The Role of the Gut Microbiome in Autoimmunity

Written by Jonah Udall; Select sections of article written by and article reviewed by Dr. Bojana Jankovic Weatherly.

The gastrointestinal microbiome is increasingly recognized as an integral part of multiple systems of the human body. Many researchers believe that this community of microbes – which has as much or more metabolic capability as the liver – should be considered an organ itself.¹

Indeed, the microbiome can blur the line between what is “self” and what is “other.” If trillions of free-living microbes in our gut – which outnumber the human cells in our body – are in a relationship with nearly every body system, are they really distinct from “self”?

Considering this, it is easy to see why research is showing that the microbiome is closely related to autoimmune diseases – conditions which involve confusing “self” tissue for an invading “other.” A confused immune response to our microbiome (the “other self”) may contribute to a confused response to our own tissue – the basis of autoimmunity.

Many experts have argued for the “hygiene hypothesis,” which proposes that reduced exposure to diverse microbes deprives our immune system of the stimulus it needs to reliably differentiate “self” from “other” and avoid autoimmunity.² Overuse of antibiotics may contribute by depleting our gut microbiome.

But the story of the microbiome in autoimmune disease doesn’t end there. In a study of people with rheumatoid arthritis, the composition of their gut microbiome was the one of biggest determinants of clinical improvement over time – second only to age.³ This suggests that shifting the microbiome may have the power to alter the course of disease even once it’s already here.

The autoimmune microbiome

So, what does a healthy (or unhealthy) microbiome look like in autoimmunity? We dug into the research to find out, with a focus on the three autoimmune conditions we see most often: rheumatoid arthritis (hereafter referred to as “RA”), systemic lupus erythematosus (or SLE, from here on called “lupus”), and Hashimoto’s thyroiditis.

Diversity is key

First, low diversity is strongly associated with RA, lupus, and Hashimoto’s in numerous studies.^4–7 Even more, diversity is a key component of predicting clinical improvement in RA.³ This is important because diversity helps the microbiome stay in balance to prevent the overgrowth of problematic microbes, and provides the body with healthy immune stimulation. Eating a diet rich in polyphenols (the deep-colored antioxidants in plant foods) and fermented foods, and spending time with soil outdoors are powerful ways to boost your microbiome diversity.^8–10

Proteobacteria – the pro-inflammatory microbes

The other most common trait of the gut microbiome in autoimmunity is increased levels of a type of bacteria called Proteobacteria. These bacteria include pathogens like Salmonella, Rickettsia, Shigella, and Yersinia. Proteobacteria produce a particularly inflammatory form of a compound called lipopolysaccharide (LPS), otherwise known as “endotoxin,” and may play a role in numerous human diseases.¹¹ Low levels of these bacteria are perfectly normal, but higher levels may cause trouble.

In RA, increased Enterobacteriaceae – a group of Proteobacteria including Escherichia coli (E. coli) and Klebsiella – is associated with higher inflammation, suggesting that reducing these bacteria may support the body’s ability to heal.^12–14 Higher E. coli in particular may be one of the most important microbiome disturbances in RA, representing the overall changes in its metabolic activity.^6,7,15–17

Numerous studies have found similar Proteobacteria are elevated in the gut microbiome in people with lupus,^4,18,19 and people with Hashimoto’s.^20–22 In Hashimoto’s, the same Enterobacteriaceae have been correlated positively with thyroid antibody levels, suggesting they may contribute to autoimmunity.⁵

Check out our comprehensive article on LPS for more information and strategies for how to reduce it. If a stool test identifies high levels of a pathogenic species, speak with a doctor about targeted approaches for you.

Butyrate – the microbial anti-inflammatory

One of the most important products of the gut microbiome is butyrate. Butyrate is a short-chain fatty acid (SCFA) produced when the microbiome ferments undigested dietary fiber and resistant starch. Butyrate serves as healthy fuel for our intestines, and also supports immune system balance. In RA, depleted levels of butyrate-producing microbes and increased levels of butyrate consumers, which steal butyrate from our intestinal cells, may contribute to driving inflammation.²³

Numerous studies have found reduced butyrate producers in autoimmune conditions. Two butyrate producers in particular stand out. Coprococcus and Faecalibacterium prausnitzii have been found to be depleted in RA, lupus, and Hashimoto’s in numerous studies.^{4,7,16,20,24,25} Higher levels of Coprococcus have been associated with clinical improvements in RA patients,³ while lower levels correlate with elevated thyroid antibodies in Hashimoto’s.⁵ Inflammation is known to be central to autoimmune disease processes, and butyrate from a healthy microbiome may play an important part in keeping it in check.

The good news is, there are many ways to boost your butyrate producers. A Mediterranean diet rich in vegetables, whole grains, legumes, nuts, and fish has been found to be beneficial for both RA and lupus in clinical trials.^26,27 This may relate in part to its ability to shift the microbiome, including promoting Faecalibacterium prausnitzii.²⁸

Oral microbes in the gut?

Our gut isn’t the only place in the body with important microbes. The mouth has an incredibly diverse and unique microbiome, which may also have important effects on our health. In fact, RA is strongly associated with periodontitis – severe inflammation in the gums which often originates from imbalances in the oral microbiome.²⁹

But both RA and lupus have also been frequently associated with increased levels of oral microbes residing in the gut, such as Streptococcus and Lactobacillus salivarius.^16,25,30,31 Interestingly, these oral microbes are also often associated with small intestinal bacterial overgrowth (SIBO). Normally, the small intestine houses very few microbes, but in SIBO they increase, causing gastrointestinal symptoms such as bloating, gas and change in bowel habits. SIBO doesn’t always come with gut symptoms, however, and one study has suggested that people with RA may have high rates of SIBO.³² While stool samples can only measure the microbiome in the colon, small bowel microbes may be equally if not more important for our health. Talk to a health professional about testing for SIBO and supporting a healthy small intestine environment. In our practice, we have expertise in diagnosing and treating SIBO and would be happy to see you for an evaluation if you are in one of the states where we are licensed.

Harnessing your microbiome

Every microbiome is unique. While the patterns we discuss here are repeated across numerous studies, not everyone with autoimmunity has the same microbial alterations.¹⁶ Comprehensive microbiome analysis with a high-sensitivity stool test, under the guidance of a doctor, is the best way to know exactly how your microbiome and gut ecosystem may factor into your condition, and what should be done about it.

It’s also important to recognize that the microbiome can be a consequence as well as a cause of disease improvement. Some standard antirheumatic therapies can shift microbial populations for the better on their own.¹⁴ Whether or not you are targeting it intentionally, the microbiome will likely play an important role in your healing journey. But if you choose to focus on the microbiome, this powerful organ has much to offer.

References

1. Bäckhed F. Host responses to the human microbiome. Nutr Rev. 2012;70(suppl_1):S14-S17. doi:10.1111/j.1753-4887.2012.00496.x
2. Bach JF. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Immunol. 2018;18(2):105-120. doi:10.1038/nri.2017.111
3. Gupta VK, Cunningham KY, Hur B, et al. Gut microbial determinants of clinically important improvement in patients with rheumatoid arthritis. Genome Med. 2021;13(1):149. doi:10.1186/s13073-021-00957-0
4. Vieira JRP, Rezende AT de O, Fernandes MR, da Silva NA. Intestinal microbiota and active systemic lupus erythematosus: a systematic review. Adv Rheumatol Lond Engl. 2021;61(1):42. doi:10.1186/s42358-021-00201-8
5. Gong B, Wang C, Meng F, et al. Association Between Gut Microbiota and Autoimmune Thyroid Disease: A Systematic Review and Meta-Analysis. Front Endocrinol. 2021;12:774362. doi:10.3389/fendo.2021.774362
6. Sun Y, Chen Q, Lin P, et al. Characteristics of Gut Microbiota in Patients With Rheumatoid Arthritis in Shanghai, China. Front Cell Infect Microbiol. 2019;9:369. doi:10.3389/fcimb.2019.00369
7. Li Y, Zhang SX, Yin XF, et al. The Gut Microbiota and Its Relevance to Peripheral Lymphocyte Subpopulations and Cytokines in Patients with Rheumatoid Arthritis. J Immunol Res. 2021;2021:6665563. doi:10.1155/2021/6665563
8. Blum WEH, Zechmeister-Boltenstern S, Keiblinger KM. Does Soil Contribute to the Human Gut Microbiome? Microorganisms. 2019;7(9):287. doi:10.3390/microorganisms7090287
9. Vetrani C, Maukonen J, Bozzetto L, et al. Diets naturally rich in polyphenols and/or long-chain n-3 polyunsaturated fatty acids differently affect microbiota composition in high-cardiometabolic-risk individuals. Acta Diabetol. 2020;57(7):853-860. doi:10.1007/s00592-020-01494-9
10. Wastyk HC, Fragiadakis GK, Perelman D, et al. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021;184(16):4137-4153.e14. doi:10.1016/j.cell.2021.06.019
11. Rizzatti G, Lopetuso LR, Gibiino G, Binda C, Gasbarrini A. Proteobacteria: A Common Factor in Human Diseases. BioMed Res Int. 2017;2017:9351507. doi:10.1155/2017/9351507
12. Chen Y, Ma C, Liu L, et al. Analysis of gut microbiota and metabolites in patients with rheumatoid arthritis and identification of potential biomarkers. Aging. 2021;13(20):23689-23701. doi:10.18632/aging.203641
13. Chiang HI, Li JR, Liu CC, et al. An Association of Gut Microbiota with Different Phenotypes in Chinese Patients with Rheumatoid Arthritis. J Clin Med. 2019;8(11):1770. doi:10.3390/jcm8111770
14. Picchianti-Diamanti A, Panebianco C, Salemi S, et al. Analysis of Gut Microbiota in Rheumatoid Arthritis Patients: Disease-Related Dysbiosis and Modifications Induced by Etanercept. Int J Mol Sci. 2018;19(10):2938. doi:10.3390/ijms19102938
15. Cheng M, Zhao Y, Cui Y, et al. Stage-specific roles of microbial dysbiosis and metabolic disorders in rheumatoid arthritis. Ann Rheum Dis. 2022;81(12):1669-1677. doi:10.1136/ard-2022-222871
16. Thompson KN, Bonham KS, Ilott NE, et al. Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes. Sci Transl Med. 2023;15(706):eabn4722. doi:10.1126/scitranslmed.abn4722
17. Yu D, Du J, Pu X, et al. The Gut Microbiome and Metabolites Are Altered and Interrelated in Patients With Rheumatoid Arthritis. Front Cell Infect Microbiol. 2021;11:763507. doi:10.3389/fcimb.2021.763507
18. Chen B di, Jia XM, Xu JY, et al. An Autoimmunogenic and Proinflammatory Profile Defined by the Gut Microbiota of Patients With Untreated Systemic Lupus Erythematosus. Arthritis Rheumatol Hoboken NJ. 2021;73(2):232-243. doi:10.1002/art.41511
19. Xiang S, Qu Y, Qian S, et al. Association between systemic lupus erythematosus and disruption of gut microbiota: a meta-analysis. Lupus Sci Med. 2022;9(1):e000599. doi:10.1136/lupus-2021-000599
20. Su X, Zhao Y, Li Y, Ma S, Wang Z. Gut dysbiosis is associated with primary hypothyroidism with interaction on gut-thyroid axis. Clin Sci Lond Engl 1979. 2020;134(12):1521-1535. doi:10.1042/CS20200475
21. Ishaq HM, Mohammad IS, Guo H, et al. Molecular estimation of alteration in intestinal microbial composition in Hashimoto’s thyroiditis patients. Biomed Pharmacother Biomedecine Pharmacother. 2017;95:865-874. doi:10.1016/j.biopha.2017.08.101
22. Zhao H, Yuan L, Zhu D, Sun B, Du J, Wang J. Alterations and Mechanism of Gut Microbiota in Graves’ Disease and Hashimoto’s Thyroiditis. Pol J Microbiol. 2022;71(2):173-189. doi:10.33073/pjm-2022-016
23. He J, Chu Y, Li J, et al. Intestinal butyrate-metabolizing species contribute to autoantibody production and bone erosion in rheumatoid arthritis. Sci Adv. 2022;8(6):eabm1511. doi:10.1126/sciadv.abm1511
24. El-Zawawy HT, Ahmed SM, El-Attar EA, Ahmed AA, Roshdy YS, Header DA. Study of gut microbiome in Egyptian patients with autoimmune thyroid diseases. Int J Clin Pract. 2021;75(5):e14038. doi:10.1111/ijcp.14038
25. Wang Y, Wei J, Zhang W, et al. Gut dysbiosis in rheumatic diseases: A systematic review and meta-analysis of 92 observational studies. EBioMedicine. 2022;80:104055. doi:10.1016/j.ebiom.2022.104055
26. Papandreou P, Gioxari A, Daskalou E, Grammatikopoulou MG, Skouroliakou M, Bogdanos DP. Mediterranean Diet and Physical Activity Nudges versus Usual Care in Women with Rheumatoid Arthritis: Results from the MADEIRA Randomized Controlled Trial. Nutrients. 2023;15(3):676. doi:10.3390/nu15030676
27. Pocovi-Gerardino G, Correa-Rodríguez M, Callejas-Rubio JL, et al. Beneficial effect of Mediterranean diet on disease activity and cardiovascular risk in systemic lupus erythematosus patients: a cross-sectional study. Rheumatol Oxf Engl. 2021;60(1):160-169. doi:10.1093/rheumatology/keaa210
28. Meslier V, Laiola M, Roager HM, et al. Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut. 2020;69(7):1258-1268. doi:10.1136/gutjnl-2019-320438
29. Chu XJ, Cao NW, Zhou HY, et al. The oral and gut microbiome in rheumatoid arthritis patients: a systematic review. Rheumatol Oxf Engl. 2021;60(3):1054-1066. doi:10.1093/rheumatology/keaa835
30. Tomofuji Y, Maeda Y, Oguro-Igashira E, et al. Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese. Ann Rheum Dis. 2021;80(12):1575-1583. doi:10.1136/annrheumdis-2021-220687
31. Zhang X, Zhang D, Jia H, et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015;21(8):895-905. doi:10.1038/nm.3914
32. Henriksson AE, Blomquist L, Nord CE, Midtvedt T, Uribe A. Small intestinal bacterial overgrowth in patients with rheumatoid arthritis. Ann Rheum Dis. 1993;52(7):503-510. doi:10.1136/ard.52.7.503