Microbiome & miracles: unravelling the gut-fertility connection

The concept of the gut-fertility axis is gaining attention in both functional and traditional medicine. It explores how our digestive health may influence our ability to conceive and maintain a healthy pregnancy.

But before we get into what the gut microbiome (GM) does and how it impacts fertility, let’s have a look at some statistics:

-           I guess the most shocking one perhaps is that over the past 50 years, the global fertility rate has halved (Aitken, 2022). 

-           In line with this, a comprehensive analysis of > 100 studies reported a 50-60% decrease in sperm counts between 1973 and 2011 (Levine,2017).

 -          And if we were to list the top clinical reasons for female infertility, ovulatory disorders are most common, followed by endometriosis (an endocrine disorder), pelvic adhesions (e.g. scar tissue), tubal blockages (e.g. fibroids in fallopian tubes), other tubal or uterine abnormalities and hyperprolactinemia (abnormally high levels of the hormone prolactin) (Walker and Tobler, 2022).

Interestingly, many causes of idiopathic (“unexplained” infertility) are now thought to be related to microbial aetiologies, i.e. vaginal dysbiosis (Chopra, 2023).

So let's first explore what the gut microbiome is, what it does and how it impacts fertility. 

The gut microbiome refers to the vast community of microorganisms (we're talking trillions) that live in the digestive tract, primarily the large intestine. It is comprised of bacteria, viruses, fungi, and other microbes, which collectively are thought to outweigh the number of human cells in the body by 1.3 to 1 (Sender, Fuchs and Milo, 2016).

The composition of the gut microbiome is both unique and dynamic, changing over the lifespan and influenced by multiple factors such as genetics, gender, birth (i.e. vaginal or caesarean), infantile nutrition (breast or bottle fed), nutrition, lifestyle, the environment (including medication and antibiotic use) and stress.

And whilst in this article I’m focusing primarily on the gut microbiome, it's important to note that the human body has several other distinct microbiomes, for example oral, nasal, skin, lung and genital (i.e. vaginal and testicular). 

So what do these gut microorganisms actually do? Well they play numerous crucial roles in maintaining our overall health (including our reproductive health), so much so that the gut microbiome is often considered by researchers to be an endocrine organ in its own right.

I’m going to come onto each of these roles specifically with fertility in mind in a moment but in a nutshell, the gut microbiome:

1.        Aids in the breakdown and absorption of nutrients from the diet

The GM aids digestion and nutrient absorption. The gut bacteria help to break down complex carbohydrates & dietary fibres that the body can't digest on its own. Via a fermentation process, dietary fibres are broken down into short chain fatty acids, a necessary waste product to the bacterium, but vital nutrients to us (Besten et al., 2013).

Butyrate for example is the preferred energy source for the epithelial cells that line the large intestine. Which is important because it's the epithelial cells that make up the gut barrier that shields the body from pathogens while allowing nutrients to pass through.

Research shows that certain gut bacteria (so for example Bacteroides, Bifidobacterium, and Enterococcus) are also responsible for providing the enzymes necessary to synthesise B vitamins including B1 (thiamine), B2 (riboflavin), B5 (pantothenic acid), B7 (biotin), B9 (folate) & B12 (cobalamin) (Morowitz, Carlisle & Alverdy, 2011). And that's important because not only does B9 (folic acid) improve oocyte quality, it's also thought to be involved in embryonic development & to increase embryo implantation rates in the endometrium.

If there's dysbiosis, Vitamin B12 deficiency can lead to increased levels of homocysteine, an amino acid that can damage the endometrium & impair ovulation. This can increase the risk of miscarriage, implantation issues & chemical pregnancy. And like Vitamin B9, Vitamin B12 deficiency can also increase the risk of neural tube defects in the developing foetus (Isomah et al., 2021).

So it makes sense that dysbiosis in the gut microbiome can impair both nutrient synthesis & absorption, leading to deficiencies in key nutrients required for optimal reproductive health. I.e. gut dysbiosis can adversely affect fertility.

2.        Regulates immune homeostasis (balance)

We also know that the GM plays a critical role in regulating both innate & adaptive immune responses against pathogenic bacteria. And there are several mechanisms by which the gut microbiota ensures the prevention of infection of the host (human). One is referred to as colonisation resistance, where the commensal (beneficial) bacteria compete with invading microorganisms for resource availability, either in terms of nutritional or functional space (Chiu et al., 2017). And research shows that a non-beneficial microbiota composition, potentially induced by diet, stress, and/or antibiotic & medication use, can result in reduced colonisation resistance, impaired intestinal barrier function, low-grade inflammation and subsequently, increased susceptibility to infection (Forgie,  Fouhse and Willing, 2019).

Secondly there's the mucosal immune system (commonly known as the mucus layer). Mucus is secreted by goblet cells within the intestinal epithelial barrier, serving as the first physical defence and preventing antigens, toxins and bacteria from coming into direct contact with the epithelial cells. The mucus layer also acts as a habitat for certain beneficial gut microbes. Some bacteria species such as Akkermansia and Bacteroides can also use the mucus as a source of nutrients, breaking down mucins (the proteins in the mucus) for their growth. This symbiotic relationship helps maintain a healthy mucus layer while supporting the growth of beneficial bacteria that contribute to overall gut health. (Camilleri, 2019).

And thirdly there's the intestinal epithelial barrier; a physical barrier consisting of a single layer of epithelial cells linked by tight-junction (t-junction) protein complexes. These t-junctions seal the gaps between adjacent epithelial cells, forming a selectively permeable barrier which separates the contents of the intestinal lumen (including bacteria and pathogens) from the underlying tissues. And because the barrier is selectively permeable, it selectively allows the passage of essential nutrients and water between cells whilst preventing harmful substances like pathogens and toxins from leaking into the bloodstream, causing inflammation and potentially, infection.

By keeping epithelial cells tightly joined, T-junctions preserve the structural integrity of the gut lining, preventing the breakdown of the barrier. Disruptions in t-junctions therefore can lead to increased intestinal permeability, commonly known as "leaky gut," which can result in inflammation and disease (and has been shown to be exacerbated in inflammatory diseases like PCOS and endo) (Talwar, Singh & Kommagani, 2022).

So what does immunity have to do with fertility? Well, dysbiosis in the gut (and vaginal) microbiome has been shown to result in compromised immunosurveillance (the process by which the body's immune system identifies and eliminates foreign pathogens), disrupt normal immune function (leading to the elevation of proinflammatory cytokines (which in turn can trigger or exacerbate inflammation)), and altered immune cell profiles, all of which may contribute to the pathogenesis of PCOS and endometriosis.

So as we can see, a healthy gut microbiome is essential for a balanced immune response. It helps to distinguish between harmless and harmful agents, thus preventing an overactive immune response. That's crucial for successful implantation and a sustained pregnancy, because an overactive or dysregulated immune system may mistakenly target & reject the embryo, leading to difficulties in implantation and an increased risk of miscarriage.

There is also a significant link between gut health and autoimmune conditions, which can directly affect fertility. Conditions like Hashimoto's thyroiditis & certain types of autoimmune-induced inflammation can also impair reproductive function (Cuadrado-Torroglosa, Garcia-Velasco and Alecsandru, 2024)

3.        Contributes to hormonal balance and metabolism

The gut microbiome also plays a significant role in regulating hormones, influencing various aspects of the body's endocrine system. And the relationship between the gut microbiome and hormones occurs through several pathways, impacting hormone production, metabolism and signalling.

The 'estrobolome' for example is a specific collection of bacteria in the gut which are involved in the metabolism and recycling of oestrogen in the body (Pai et al., 2023). Commensal gut bacteria may facilitate the proper breakdown & excretion of oestrogen. However, when dysbiosis occurs, this balance may be disrupted with results including oestrogen dominance, where the body has an excessive amount of oestrogen relative to progesterone. This imbalance is linked to various reproductive issues, including irregular menstrual cycles, PCOS and Endometriosis. Similarly, oestrogen levels can fall too low, which can contribute to menstrual irregularities and subsequently, fertility issues.

Additionally, gut inflammation, often a consequence of dysbiosis, may further exacerbate hormonal imbalances. Chronic inflammation may disrupt the adrenal glands' production of cortisol, the stress hormone, which in turn can influence the balance of progesterone and oestrogen, affecting reproductive processes.

Interestingly, gut inflammation and dysbiosis have both been shown to be correlated with the severity of endometriosis symptoms as well as the conditions impact on fertility (Ustianowska et al., 2022).

The microbiome also plays an important role in the metabolism of androgens (Collden et al., 2019), particularly in PCOS. Research has demonstrated that restoring microbiome balance support the reduction of circulating androgens and thus promote a more balanced hormonal environment (Torres et al., 2018). A healthy gut microbiome is therefore essential for metabolising oestrogen effectively, with a view to preventing hormone-related fertility disorders.

Now I can't discuss the gut-fertility connection without also taking a look at male factor fertility. In 2020, Agarwal et al concluded that in 50% of couples affected by infertility (globally), male factor infertility is either the primary or a contributing cause. Which makes sense when the research also shows that over the last 40 years, sperm counts have decreased by 50-60% (Levine, 2017).

Causes of male subfertility vary highly, but can be related to congenital, acquired, or idiopathic factors that impair spermatogenesis. So let's take a look at how the GM and gut health affect male factor fertility.

Recent studies have found a direct relationship between dysbiosis of gut microbiota and male infertility (Ding et al., 2020; Zhao et al., 2020; Lundy et al., 2021). And it's thought that dysbiosis may lead to impaired spermatogenesis via failure of the blood-testis barrier, seminal inflammation, oxidative stress & DNA damage (Leelani et al, 2023). And much like dysbiosis and subsequent chronic inflammation negatively impact female reproductive processes, they also negatively affect sperm count, motility and morphology.

Valcarce et al., (2017) found that following the administration of probiotics containing strains Lactobacillus rhamnosus CECT8361 + Bifidobacterium longum CECT7347, sperm quality parameters of males with reduced sperm motility were statistically improved as follows:

-            Significantly increased sperm motility (about sixfold)

-            Decreased DNA fragments (about 1.2-fold)

-            Decreased intracellular H2O2 levels (reactive oxygen species) (about 3.5-fold).

Similarly, a pilot study in 2017 showed that after 6 months' supplementing with Flortec (one sachet containing Lactobacillus paracasei B21060 + prebiotic per day) in infertile men, many indicators that optimise sperm quality & quantity improved. These included the volume of ejaculate, sperm concentration, progressive motility & the percentage of typical forms (Maretti and Cavallini, 2017). In addition, participants' FSH, LH & testosterone also improved. No modification was found in infertile men treated with a control substance (starch).

So as we can see, dysbiosis of the GM has a significant impact on male factor fertility too.

Clearly, interest in the symbiotic relationship between the GM and fertility is growing. Quickly. But it's important to remember that there are numerous limitations that impede our understanding of it. Firstly, there is a huge variability and complexity of the gut microbiome across individuals, tissues and time (Bharti & Grimm 2021). And as we said before, the composition and function of the GM is influenced by several factors including genetics, gender, birth, age, nutrition, lifestyle, geography, environment, medication & stress. And it's this variability that poses challenges in establishing consistent associations between specific microbial profiles and reproductive outcomes.

Secondly, there is a lack of standardised protocols for sampling & analysis of the microbiome in reproductive biology (Bharti & Grimm 2021). Variations in sample collection techniques, storage, DNA extraction, sequencing methods & bioinformatics pipelines can introduce biases and therefore hinder comparability across studies. Developing standardised procedures and establishing robust quality control measures are essential to enable more accurate comparisons and meta-analyses (Kim et al. 2017).

Establishing causality between specific microbiome alterations and reproductive outcomes remains challenging. Many studies rely on correlation analysis which alone cannot determine whether microbial changes directly impact fertility or if they are simply bystanders given the bidirectional relationships of hormones and the microbiome.

Ethical considerations also pose limitations on conducting microbiome studies in reproductive health. Collecting samples from reproductive tissues, such as the uterus or fallopian tubes, are invasive and challenging. Additionally, designing studies that account for confounding factors, such as lifestyle, medications, hormonal fluctuations, and fertility treatments, requires careful consideration. Ethical guidelines and innovative study designs that overcome these challenges are essential to advance our knowledge in this field.

Phew! Interesting stuff. If you’d like to know more about your own gut microbiome and how this might be impacting your fertility, send me a message via my contact page and let’s talk testing!