Understanding the Role of Your Gut in Common Symptoms
An MTHFR gene mutation might seem to explain your symptoms, from chronic fatigue and pain to brain fog, anxiety, and hormonal imbalances. But a closer look at the research shows that the health impacts of these common gene variants may actually be quite minimal.
The symptoms that have been associated with MTHFR gene variations are more likely to be caused by gut imbalances and inflammation. This is good news, because these imbalances and their treatments are better understood.
In this article, we’ll explain the more likely causes of symptoms like fatigue, pain, brain fog, digestive symptoms, and hormonal imbalances, and how to treat them.
We’ll also break down why MTHFR research can be so misleading, what the evidence says about the folic acid debate, and why gene testing in general is likely more trouble than it’s worth.
What Is MTHFR?
MTHFR (short for methylenetetrahydrofolate reductase) is both a gene and an enzyme. When people talk about MTHFR, they are generally referring to the gene that tells the body how to make the enzyme. The MTHFR enzyme plays a role in various functions in the body, which we’ll cover in more detail below.
Common alterations in the MTHFR gene have been tenuously linked to several different health conditions and problems, including depression, chronic pain, heart disease, and autism.
Common variants of the MTHFR gene are often referred to as “mutations,” but experts have clarified that the term “polymorphism” is more accurate . This might not seem very important, but it’s worth acknowledging that variants in the MTHFR gene are probably not harmful, and the term “genetic mutation” might have unnecessarily negative connotations.
True mutations of the MTHFR gene (which are known to cause health problems including seizures and intellectual disabilities) are extremely rare.
In contrast, MTHFR gene polymorphisms affect 30-60% of the population . This includes a few common variants, including mthfr c677t and a1298c polymorphisms. Some MTHFR gene polymorphisms are inherited from one parent (heterozygous), and others are inherited from both parents (homozygous).
Despite all the attention the MTHFR gene mutation symptoms get on the internet, research suggests that having “abnormalities” in your MTHFR gene might actually be what’s normal. A 2019 review found that only 15% of the population had a genetic profile of MTHFR completely free of variants .
Should You Test for MTHFR or Other Genes?
With the advances in genetic understanding in recent years, the popularity of testing for variants in genes (like MTHFR) for health optimization purposes is booming. But research suggests that the results are generally not useful.
- A review paper found that there was at best minimal clinical utility to testing for MTHFR gene variants .
- The American Heart Association also concluded that there was no valid reason to routinely test for MTHFR polymorphisms in any patient group .
- Review papers have concluded that in most cases, consumer-based genetic test results do not correlate with a person’s actual risk of developing a disease [5, 6].
Genetic testing results can be a distraction from what’s really causing your symptoms and the types of treatment that can help you.
Gene testing can also be very disempowering for patients. Why focus on one small thing you can’t control when there are clear and proven approaches for taking charge of your health?
What Do Variations in the MTHFR Gene Mean?
The MTHFR gene tells the body how to make the MTHFR enzyme, which is responsible for converting folic acid (obtained from food and/or supplements) into methyl-folate (the form of folate used by your body).
Methyl-folate is one of the components that’s necessary for the body’s methylation process, which helps to regulate things like energy production, detoxification, nutrient metabolism, brain and neurotransmitter function, digestion, and hormonal balance.
Some people have concluded that MTHFR gene polymorphisms inhibit folic acid conversion and slow the methylation process to the point that it disrupts those functions, eventually leading to symptoms and serious health issues.
But does scientific evidence back up these conclusions?
We’ve had a close look at the research and found very little scientific evidence that having a common MTHFR gene polymorphism leads to any meaningful health changes or risks. While it’s true that MTHFR enzyme production may be somewhat reduced, it does not appear to be a significant reduction that leads to poor health. We’ll dive deeper into this concept below.
Why MTHFR Research Can Be Misleading
The confusion with MTHFR research often comes down to what we call the “effect size.”
Let’s break that down. When a research paper is published and states that there is an increased risk of a disease or symptom as a result of a specific factor (like the MTHFR gene), it can be understandably alarming. But how great is that increased risk, or the actual impact on your health? That’s where things get a little bit more complicated.
To understand the importance of effect size in research, consider the example of weight loss. Imagine that a paper is published with the conclusion that a particular supplement has been linked to weight loss. If your weight is a concern, you might want to rush out and buy that supplement.
But what if, when the research is analyzed more thoroughly, it turns out that the average weight loss associated with the supplement is 2 pounds (roughly equivalent to 1% of body weight) over a period of several months or even years? Is the impact– or the effect size– great enough for you to invest your healthcare dollars on this supplement?
Keeping this in mind, one of the most commonly cited risks associated with MTHFR gene polymorphisms is higher homocysteine levels.
Technically, the research data supports this link between MTHFR and homocysteine, but on closer scrutiny, we see the effect size is very small. A 2019 analysis of the data showed that the impact of the MTHFR gene on homocysteine levels is at most 1% . Your homocysteine levels are actually more likely to be high as a result of improper lab processing than as a result of an MTHFR gene variant.
All of this means that you probably don’t need to make drastic changes to your diet, lifestyle, or supplement routine based on your MTHFR gene variants, which is good news.
Untangling the Folic Acid Controversy
Another common misconception is that people with the MTHFR gene variant should avoid folic acid supplementation and opt for a more costly form of folate supplements instead.
However, the effects and benefits of folic acid and folate supplements are similar, and there don’t seem to be any risks associated with taking the more cost-effective folic acid even for those who have MTHFR polymorphisms .
- A large study on a Chinese population with common MTHFR polymorphisms found a 30% reduction in the risk of stroke with folic acid supplementation. This demonstrates that folic acid is effective (and not harmful) for those with MTHFR polymorphisms .
- Folic acid supplementation is often recommended for women of reproductive age in order to help prevent possible neural tube defects in their children. The available research shows a protective benefit from prenatal folic acid supplements for mothers with and without MTHFR polymorphisms .
MTHFR, Homocysteine, and Heart Disease
Many proponents of the MTHFR theory have warned of an increased risk of cardiovascular disease and related conditions, including blood clots, stroke, high blood pressure, and thrombosis (blood clotting within a blood vessel).
This is largely based on the concern that MTHFR gene variants may contribute to lower levels of folate (vitamin B9) and vitamin B12, and higher levels of homocysteine, all of which have been linked to a greater risk of heart disease.
One study on a Chinese population did find that individuals with one common MTHFR polymorphism had higher levels of homocysteine and lower levels of folate and B12. However, other factors affecting the prevalence of heart disease in this population are also likely to have contributed .
The Bigger Picture of Heart Disease
There are a number of risk factors that can contribute to elevated homocysteine levels. More broadly, factors related to diet, lifestyle, and gut health are known to be essential for heart health and for the prevention of cardiovascular disease. These include eating an anti-inflammatory diet, getting enough sleep, and engaging in regular exercise.
Inflammation and imbalances in the gut have also been linked to heart disease [9, 10, 11, 12, 13], and probiotics have been shown to help reduce homocysteine levels and increase levels of B vitamins by modifying bacteria in the gut .
It’s important to keep these heath fundamentals in mind, as too much emphasis on a single gene (which is something you can’t control) may end up distracting from the modifiable diet and lifestyle factors that have been proven to support a healthy heart.
If folate, vitamin B12, or high homocysteine levels are a concern for any reason, simple blood tests can determine your actual status [15, 16].
Symptoms Attributed To MTHFR Mutations
Beyond heart disease, several different kinds of symptoms have been attributed to MTHFR gene mutations, including fatigue, chronic pain, brain fog, depression and anxiety, estrogen dominance, and headaches.
These are common symptoms that we see and treat daily in our clinic. While the symptoms themselves are very real and troubling for patients, chances are, they’re not caused by MTHFR gene polymorphisms. Generally, these symptoms are signs of systemic inflammation and imbalances in the gut.
Let’s take a closer look at some of these symptoms, explore other likely causes, and discuss how to treat them.
The symptoms of gut imbalances often go well beyond digestive distress, and fatigue is a clear example.
There’s a strong connection between fatigue and several different gut conditions, including irritable bowel syndrome (IBS), intestinal permeability (leaky gut), gut infections, and non-celiac gluten sensitivity [17, 18, 19, 20, 21, 22, 23].
- Fatigue is one of the most common symptoms of IBS . A meta-analysis of 17 studies showed that more than 50% of IBS patients experience fatigue .
- Tiredness is one of the most common symptoms of non-celiac gluten sensitivity, reported by 64% of patients .
- Fatigue has been linked to imbalances in the gut microbiome and gut infections [21, 23].
- Fatigue is a common symptom of leaky gut [20, 22].
Healing the gut may help to resolve chronic fatigue or low energy.
- Treating leaky gut has been shown to improve symptoms of fatigue in patients with chronic fatigue syndrome .
- Following a low FODMAP diet, a common treatment for patients with small intestinal bacterial overgrowth (SIBO) and IBS, has been found to improve fatigue as well as digestive symptoms .
- Probiotics may help to improve symptoms associated with gut imbalances, like fatigue, by balancing bacteria in the gut, reducing inflammation, and improving leaky gut [25, 26, 27, 28, 29].
Chronic joint and muscle pain are often related to gut imbalances.
- Leaky gut and other gut imbalances have been linked to joint pain and inflammation in rheumatoid arthritis and related conditions [30, 31, 32, 33, 34, 35].
- Joint pain is a common symptom of IBS .
- Muscle and joint pain are common symptoms of non-celiac gluten sensitivity, reported in 31% of patients .
- One study showed that 48% of fibromyalgia patients also have IBS .
- Gut dysbiosis (an imbalance between beneficial and harmful gut bacteria) has been shown to be a contributing factor to the development of osteoarthritis .
Dietary strategies and therapies that target the gut have been shown to improve joint and muscle pain in both patients with gastrointestinal disorders and patients with chronic pain disorders [38, 39, 40].
- A 2019 clinical trial found that reducing dietary sugar, which contributes to intestinal inflammation and imbalances, improved muscle and joint pain for patients with IBS .
- In one study, an elemental diet (a therapy that reduced gut dysbiosis) was shown to improve pain and joint stiffness in patients with rheumatoid arthritis .
- Following a low FODMAP diet, which is often used to starve bacterial overgrowth in the gut, has been shown to reduce pain for patients with fibromyalgia .
Brain fog, or difficulty thinking clearly, concentrating, or remembering, is commonly reported among patients with gut imbalances.
- Gut dysbiosis, or imbalances in the gut microbiome, have been shown to affect brain function [41, 42, 43].
- Patients with IBS report a lower sense of coherence as a common symptom .
- Brain fog is a common symptom of celiac disease and non-celiac gluten sensitivity [45, 46].
Diets and treatments that address inflammation and gut imbalances may help improve cognitive function and symptoms like brain fog.
- A 2019 review showed that an anti-inflammatory diet can help reduce brain inflammation and leaky gut, which may improve brain fog .
- Probiotics have been shown to improve cognitive function in patients with fibromyalgia, Alzheimer’s disease, and among healthy older adults [41, 48, 49, 50].
Depression and Anxiety
Anxiety, depression, and other mental health conditions are often connected to inflammation and gut health [17, 19, 51].
- Depression and anxiety are common in patients with digestive disorders like IBS and non-celiac gluten sensitivity [17, 19].
- Leaky gut has been shown to contribute to depression and anxiety .
Healing the gut with the help of probiotics and diet has been shown to help treat depression and anxiety [52, 53, 54].
- A systematic review of 21 studies showed that anxiety improved in more than 50% of patients with the use of therapies that support a balanced gut microbiome, including probiotics and diet .
- A meta-analysis of 10 clinical trials concluded that probiotics were an effective treatment for mild to moderate depression .
- A study found that following a low FODMAP diet led to significant improvements in anxiety, depression, and overall happiness among patients with IBS .
Hormonal imbalances, especially estrogen dominance, are sometimes attributed to MTHFR gene polymorphisms. However, research does not support this connection.
Estrogen dominance and its symptoms, including irregular menstruation, mood swings, heavy or painful periods, bloating, and conditions including PCOS, may actually be caused by imbalances in the gut microbiome, which have been shown to disrupt estrogen levels [55, 56].
While research is limited, preliminary evidence suggests that probiotics may help to balance estrogen and other hormones by improving balance in the gut microbiome and reducing inflammation .
Migraines and Headaches
Migraines and headaches are common symptoms of gastrointestinal conditions including IBS and non-celiac gluten sensitivity [57, 19]. One study showed that a diet aimed at reducing inflammation (in this case, a gluten-free diet) improved migraine symptoms among patients with non-celiac gluten sensitivity .
Diet, Lifestyle, and Gut Health Should Come First
When it comes to your health, it’s very important to take a step back from the minutia and focus on the big picture. Research demonstrates, over and over again, the importance of health fundamentals. Diet, lifestyle, and gut health are among the most important factors when it comes to truly improving your health and resolving the symptoms commonly associated with MTHFR mutations.
Key lifestyle factors, like eating an anti-inflammatory diet and getting enough sleep, lead to clear and meaningful health and wellness benefits, regardless of your genetic profile.
Treatments that target the gut, including probiotics, can help to resolve many of the imbalances and symptoms associated with MTHFR gene variants.
To learn more about how to heal your gut and resolve your symptoms, check out my book, Healthy Gut, Healthy You. For more personalized help sorting out the true cause of your symptoms, my clinic is accepting new patients both virtually and in person. You can request a consultation here to get medical advice from our healthcare professionals.
- Sarah Long, Jack Goldblatt. MTHFR genetic testing: Controversy and clinical implications. Men’s health, April 2016. Australian Family Physician. Volume 45, No.4, Pages 237-240.
- Stephan Moll, Elizabeth A. Varga. Homocysteine and MTHFR Mutations. AHA Journals, Circulation. July 7, 2015. Vol 132, Issue 1. https://doi.org/10.1161/CIRCULATIONAHA.114.013311
- Wood TR and Owens N. Using synthetic datasets to bridge the gap between the promise and reality of basing health-related decisions on common single nucleotide polymorphisms [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2019, 8:2147 (https://doi.org/10.12688/f1000research.21797.1)
- Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153-6. doi: 10.1038/gim.2012.165. Epub 2013 Jan 3. PMID: 23288205.
- Tandy-Connor, S., Guiltinan, J., Krempely, K. et al. False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med 20, 1515–1521 (2018). https://doi.org/10.1038/gim.2018.38
- Direct-to-consumer genetic testing doi:10.1136/bmj.l5688
- Viswanathan M, Treiman KA, Kish-Doto J, Middleton JC, Coker-Schwimmer EJ, Nicholson WK. Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2017 Jan 10;317(2):190-203. doi: 10.1001/jama.2016.19193. PMID: 28097361.
- Zhao M, Wang X, He M, Qin X, Tang G, Huo Y, Li J, Fu J, Huang X, Cheng X, Wang B, Hou FF, Sun N, Cai Y. Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention. Stroke. 2017 May;48(5):1183-1190. doi: 10.1161/STROKEAHA.116.015324. Epub 2017 Mar 30. PMID: 28360116.
- Carrizales-Sepúlveda EF, Ordaz-Farías A, Vera-Pineda R, Flores-Ramírez R. Periodontal Disease, Systemic Inflammation and the Risk of Cardiovascular Disease. Heart Lung Circ. 2018 Nov;27(11):1327-1334. doi: 10.1016/j.hlc.2018.05.102. Epub 2018 Jun 2. PMID: 29903685.
- Shah PK, Lecis D. Inflammation in atherosclerotic cardiovascular disease. F1000Res. 2019 Aug 9;8:F1000 Faculty Rev-1402. doi: 10.12688/f1000research.18901.1. PMID: 31448091; PMCID: PMC6694447.
- Peng J, Xiao X, Hu M, Zhang X. Interaction between gut microbiome and cardiovascular disease. Life Sci. 2018 Dec 1;214:153-157. doi: 10.1016/j.lfs.2018.10.063. Epub 2018 Oct 29. PMID: 30385177.
- Tang WHW, Li DY, Hazen SL. Dietary metabolism, the gut microbiome, and heart failure. Nat Rev Cardiol. 2019 Mar;16(3):137-154. doi: 10.1038/s41569-018-0108-7. PMID: 30410105; PMCID: PMC6377322.
- Moludi J, Maleki V, Jafari-Vayghyan H, Vaghef-Mehrabany E, Alizadeh M. Metabolic endotoxemia and cardiovascular disease: A systematic review about potential roles of prebiotics and probiotics. Clin Exp Pharmacol Physiol. 2020 Jun;47(6):927-939. doi: 10.1111/1440-1681.13250. Epub 2020 Jan 24. PMID: 31894861.
- Valentini L, Pinto A, Bourdel-Marchasson I, Ostan R, Brigidi P, Turroni S, Hrelia S, Hrelia P, Bereswill S, Fischer A, Leoncini E, Malaguti M, Blanc-Bisson C, Durrieu J, Spazzafumo L, Buccolini F, Pryen F, Donini LM, Franceschi C, Lochs H. Impact of personalized diet and probiotic supplementation on inflammation, nutritional parameters and intestinal microbiota – The “RISTOMED project”: Randomized controlled trial in healthy older people. Clin Nutr. 2015 Aug;34(4):593-602. doi: 10.1016/j.clnu.2014.09.023. Epub 2014 Oct 8. PMID: 25453395.
- Henderson AM, Aleliunas RE, Loh SP, Khor GL, Harvey-Leeson S, Glier MB, Kitts DD, Green TJ, Devlin AM. l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women. J Nutr. 2018 Jun 1;148(6):885-890. doi: 10.1093/jn/nxy057. PMID: 29878267.
- Crider KS, Devine O, Qi YP, Yeung LF, Sekkarie A, Zaganjor I, Wong E, Rose CE, Berry RJ. Systematic Review and Bayesian Meta-analysis of the Dose-response Relationship between Folic Acid Intake and Changes in Blood Folate Concentrations. Nutrients. 2019 Jan 2;11(1):71. doi: 10.3390/nu11010071. PMID: 30609688; PMCID: PMC6356991.
- Frändemark Å, Jakobsson Ung E, Törnblom H, Simrén M, Jakobsson S. Fatigue: a distressing symptom for patients with irritable bowel syndrome. Neurogastroenterol Motil. 2017 Jan;29(1). doi: 10.1111/nmo.12898. Epub 2016 Jul 11. PMID: 27401139.
- Han CJ, Yang GS. Fatigue in Irritable Bowel Syndrome: A Systematic Review and Meta-analysis of Pooled Frequency and Severity of Fatigue. Asian Nurs Res (Korean Soc Nurs Sci). 2016 Mar;10(1):1-10. doi: 10.1016/j.anr.2016.01.003. Epub 2016 Feb 1. PMID: 27021828.
- Volta U, Bardella MT, Calabrò A, Troncone R, Corazza GR; Study Group for Non-Celiac Gluten Sensitivity. An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Med. 2014 May 23;12:85. doi: 10.1186/1741-7015-12-85. PMID: 24885375; PMCID: PMC4053283.
- Maes M, Coucke F, Leunis JC. Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome. Neuro Endocrinol Lett. 2007 Dec;28(6):739-44. PMID: 18063928.
- Nagy-Szakal, D., Williams, B.L., Mishra, N. et al. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome 5, 44 (2017). https://doi.org/10.1186/s40168-017-0261-y
- Maes M, Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10. PMID: 19112401.
- Naess H, Nyland M, Hausken T, Follestad I, Nyland HI. Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence. BMC Gastroenterol. 2012 Feb 8;12:13. doi: 10.1186/1471-230X-12-13. PMID: 22316329; PMCID: PMC3292445.
- Altobelli E, Del Negro V, Angeletti PM, Latella G. Low-FODMAP Diet Improves Irritable Bowel Syndrome Symptoms: A Meta-Analysis. Nutrients. 2017 Aug 26;9(9):940. doi: 10.3390/nu9090940. PMID: 28846594; PMCID: PMC5622700.
- Leblhuber F, Steiner K, Schuetz B, Fuchs D, Gostner JM. Probiotic Supplementation in Patients with Alzheimer’s Dementia – An Explorative Intervention Study. Curr Alzheimer Res. 2018;15(12):1106-1113. doi: 10.2174/1389200219666180813144834. PMID: 30101706; PMCID: PMC6340155.
- Toribio-Mateas M. Harnessing the Power of Microbiome Assessment Tools as Part of Neuroprotective Nutrition and Lifestyle Medicine Interventions. Microorganisms. 2018 Apr 25;6(2):35. doi: 10.3390/microorganisms6020035. PMID: 29693607; PMCID: PMC6027349.
- Mujagic Z, de Vos P, Boekschoten MV, Govers C, Pieters HH, de Wit NJ, Bron PA, Masclee AA, Troost FJ. The effects of Lactobacillus plantarum on small intestinal barrier function and mucosal gene transcription; a randomized double-blind placebo controlled trial. Sci Rep. 2017 Jan 3;7:40128. doi: 10.1038/srep40128. PMID: 28045137; PMCID: PMC5206730.
- Sindhu KN, Sowmyanarayanan TV, Paul A, Babji S, Ajjampur SS, Priyadarshini S, Sarkar R, Balasubramanian KA, Wanke CA, Ward HD, Kang G. Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2014 Apr;58(8):1107-15. doi: 10.1093/cid/ciu065. Epub 2014 Feb 5. PMID: 24501384; PMCID: PMC3967829.
- Lamprecht M, Bogner S, Schippinger G, Steinbauer K, Fankhauser F, Hallstroem S, Schuetz B, Greilberger JF. Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammation in trained men; a randomized, double-blinded, placebo-controlled trial. J Int Soc Sports Nutr. 2012 Sep 20;9(1):45. doi: 10.1186/1550-2783-9-45. PMID: 22992437; PMCID: PMC3465223.
- Horta-Baas G, Romero-Figueroa MDS, Montiel-Jarquín AJ, Pizano-Zárate ML, García-Mena J, Ramírez-Durán N. Intestinal Dysbiosis and Rheumatoid Arthritis: A Link between Gut Microbiota and the Pathogenesis of Rheumatoid Arthritis. J Immunol Res. 2017;2017:4835189. doi: 10.1155/2017/4835189. Epub 2017 Aug 30. PMID: 28948174; PMCID: PMC5602494.
- Wu X, He B, Liu J, Feng H, Ma Y, Li D, Guo B, Liang C, Dang L, Wang L, Tian J, Zhu H, Xiao L, Lu C, Lu A, Zhang G. Molecular Insight into Gut Microbiota and Rheumatoid Arthritis. Int J Mol Sci. 2016 Mar 22;17(3):431. doi: 10.3390/ijms17030431. PMID: 27011180; PMCID: PMC4813281.
- Maeda Y, Kumanogoh A, Takeda K. [Altered composition of gut microbiota in rheumatoid arthritis patients]. Nihon Rinsho Meneki Gakkai Kaishi. 2016;39(1):59-63. Japanese. doi: 10.2177/jsci.39.59. PMID: 27181236.
- Katz KD, Hollander D. Intestinal mucosal permeability and rheumatological diseases. Baillieres Clin Rheumatol. 1989 Aug;3(2):271-84. doi: 10.1016/s0950-3579(89)80021-4. PMID: 2670255.
- Bjarnason I, Williams P, So A, Zanelli GD, Levi AJ, Gumpel JM, Peters TJ, Ansell B. Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs. Lancet. 1984 Nov 24;2(8413):1171-4. doi: 10.1016/s0140-6736(84)92739-9. PMID: 6150232.
- Yang L, Wang L, Wang X, Xian CJ, Lu H. A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis. Int J Mol Sci. 2016 Dec 17;17(12):2126. doi: 10.3390/ijms17122126. PMID: 27999312; PMCID: PMC5187926.
- Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002 Apr;122(4):1140-56. doi: 10.1053/gast.2002.32392. PMID: 11910364.
- Maeda Y, Kurakawa T, Umemoto E, Motooka D, Ito Y, Gotoh K, Hirota K, Matsushita M, Furuta Y, Narazaki M, Sakaguchi N, Kayama H, Nakamura S, Iida T, Saeki Y, Kumanogoh A, Sakaguchi S, Takeda K. Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine. Arthritis Rheumatol. 2016 Nov;68(11):2646-2661. doi: 10.1002/art.39783. PMID: 27333153.
- Nilholm C, Roth B, Ohlsson B. A Dietary Intervention with Reduction of Starch and Sucrose Leads to Reduced Gastrointestinal and Extra-Intestinal Symptoms in IBS Patients. Nutrients. 2019; 11(7):1662. https://doi.org/10.3390/nu11071662
- Podas T, Nightingale JM, Oldham R, Roy S, Sheehan NJ, Mayberry JF. Is rheumatoid arthritis a disease that starts in the intestine? A pilot study comparing an elemental diet with oral prednisolone. Postgrad Med J. 2007 Feb;83(976):128-31. doi: 10.1136/pgmj.2006.050245. PMID: 17308218; PMCID: PMC2805936.
- Marum AP, Moreira C, Saraiva F, Tomas-Carus P, Sousa-Guerreiro C. A low fermentable oligo-di-mono saccharides and polyols (FODMAP) diet reduced pain and improved daily life in fibromyalgia patients. Scand J Pain. 2016 Oct;13:166-172. doi: 10.1016/j.sjpain.2016.07.004. Epub 2016 Aug 22. PMID: 28850525.
- Roman, P., Estévez, A.F., Miras, A. et al. A Pilot Randomized Controlled Trial to Explore Cognitive and Emotional Effects of Probiotics in Fibromyalgia. Sci Rep 8, 10965 (2018). https://doi.org/10.1038/s41598-018-29388-5
- Dopkins N, Nagarkatti PS, Nagarkatti M. The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders. Immunology. 2018 Jun;154(2):178-185. doi: 10.1111/imm.12903. Epub 2018 Feb 27. PMID: 29392733; PMCID: PMC5980216.
- Sun MF, Shen YQ. Dysbiosis of gut microbiota and microbial metabolites in Parkinson’s Disease. Ageing Res Rev. 2018 Aug;45:53-61. doi: 10.1016/j.arr.2018.04.004. Epub 2018 Apr 26. PMID: 29705121.
- Frändemark, Å., Jakobsson Ung, E., Törnblom, H., Simrén, M. and Jakobsson, S. (2017), Fatigue: a distressing symptom for patients with irritable bowel syndrome. Neurogastroenterol. Motil., 29: e12898. https://doi.org/10.1111/nmo.12898
- Croall ID, Hoggard N, Aziz I, Hadjivassiliou M, Sanders DS. Brain fog and non-coeliac gluten sensitivity: Proof of concept brain MRI pilot study. PLoS One. 2020 Aug 28;15(8):e0238283. doi: 10.1371/journal.pone.0238283. PMID: 32857796; PMCID: PMC7454984.
- Manuela P, Alessia B, Mariagiovanna C, Giovanni P, Rita B, Giuseppe L. Neurophysiology of the “Celiac Brain”: Disentangling Gut-Brain Connections. Frontiers in Neuroscience. 2017. Volume 11, Pages 498. ISSN 1662-453X. doi: 10.3389/fnins.2017.00498.
- Riccio P, Rossano R. Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity. Nutrients. 2019 Nov 9;11(11):2714. doi: 10.3390/nu11112714. PMID: 31717475; PMCID: PMC6893834.
- Kim CS, Cha L, Sim M, Jung S, Chun WY, Baik HW, Shin DM. Probiotic Supplementation Improves Cognitive Function and Mood with Changes in Gut Microbiota in Community-Dwelling Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. J Gerontol A Biol Sci Med Sci. 2021 Jan 1;76(1):32-40. doi: 10.1093/gerona/glaa090. PMID: 32300799; PMCID: PMC7861012.
- Akbari E, Asemi Z, Daneshvar Kakhaki R, Bahmani F, Kouchaki E, Tamtaji OR, Hamidi GA, Salami M. Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer’s Disease: A Randomized, Double-Blind and Controlled Trial. Front Aging Neurosci. 2016 Nov 10;8:256. doi: 10.3389/fnagi.2016.00256. PMID: 27891089; PMCID: PMC5105117.
- Tamtaji OR, Heidari-Soureshjani R, Mirhosseini N, Kouchaki E, Bahmani F, Aghadavod E, Tajabadi-Ebrahimi M, Asemi Z. Probiotic and selenium co-supplementation, and the effects on clinical, metabolic and genetic status in Alzheimer’s disease: A randomized, double-blind, controlled trial. Clin Nutr. 2019 Dec;38(6):2569-2575. doi: 10.1016/j.clnu.2018.11.034. Epub 2018 Dec 10. PMID: 30642737.
- Stevens BR, Goel R, Seungbum K, Richards EM, Holbert RC, Pepine CJ, Raizada MK. Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut. 2018 Aug;67(8):1555-1557. doi: 10.1136/gutjnl-2017-314759. Epub 2017 Aug 16. PMID: 28814485; PMCID: PMC5851874.
Effects of regulating intestinal microbiota on anxiety symptoms: A systematic review
- Ng QX, Peters C, Ho CYX, Lim DY, Yeo WS. A meta-analysis of the use of probiotics to alleviate depressive symptoms. J Affect Disord. 2018 Mar 1;228:13-19. doi: 10.1016/j.jad.2017.11.063. Epub 2017 Nov 16. PMID: 29197739.
- Kortlever TL, Ten Bokkel Huinink S, Offereins M, Hebblethwaite C, O’Brien L, Leeper J, Mulder CJJ, Barrett JS, Gearry RB. Low-FODMAP Diet Is Associated With Improved Quality of Life in IBS Patients-A Prospective Observational Study. Nutr Clin Pract. 2019 Aug;34(4):623-630. doi: 10.1002/ncp.10233. Epub 2019 Jan 15. PMID: 30644587.
- Fuhrman BJ, Feigelson HS, Flores R, Gail MH, Xu X, Ravel J, Goedert JJ. Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women. J Clin Endocrinol Metab. 2014 Dec;99(12):4632-40. doi: 10.1210/jc.2014-2222. PMID: 25211668; PMCID: PMC4255131.
- Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen-gut microbiome axis: Physiological and clinical implications. Maturitas. 2017 Sep;103:45-53. doi: 10.1016/j.maturitas.2017.06.025. Epub 2017 Jun 23. PMID: 28778332.
- Li C, Yu S, Li H, Zhou J, Liu J, Tang W, Zhang L. Clinical features and risk factors for irritable bowel syndrome in Migraine patients. Pak J Med Sci. 2017 May-Jun;33(3):720-725. doi: 10.12669/pjms.333.12379. PMID: 28811802; PMCID: PMC5510134.
- K. Griauzdaitė, K. Maselis, A. Žvirblienė, A. Vaitkus, D. Jančiauskas, I. Banaitytė-Baleišienė, L. Kupčinskas, D. Rastenytė. Associations between migraine, celiac disease, non-celiac gluten sensitivity and activity of diamine oxidase. Medical Hypotheses. 2020. Volume 142, 109738. ISSN 0306-9877. https://doi.org/10.1016/j.mehy.2020.109738.