indicating a shift away from the Lactobacillus-dominated environment.

The endometrial microbiome, initially believed to be sterile, is now recognized as harbouring a complex microbial ecosystem. While research on the endometrial microbiome is challenging due to low microbial biomass and contamination risks, studies suggest that dysbiosis in the endometrial microbiome is associated with impaired IVF outcomes and RPL. Some studies found a lower prevalence of Lactobacillus species in the endometrium of RPL patients, while others observed an increased abundance of bacteria such as Acinetobacter, Anaerobacillus, Erysipelothrix, and Hydrogenophilus.

Endometrial dysbiosis is summarised as impacting RPL by:

Altered microbial composition: Similar to the vagina, the endometrium (the lining of the uterus) has a unique microbiome. Dysbiosis in the endometrium involves an imbalance in the microbial community, often characterized by a decrease in beneficial bacteria and an increase in potentially harmful ones.
Impaired implantation and embryonic development: This altered endometrial microbiome can directly impact implantation. Inflammation and immune dysregulation within the endometrium can make it less receptive to a fertilized egg, making it difficult for the embryo to successfully implant and develop.
Impact on placental function: Endometrial dysbiosis can also affect the development and function of the placenta, the vital organ that nourishes and supports the growing foetus. Problems with placental function can lead to various pregnancy complications, including miscarriage.

Research on the endometrial microbiome in relation to miscarriage is more limited, but the findings also point to a shift away from Lactobacillus dominance.

The gut microbiome's role in RPL is less clear. While research is limited, some findings suggest that alterations in the gut microbiome might contribute to RPL, possibly through its influence on the immune system. However, more research is needed to fully understand the gut microbiome's impact on RPL. The gut microbiome undergoes significant changes throughout pregnancy in terms of quantity, composition, and function:

First trimester: Resembles that of a healthy non-pregnant woman, there is predominance of Firmicutes (especially Clostridiales and Faecalibacterium prausnitzii) over Bacteroides.
Second trimester: Butyrate-producing bacteria, known for their anti-inflammatory properties, decrease. There's an increase in Bifidobacteria, Proteobacteria, and lactic acid-producing bacteria.
Third trimester: In the third trimester, there's a significant reduction in bacteria that produce short-chain fatty acids, like Faecalibacterium prausnitzii, resulting in lower butyrate production. This change is linked to low-grade inflammation, reduced insulin sensitivity, and increased intestinal absorption of essential nutrients. Many studies suggest those with unexplained repeat miscarriage, have microbiomes whereby the number of butyrate-producing bacteria is reduced. This reduction is significant because butyrate-producing bacteria play a crucial role in maintaining immunity and providing anti-inflammatory properties. One study demonstrated a link between gut bacterial dysbiosis and a Th1/Th17-mediated proinflammatory state in miscarriage with unknown aetiology.

While direct evidence is limited, the gut microbiome's influence on the immune system provides a plausible mechanism for its potential role in RPL.

To summarize, the gut microbiome could impact RPL by:

Immune modulation: The gut microbiome plays a crucial role in shaping the host's immune response, impacting both innate and adaptive immunity. It can influence the differentiation of T-cells, which are crucial for immune regulation throughout the body.

Gut-reproductive tract axis: The gut and reproductive tract microbiomes are interconnected. An imbalance in the gut microbiome could potentially influence the immune response in the reproductive tract, contributing to an environment less conducive to pregnancy.
Inflammation: Alterations in the gut microbiome can contribute to systemic inflammation, which could disrupt the delicate immune balance needed for successful pregnancy.

Addressing these imbalances through appropriate interventions could potentially reduce the risk of RPL and improve reproductive outcomes. So how can be prevent pregnancy loss via reproductive microbiome modulation?

Studies showing that microbial metabolites, such as SCFAs, can promote the differentiation of regulatory T cells (Tregs), which suppress excessive immune responses and contribute to a tolerogenic environment. This suggests that a healthy microbiome, capable of producing sufficient levels of these immunomodulatory metabolites, might contribute to preventing immune-mediated pregnancy loss.

The gut microbiome is known to influence inflammatory processes throughout the body. A balanced microbiome helps to keep inflammation in check, while dysbiosis, often linked to poor diet, can contribute to heightened inflammation. This suggests that maintaining a healthy microbiome through a balanced diet might indirectly help prevent pregnancy loss by regulating inflammation.

While studies don't explicitly detail how the microbiome prevents pregnancy loss, they highlight its role in supporting a healthy pregnancy, which can indirectly reduce the risk of loss. Here's how:

Promoting a tolerogenic immune environment: A successful pregnancy hinges on the mother's immune system tolerating the genetically distinct foetus. A balanced microbiome helps achieve this by enhancing regulatory T Cell (Treg) activity, SCFA’s from dietary fibre can boost Treg cell differentiation. The microbiome influences the balance of pro-inflammatory and anti-inflammatory immune cells in the reproductive tract. A healthy microbiome supports an immune profile that favours tolerance, reducing the risk of foetal rejection.

Regulating inflammation: While a degree of inflammation is normal during pregnancy, excessive inflammation can disrupt implantation and foetal development, increasing the risk of loss. SCFAs, particularly butyrate, have potent anti-inflammatory effects.
Maintaining gut barrier integrity: A healthy microbiome supports a strong gut barrier, preventing the leakage of bacterial products like lipopolysaccharide (LPS) into the bloodstream. LPS can trigger systemic inflammation that could negatively impact pregnancy.
Supporting foetal growth and development: a well-functioning maternal microbiome produces metabolites vital for foetal health. These metabolites, transferred across the placenta, impact various aspects of development, contributing to a healthier pregnancy.

A 2020 study by Amir et al also suggested a balanced and healthy microbiome, particularly in the gut and reproductive tract, is crucial for a successful pregnancy because it helps to create an environment that supports implantation, foetal development, and maternal health. The study focused on the gut and suggested that the gut microbiome plays an important role in a healthy immune response at the maternal-foetal interface. It also spoke about the impact that the gut microbiota composition can have on metabolic health, inflammation and gestational diabetes, which are all crucial in preventing pregnancy loss. In addition, pregnancy can increase gut permeability which is exacerbated by a high-fat diet leading to inflammatory markers in maternal circulation and therefore a healthy gut microbiome contributes to a maintained gut barrier integrity, reducing inflammation and potential complications that can lead to pregnancy loss.

A holistic approach, encompassing a healthy diet, lifestyle choices, and addressing all potential risk factors, is essential for promoting successful pregnancies and reducing the risk of loss. A healthy and balanced microbiome plays a vital role in this process.

Dietary factors

Fibre is key: A fibre-rich diet, emphasizing fruits, vegetables, legumes, and whole grains, is crucial. Dietary fibre nourishes beneficial gut bacteria like Prevotella and Bifidobacterium. These bacteria produce short-chain fatty acids (SCFAs), especially butyrate, with anti-inflammatory properties. They help regulate the immune response, likely crucial in preventing pregnancy loss caused by immune dysregulation.
Fat matters: A Western diet, high in saturated and trans fats, negatively impacts gut microbiota. This can increase inflammation and permeability of the gut, potentially leading to complications. Reducing these unhealthy fats and choosing healthier options like olive oil and avocados may promote a more balanced microbiome.
Nourishment beyond calories: A diet abundant in vitamins, minerals, and antioxidants, obtained from diverse fruits, vegetables, lean protein, and healthy fats supports a thriving gut microbiome. This can positively impact metabolic function, reducing the risk of gestational diabetes and other complications that might lead to pregnancy loss.
Increasing pre an probiotic dietary sources and/or supplements: Prebiotics, as non-digestible food ingredients, selectively stimulate the growth and activity of beneficial bacteria, particularly Lactobacillus and Bifidobacterium, in the gut. This can help restore a balanced gut microbiome, which is associated with reduced inflammation and a well-regulated immune response. Probiotics, on the other hand, directly introduce live beneficial bacteria into the gut, also aiming to restore a balanced microbiome and · promote overall health but this approach is strain specific and should only be prescribed by a qualified practitioner with strain specific knowledge.

Lifestyle factors

Stress management is gut management: chronic stress can disrupt the gut microbiome and increase inflammation, potentially contributing to pregnancy complications. Techniques like yoga, meditation, mindfulness, and nature immersion aren't just relaxation; they can have a tangible impact on gut health, indirectly supporting a successful pregnancy.
Exercise for microbial diversity: moderate physical activity has a positive effect on gut microbiota diversity. It also helps maintain a healthy weight, which further contributes to a balanced microbiome.
Sleep and hormones: adequate sleep is vital for hormone regulation and immune function. A well-functioning immune system is crucial in preventing complications that can lead to pregnancy loss. Prioritizing 7-9 hours of quality sleep may seem simple, but it's a powerful support for a healthy microbiome.
Avoiding smoking and excessive alcohol: both habits disrupt the gut microbiome, this disruption can negatively impact both fertility and pregnancy, potentially increasing the risk of loss.

In summary, a balanced and healthy microbiome contributes to a successful pregnancy by promoting immune tolerance, regulating inflammation, and supporting foetal development. These factors can indirectly reduce the risk of pregnancy loss by creating a more favourable environment for implantation and foetal growth.

References

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