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I have been doing a lot of research recently about silent low-grade inflammation and its role in unexplained infertility and recurring pregnancy loss. In my research, I have discovered that many women with unexplained infertility and recurring pregnancy loss may have an immune system imbalance with a pattern of elevated Th17 immune cells and decreased T regulatory cells. This is an imbalance that often occurs with chronic inflammation and autoimmunity. The immune system is complex with many players, but this pattern is worth noting as this Th17/T regulatory cell imbalance can be influenced by our diet, lifestyle and environment. What's more, the key player in all the complexities of our immune orchestra is the gut microbiome.
Unexplained Infertility
Unexplained infertility is when there is no obvious physiological reason that you cannot get pregnant, despite standard testing and scans from your GP or fertility clinic. Unexplained infertility affects approximately 16% of infertile females.
I know firsthand how hopeless it feels to be told you have unexplained infertility. For 10 years, I was on this journey with over 17 chemical pregnancies and 3 miscarriages at 6 – 8 weeks. Despite being told at age 41 (after my IVF ended in miscarriage) that my only hope was to use a donor egg, I went on to conceive naturally at age 43. I had a healthy pregnancy and gave birth to my miracle baby girl at age 44.
When your doctor first tells you that you have unexplained infertility, it seems a relief that there is nothing actually wrong with you or your partner. Most doctors recommend IVF or other assisted reproductive treatment as the next steps with unexplained infertility. However, for many couples like myself, IVF doesn't fix the unexplained infertility issue and the heartache and frustration continues but without a sense of direction and hope.
Is silent low-grade inflammation the cause
Silent low-grade inflammation may be barely noticeable to you with only mild, easy to ignore symptoms such as a skin rash, asthma, reflux or abdominal discomfort. Although the symptoms are manageable and not that troublesome, under the surface, your symptoms may be permanently triggering the adaptive immune system and creating inflammation. Long-term activation of the adaptive immune system can lead to autoimmunity and a lack of self-tolerance, which means the body is unable to identify between cells and tissues that are self and nonself, and so attacks itself. More on this later.
Researchers estimate that silent, low-grade inflammation can cause up to 50% of cases of unexplained infertility. If this is you, check in with yourself to see what symptoms you are experiencing and whether working to resolve your chronic condition can help to enhance your fertility.
Acute and Chronic Inflammation
Inflammation is an important, natural response of the body to protect itself against harm, which may come from an irritant, cut, injury or pathogen. There are two types of inflammation: acute and chronic.
Acute Inflammation
Acute inflammation is the rapid response of the body when a cut or injury occurs. White blood cells swarm the area and surrounding area of the injury, cut or infection, causing redness, pain and swelling. The cells involved in this inflammatory response trap bacteria and help the healing process. Inflammation is an essential immune response to protect the area and prevent injuries and infections from getting worse and spreading. Once the injury or infection has healed inflammation is usually resolved.
Chronic Inflammation
If acute inflammation doesn't resolve itself quickly and remains untreated, it may lead to chronic inflammation as the immune system becomes continually activated. Long-term exposure to environmental toxins, irritants, infections and food sensitivities that trigger the immune system can also cause chronic inflammation.
Chronic inflammation may manifest in the body as:
Pain anywhere in the body (joints, stomach, back, chest, etc)
Fatigue
Skin rashes, eczema, psoriasis.
Asthma
Endometriosis or PCOS.
IBS or inflammatory bowel disease.
If we don't address chronic inflammation and let it persist, it can tip us over the threshold into autoimmunity, which is where tissue destruction starts to occur. This is when the immune system goes awry and attacks healthy body cells and tissues, essentially attacking itself. Examples of this are the autoimmune condition, rheumatoid arthritis, where inflammatory cytokines attack the tissues of the joints or the tissues of the thyroid with Hashimoto's thyroiditis.
How can inflammation affect fertility?
Chronic inflammation can damage reproductive cells and tissues such as the egg, uterus, ovaries and sperm.
Chronic inflammation can be the driver of an autoimmune response in the body in which elevated antibodies cause the body to attack its own tissues, which may include a fetus.
Inflammation and oxidative stress are closely related, and high levels of oxidative stress can cause unexplained infertility. Oxidative stress occurs when there is an imbalance of free radicals (created by factors such as a poor diet, stress, smoking and excessive exercise) and antioxidants in the body. An antioxidant rich diet helps to prevent free radical damage to cells and DNA, which is why a high intake of brightly coloured vegetables and fruit are an important part of a fertility diet.
Autoimmunity
It is estimated that as many as half of women with unexplained infertility and/or recurring pregnancy loss have issues with autoimmunity but are not even aware of it. This occurs when there is an imbalance in the adaptive (acquired) immune system. The common patterns seen with autoimmunity are an imbalance in Th1/Th2 immune cells, elevated Th17 cells and a reduction of T regulatory cells (Tregs), which help to calm down the overactive immune response.
T helper 1/T helper 2 ratio
The immune system has two major arms, T helper 1 and T helper 2 cells. Our gut microbiome plays an important role in keeping these two arms of the immune system in a healthy balance. A dominance of T helper 1 cells has been linked to various autoimmune conditions. T helper 2 dominance has been linked to more allergic conditions, such as asthma and hay fever.
For a successful pregnancy, the Th1/Th2 balance needs to shift towards Th2 dominance, a protective mechanism so that the immune system doesn't attack the baby. `While in the pregnancy, Th1 cells inhibit the invasion of a trophoblastic cell, Th2 cells modulate a Th1 response, promote the trophoblast invasion and maintain the fetus' (1) The trophoblast cells are the major cell type of the placenta that makes the hormone human chorionic gonadotrophin (HCG) to ensure the endometrium will be receptive to the embryo during implantation. So, if the immune system is leaning towards Th1 dominance, there is a chance that implantation will fail.
Th17 cells
Th17 cells are also often increased in cases of unexplained infertility and recurring pregnancy loss. Th17 cells facilitate the immune response against extracellular bacterial and fungal infections. Th17 cells promote inflammation, which not only creates an unreceptive environment for implantation, but plays a key role in the development of autoimmunity. `Collectively, Th17 cells are highly potent inflammatory cells that initiate tissue inflammation and induce the infiltration of other inflammatory cells into the target organ’ (2)
Studies have also linked high numbers of Th17 cells to fetus rejection and recurring pregnancy loss. `The proportion of Th17 cells in the peripheral blood and decidua were significantly higher in unexplained recurrent spontaneous abortion (URSA) patients, compared to normal, early pregnant women ' (3)
Regulatory T Cells (Tregs)
It is a decrease in regulatory T cells, along with the increase in Th17 cells, that is thought to contribute to unexplained infertility, especially implantation failure and recurring pregnancy loss. Regulatory T cells play a role as a key regulator to counteract the inflammatory effects of the Th17 cells. A balance between the immune effector cells (Th17) and immune regulator cells (regulatory T cells) is important for fertility and pregnancy success. T regulatory cells help to calm down autoimmunity and the overactivity of the immune system. `Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses' (4)
What causes this imbalance in the adaptive immune system (high Th17 and low T regulatory cells)
There are many causes of this breakdown in immune tolerance. Some of the most common ones are:
Chronic Infection – viral, bacterial, fungal
Stress/oxidative stress
Poor gut health
Intestinal permeability (leaky gut)
Imbalanced gut microbiome
Food intolerances
Diet high in refined sugar and processed foods
Diet low in antioxidants
Nutritional deficiencies
Poor sleep
Environmental factors, such as toxins, allergies, chemicals
Lifestyle factors such as smoking, excessive alcohol
Too little or too much exercise
The Th17/T regulatory cell imbalance is fairly new research. In fact, one study I was reading to do some background research for this article is from 2023, which shows how new this information is.
When I was experiencing recurring chemical pregnancies and miscarriages, I hadn't made the connection at the time that it could have been a lack of self-tolerance at the implantation stage. It now makes sense that in the absence of T regulatory cells to calm things down, the immune system can attack the fetus. A healthy balance between Th17 cells and T regulatory cells is therefore crucial to achieve implantation and to maintain a pregnancy until term.
Looking back, I have now realised that prior to conceiving my miracle baby at age 43; I was actually inadvertently increasing my T regulatory cells and reducing my Th17 cells, which may have helped calm down my overactive immune system that was contributing to implantation failure. I believe I achieved this by:
Spending a few months on the GAPS diet healing my gut, replenishing my gut microbiome and removing food sensitivities that triggered my immune system.
I had increased my Vitamin D supplement intake as it was June in New Zealand when I conceived, which is winter.
I was supporting my immune system over the winter with Reishi mushroom. I was really just trying to build a robust immune system for the winter months and not really thinking about getting pregnant. Now that I have reviewed what these supplements can do, I believe Reishi may have played a part in regulating my dysfunctional immune system and building self-tolerance.
I will go into more details shortly about each of these supplements and how they influence T regulatory cells along with a microbiome supportive diet.
Looking at research, it is clear that supporting T regulatory cell production is important for women suffering from implantation failure and recurring pregnancy loss.
Increasing T regulatory cells (Tregs)
T regulatory cells play an important role in immune homeostasis and help to suppress and calm down an overactive immune system. This may help to reduce inflammation and autoimmunity. Diet, lifestyle and the health of the gut microbiome play a key role in this.
Gut Microbiome
The gut microbiome communicates with the immune cells in the gut associated lymphoid tissue (GALT) and plays an important role in regulating the balance of Th17 and T regulatory cells (as well as other immune cells). The status of the gut microbiome can affect the levels of inflammatory T h 17 cells, which become elevated when there is an imbalanced gut microbiome.
Th17 secretes IL 17 the proinflammatory cytokine when it tries to clear the body of bacterial or fungal infections. So having any unresolved, low-grade infections such as candida albicans the yeast overgrowth, urinary tract bacterial infections, or small intestinal bacterial overgrowth (SIBO) can upregulate Th17 cells and promote silent, low-grade inflammation. It is called silent as you may not be aware of it or it is mild enough that you can happily just carry on with it. If left unresolved, this silent inflammation may lead to autoimmunity and a loss of self-tolerance, which is especially harmful for fertility. Self-tolerance is the ability of the immune system to recognise self (cells and self-producing antigens) as a non threat and to identify and mount an appropriate response to nonself, foreign antigens. When the body loses its self-tolerance, it attacks itself, unable to differentiate between self and non-self.
When Th17 cells remain constantly elevated, it results in a shortage of T regulatory cells responsible for calming down and resolving the inflammatory immune response. T regulatory cells maintain immune tolerance by distinguishing self-antigens from foreign antigens.
Optimising our gut microbiome with prebiotic foods, probiotic foods and probiotic supplements is important for a diverse gut microbiome and for increasing T regulatory cells to dampen down an overactive immune system.
My approach was to increase microbiome diversity by rotating probiotics and fermented foods rather than taking the same isolated strains. I rotated spore forming probiotics along with general multi strain probiotics and saccharomyces boullardi, the probiotic yeast. Rotating strains introduced diversity to my gut microbiome, and this worked well for me. Spore forming probiotics were my favourite though as my gut felt healthier when I took these. Spore forming probiotics reconditions the gut by increasing microbial diversity and encouraging the growth of key health-promoting, commensal gut bacteria. They also help to reduce systemic inflammation by increasing butyrate production (more on butyrate later) and support immune modulation. Typical spore forming probiotic strains include bacillus coagulans (SC-208), bacillus indicus (HU36), bacillus licheniformis (SL-307), bacillus subtillus (HU58) and bacillus clausii (SC-109).
Diet
Diet is the most influential factor that promotes T regulatory cell development. As foods entering the digestive system are the largest source of foreign material to enter the body, it makes sense that what we eat will affect our immune system. What we eat also influences the composition of our gut microbiome.
Foods that increase Th17 and inflammation
Refined sugar
Processed foods
Excess trans fats
Food intolerances such as gluten, dairy, etc
The development of T regulatory cells depends highly on your nutritional status. Food intolerances that trigger an inflammatory immune response can also promote Th17 dominance and reduce T regulatory cells.
Foods that increase T Regulatory cells and calm down inflammation
Probiotic foods
Having a serving a day of a probiotic food such as sauerkraut, kimchi, kefir, probiotic yoghurt, kombucha and sourdough bread all help to nourish the gut and increase microbiome diversity.
Fibre
Dietary fibre can promote T regulatory cell development through the production of short-chain fatty acids (SCFAs) that are produced in the colon when our gut microbiome ferments dietary fibre and resistance starches. 'The three predominant SCFAs, acetate, butyrate and propionate, ameliorate inflammatory diseases by regulating Treg function and frequency' (5)
Eating a diet rich in fresh fruit and vegetables is one of the easiest ways to increase dietary fibre.
Butyrate
Butyrate, in particular, is a short-chain fatty acid that plays an important role in modulating the gut microbiome, which has a regulatory effect on the immune system. `Butyrate is the primary fuel source for the colonocyte where nearly 90% of generated butyrate is metabolised locally in the colon’ (6)
Some of the key functions of butyrate are:
Supports the integrity of the intestinal lining
Modulates and inhibits pro-inflammatory cytokines, reducing inflammation
Activates T regulatory cell production, which calms down an overactive immune system
Assists with the production of anti-inflammatory cytokines such as IL 10
Modulates the gut microbiome and its effect on the immune system
Maintains intestinal immune homeostasis
` Butyrate supports the integrity of the intestinal epithelial barrier by regulating the expression of tight junctional proteins and supporting intestinal mucus production’ (7)
A diet high in fermentable fibre boosts butyrate production because it fuels the short-chain fatty acid (SCFA) producing bacteria in the colon, allowing them to thrive. Vegetables, fruits, legumes, whole grains, rice, boiled potatoes (resistance starch) and prebiotic foods such as onions, garlic, asparagus and artichoke all fuel butyrate production.
Polyphenols
Foods rich polyphenols such as red wine, dark chocolate, tea, coffee, and many coloured fruits and vegetables contain antioxidants that have prebiotic properties and exert anti-microbial action against pathogenic gut microbes.
Regular consumption of dietary polyphenols feeds our beneficial gut microbes and increases our microbiome diversity. The richer and more diverse your community of gut microbes is, the lower your risk of disease and allergies.
I am not suggesting you go mad with wine, coffee, and chocolate, but it is good to know there are some benefits to our gut microbiome for moderate consumption. Consuming berries, grapes, plums, oranges, kiwifruit, pomegranate, coffee, green tea, black tea, red wine, hazelnuts, almonds, walnuts, spinach, broccoli, red onion, asparagus, and carrots can provide beneficial prebiotic action because of their rich polyphenol content.
Cod liver oil
Both vitamin D and Vitamin A have been found in studies to increase T regulatory cells and omega-3 is nature's greatest anti-inflammatory. So, a daily serving of cod liver oil packs a power punch of immune regulating and anti-inflammatory action as it is not only rich in omega-3 but also contains naturally occurring vitamin A and D. I will explain more on vitamin A and D shortly.
Green Tea
Not technically a food, but green tea has been shown in studies to increase T regulatory cell frequency. The polyphenol EGCG `One of the beneficial compounds in green tea has the powerful ability to increase the number of regulatory T cells that play a key role in immune function and the suppression of autoimmune disease’ (8) It may therefore be beneficial to change your regular coffee or black tea to green tea.
Supplements that may help to support T regulatory cells
In addition to the dietary suggestions, you could use the following supplements during the preconception and implantation stage to regulate your immune system and increase self-tolerance by increasing T regulatory cells.
Vitamin D
According to studies, supplementing with vitamin D may reduce inflammation and increase T regulatory cell function in both healthy individuals and patients with autoimmune disorders. `In five trials of autoimmune disorders which measured the proportion of T regs, a higher proportion was observed in the vitamin D group compared to controls at 12 months in all but one trail’ (9)
Vitamin D3 (cholecalciferol) is known as the `sunshine vitamin’ because it is produced by the skin when it is exposed to the sun. If we spend enough time out in the sun on a daily basis, most of us could make enough vitamin D. However, many of us don't get enough consistent sun exposure to maintain normal vitamin D levels throughout the year, with levels dropping for most people over the wintertime.
Vitamin D3 can also be found in foods such as eggs, cod liver oil, mushrooms, fatty fish such as tuna and salmon, and cow's milk, but it can be difficult to get enough in the diet.
A deficiency in vitamin D3 has been associated with various autoimmune conditions, as it has a modulating effect on the immune system. As many fertility issues can be a result of an underlying autoimmune condition, it is important to get vitamin D levels checked.
Typical symptoms of vitamin D deficiency include Infertility, excess sweating, muscle weakness, chronic infections, weak bones, bone pain, chronic pain, tiredness, depression (it affects the level of serotonin in the brain), digestive issues, and asthma.
To allow your skin the opportunity to make vitamin D, it is recommended to spend 10 - 15 minutes every day out in the sunshine with no sunscreen in the summer and at least an hour during the winter. In summer, it is best to avoid the heat of the day, so before 10 am and after 3.00 pm. Your skin will manufacture vitamin D when it is in contact with the sun.
The recommended daily dose of vitamin D3 for those trying to conceive is at least 1,000 -2,000IU per day (preferably with K2 as they work as a team for bone health), although testing is advisable as you may need more than this. I took 2,000 – 5,000iu per day to support my immune system while trying to conceive with regular testing to check my levels.
Vitamin A
Retinoic acid, the metabolite from Vitamin A, promotes the induction of T regulatory cells from native T cells, which prevents their conversion into Th17 cells. `Adequate Vitamin A status, whether derived from the ingestions of preformed retinol or beta carotene, is important for maintaining a proper balance of well-regulated T cell functions and for preventing excessive or prolonged inflammatory reactions' (10)
Beta carotene can be found in yellow and orange coloured fruits and vegetables as well as leafy green vegetables and can be eaten in abundance so we don't have to worry about the toxicity that associated with too much of the retinol form of vitamin A. Good sources of beta carotene are carrots, pumpkin, red cabbage, sweet potato, winter squash, apricots, mango, cherries, papaya, peaches, watermelon, asparagus, broccoli, Brussel sprouts, kale, lettuce, parsley and spinach. Many of these fruits and vegetables are a good source of vitamin C as well, which will provide extra support to the immune system.
Organic liver is an excellent source of preformed vitamin A (retinol) and can be frozen raw and a little bit grated in to food that is cooking. Other good sources of vitamin A are egg yolks, cod liver oil, butter and dairy products.
Reishi Mushroom
I have always been very interested in the functional properties of mushrooms, so I started to take Reishi in June 2018 to support my immunity over the winter as I had found Reishi to be very effective at providing immune protection for winter ills and chills. This was a month before I conceived my daughter, so I always wondered whether Reishi had played a role in that.
Looking at various studies, a protein found in Reishi known as RLZ -8 appears to regulate the Th17/T reg balance by down regulating Th17 cells and upregulating T regulatory cells. In a 2013 study, ` LZ-8 treatment was found to stimulate a 4-fold and 10-fold expansion in the T reg population of murine and human primary CD4 + T Regulatory Cells Respectively’ (11)
So, if my recurring chemical pregnancies were because of an imbalance in Th17 and T regulatory cells at the time of implantation, then Reishi would have helped to calm down my overactive immune system and stopped it from attacking the foetus, allowing implantation to succeed.
If you take Reishi while trying to conceive, I would recommend stopping it once a pregnancy is confirmed as the purpose is to use it to support the immune system during the complexities of the implantation process.
Silent, low-grade inflammation is exactly that silent, so you may not actually know it may be affecting you. If you are experiencing unexplained infertility and recurring pregnancy loss, think about the symptoms that you have that may contribute to this immune imbalance. This could be joint pain, abdominal gas and bloating, food intolerances, thrush, skin rashes and other allergies, asthma, gut infections, anything really.
The next step would be to work with a naturopath, nutritionist or functional medicine practitioner who can help you get to the root cause of your unexplained infertility and work with you to bring things back in to balance with a personalised treatment plan.
For clients in New Zealand (where I am based), I offer a FREE 15-minute consultation via Zoom to have a quick chat about your situation and how I can help as a Fertility Nutritionist who has also experienced unexplained infertility and recurring pregnancy loss. More information on my story can be found on my website as well as how to book a consultation.
References
Ehsani M et al, Female Unexplained Infertility: A Disease with Imbalanced Adaptive Immunity, Journal of Human Reproductive Sciences, Oct – Dec 2019, p 275
Oukka M et al, Th17 Cells in immunity and Autoimmunity, BMJ Journal, Annals of Rheumatic Disease, Vol 67, issue suppl 3.
Ehsani M et al, Female Unexplained Infertility: A Disease with Imbalanced Adaptive Immunity, Journal of Human Reproductive Sciences, Oct – Dec 2019, p 276
Rocamera- Reverte et al, The Complex Role of Regulatory T Cells in Immunity and Aging, Immunol 27/1/2021, Vol 11, Frontiers in Nutrition.
Jian Tan et al, Your Regulatory T Cells are What You Eat. How Diet and Gut Microbiome affect Regulatory T Cell Development, Frontiers in Nutrition, 20/4/22
Siddiqui MT et al, The Immunomodulatory Functions of Butyrate, J Inflamm Res, 2021, 14: 6025 – 6041, Nov 18 2021
Liu L et al, Butyrate Interferes with the Differentiation and Function of Human Monocyte – Derived Dendritic Cells, Cell Immunol 2012, 277 (1-2) p 66 – 73.
Ho E, Mechanisms Discovered for Health Benefits of Green Tea, New Approaches to Autoimmune Disease, Oregon State University, 3 June 2011, sources from sciencedaily.com.
Fisher S A et al, The Role of Vitamin D in Increasing Circulating T regulatory Cells, PLos One, 24/9/2019, sourced from www.ncbi.nlm.nih.gov
Ross A C, Vitamin A and Retinoic Acid in T Cell Related Immunity, AMJ Clinical Nutrition, 2012, Nov 96 (5) 11665 – 11725
Hsien-Yeh Hsu et al, Reishi Protein Induces FOXP3+ T Reg Expansion via a CD45 Dependent Signalling Pathway and Alleviates Acute Intestinal Inflammation in Mice, Evid Based Complement Alternate Med, 2013, June 24.