The Gut Microbiome and Autoimmunity

As many as one in 10 people in the U.K. suffers from an autoimmune disease. In these 80 or so diseases—from type 1 diabetes and rheumatoid arthritis to psoriasis and multiple sclerosis—a person’s immune system attacks healthy cells. Although these autoimmune responses take place around the body, part of the problem is initiated by changes to the gut microbiome.

According to the U.S. National Institute of Environmental Health Sciences, “The microbiome is the collection of all microbes, such as bacteria, fungi, viruses, and their genes, that naturally live on our bodies and inside us.” The human gut microbiome alone consists of as many as 39 trillion cells. To give a feel for the size of that number, there are hundreds of times more microorganisms in a person’s gut than there are stars in the Milky Way galaxy.

“The intestine is one of the largest immune organs in mammals, and the gut microbiota directs the differentiation and maturation of immune cells in the intestine,” said Tadashi Takeuchi, MD, PhD, a postdoctoral scholar in Justin Sonnenburg’s lab in the department of microbiology and immunology at Stanford University School of Medicine. “Some gut bacteria can directly attach to intestinal epithelial cells to induce a subset of immune cells.”

Gut microbiota can also affect the immune system in another way. “Small compounds, also known as metabolites, produced by gut bacteria can act as ligands for receptors on immune cells to regulate their differentiation and activation,” said Takeuchi. “These metabolites can serve as nutrients that fuel the metabolism of immune cells as well.” (for more on this, see a recent review by Takeuchi and his colleagues). Moreover, peptides from microbiota in the gut can activate the immune system’s T cells.

“In any case, aberrant expansion and depletion of key gut bacteria, also known as dysbiosis, can lead to altered immune status in the intestine as well as other organs,” explained Takeuchi. “Since autoimmune diseases are immune diseases, these seem to be the most relevant mechanisms by which gut bacteria modulate the onset and severity of such diseases.”

A good-bad balance

In normal working order, the gut microbiome benefits human health. For example, some gut bacteria produce short-chain fatty acids that play a role in the development of immune cells, such as regulatory T cells that are needed to keep a person’s entire immune system in balance. In short, healthy people depend on beneficial bacteria in their guts.

However, if the gut microbiome tips out of a healthy balance, the immune system can turn against a person and cause autoimmunity. T cells can get overly activated and inflammatory cytokines can be produced. As a result, a person’s immune system starts attacking healthy cells and tissues.

The gut–microbiome balance can go wrong in many ways, and specific changes underlie different autoimmune diseases. For example, Fatemah Sadeghpour Heravi, PhD, a medical microbiologist at the Macquarie Medical School in Sydney, Australia, pointed out that an increase in Prevotella bacteria along with a decrease in others—including Bacteroides and Bifidobacterium—can play a part in rheumatoid arthritis.

So too much of some species of microorganisms or too little of others in the gut can trigger autoimmunity, and the disease-driving combinations might seem nearly endless. In fact, Huji Xu, MD, PhD, vice president of Beijing Tsinghua Changgung Hospital in China, and his colleagues, pointed out that “the shared microbial signatures across different [autoimmune] diseases remain relatively unclear.”

Xu’s team undertook a meta-analysis of 17 autoimmune diseases and analyzed RNA-sequencing data to look for differences in the gut microbiome. From this work, the scientists noted: “Microbial alterations among autoimmune diseases were substantially more consistent compared with that of other diseases (cancer, metabolic disease and nervous system disease), with microbial signatures exhibiting notable discriminative power for disease prediction.” The team identified four microorganisms—Enterococcus, Veillonella, Streptococcu, and Lactobacillus—that at high levels can drive autoimmunity, and 18 other microbiota that at low levels can drive autoimmune diseases. In addition, Xu’s team pointed out that reduced levels of even more microorganisms in the gut might contribute to autoimmunity. Further complicating the relationship between the gut microbiome and autoimmunity, the scientists concluded that “bacterial genera associated with disease may not always be antagonistic, but may represent protective or adaptive responses to disease.”

Consequently, the balance of the gut microbiome determines if it helps or hurts a person’s health, but determining the right balance is a difficult task.

Gastrointestinal tract and beyond

Given the gut microbiome’s location, it is no surprise that some of its autoimmune impacts take place in the gastrointestinal (GI) tract, but the impact goes much further. For example, Daniel Lemberg, MBBS, head of pediatric gastroenterology at Sydney Children’s Hospital, and his colleagues reported: “A significant amount of evidence clearly points to a dysbiosis manifest in inflammatory bowel disease (IBD) when compared to healthy controls. Less understood is the microbiome profile in autoimmune liver disease (AILD).”

Lemberg and his colleagues compared the microbiomes in healthy children to those with IBD, AILD, or both. The results showed similar microbiomes in healthy children and ones with AILD. “Those with IBD-AILD and IBD have similar microbiome profiles which are distinct from AILD alone and healthy controls,” Lemberg’s team concluded. “This suggests that the dysbiosis in these groups is primarily due to IBD rather than AILD.”

Beyond the bowel and liver, the gut microbiome influences diseases in other nearby organs such as the kidney. At Monash University’s Centre for Inflammatory Diseases in Australia, Kim O’Sullivan, PhD, head of translational kidney therapies, looks for novel therapies to treat anti-neutrophil cytoplasmic antibody associated vasculitis (AAV), an autoimmune disease that can impact the small blood vessels in the kidney and lead to kidney disease. Nearly one-third of AAV patients end up needing dialysis even after being treated with current therapies.

“Kidney disease is associated with increased intestinal permeability where endotoxin (a component of the gut bacterial cell wall) translocates across the intestinal barrier into the blood stream, activating immune responses,” O’Sullivan and her colleagues recently reported. “Although data on the gut–kidney axis are sparse, evidence shows kidney injury leads to the accumulation of urea and other uremic toxins which can translocate into the intestinal lumen and perturbate the commensal bacteria.” Moreover, differences in the gut microbiota distinguish healthy people from ones with inflammatory diseases, including AAV. In particular, O’Sullivan’s team pointed out that the “ratio of gut bacteria Bacteroidetes/Firmicutes is associated with worse outcomes in multiple autoimmune kidney diseases.”

When the balance of Bacteroidetes/Firmicutes is off, a diet high in fiber can help, at least in the mouse models used in O’Sullivan’s lab. “Given the lack of current treatments that are both effective and without toxic side effects, exploring mechanisms in which we can control inflammation and mitigate disease progression through the manipulation of the gut microbiome presents potential for novel therapeutic approaches,” O’Sullivan and her colleagues concluded. “Nevertheless, numerous questions persist regarding the utilization of gut microbiome manipulation as therapy.”

Beyond a microbial imbalance in the gut, some autoimmune diseases are associated with decreased microbial diversity. This is the case for autoimmune thyroid disease (AITD), which is a disease of increasing concern. “The prevalence of thyroid disorders, including autoimmune thyroid diseases … is increasing,” according to Marian Ludgate, PhD, professor emeritus at Cardiff University’s School of Medicine in the U.K., and her colleagues. “AITD currently affects up to 5% of the population.”

Although the gut microbiomes of people with AITD vary geographically, Ludgate and her colleagues added that the gut microbiota are less diverse in patients with AITD irrespective of where they live. Current studies confirm that “the gut microbiota is significantly perturbed in thyroid disorders,” concluded Ludgate and her colleagues. Nonetheless, scientists and clinicians are a long way from turning this information into treatment. As Ludgate’s team put it: “Identifying species that are either helpful or harmful to pathogenesis, treatment response and disease relapse will pave the way for personalized treatments aimed at optimizing the composition of the microbiota.”

The gut–brain connection

The gut microbiome’s reach even impacts the immune system away from digestive and metabolic organs. As one example, microorganisms in the gut affect immune cells in the brain.

“The gut microbiome influences the nervous system innervating the gut and the gut immune cells,” says David Lawrence, PhD, professor in the departments of environmental health sciences and biomedical sciences at the University of Albany. Metabolites produced by microbes in the gut also affect the nerves and immune cells. “Under normal healthy circumstances, the commensal microbes help to maintain homeostasis in the gut and between nerve and immune interactions,” said Lawrence. “When the commensal microbe population is altered by a pathogen or ingested environmental toxins or toxicants, the homeostasis may be changed including the epithelial barrier, allowing the friendly microbes in the gut to become dangerous inducers of inflammation creating a septic condition.” Peripheral nerves—especially the vagus nerve, which runs from the medulla oblongata in the brain stem to many parts of the body, including the GI system—then signal the central nervous system.

“Any modification of the gut microbiome can be transmitted to the brain, alerting the brain to dangers,” explained Lawrence. “The peripheral inflammation also may affect the blood-brain barrier allowing additional brain changes.”

The microbiome-brain connection gets pretty complicated. For one thing, it can be impacted by diet and environmental stresses—from biological stresses like infections to chemical and physical stresses. Even psychological stress can impact the microbiome–brain connection. In thinking of all these potential sources of stress, Lawrence said: “Each has influences on nerves, immune cells, and neuroimmune interactions.”

These interactions can also trigger autoimmunity. “If inflammation is enhanced, there may be viability influences on cells in many organs, including the brain,” Lawrence explained. “This would lead to more release of damaged cell products, and the development of antibodies to them, especially when the immune system is already receiving stimulation from pathogen-associated molecular patterns from leaked gut microbes.”

Moreover, the brain is not the only part of the nervous system affected by microbes in the gut. In multiple sclerosis (MS), for example, the immune system attacks the myelin sheath of neurons in the brain and spinal cord. This sheath around a neuron serves as an insulator, sort of like the plastic casing on an electrical wire. When the myelin gets damaged, the electrical signals carried by neurons slow down or even fail to reach the intended destination.

According to Ashutosh Mangalam, PhD, associate professor of pathology at the University of Iowa’s Carver College of Medicine, and his colleagues: “Several studies, including from our groups, have shown that people with MS have gut dysbiosis characterized by a distinct gut microbiome compared to sex- and age-matched healthy controls.” By combining data from a range of studies, Mangalam’s team found many microbes were increased, such as Streptococcus, or reduced, such as Clostridium, in the gut of people with MS.

Based on these findings, Mangalam’s team displayed some optimism, writing: “The significance of gut microbiota in the pathobiology of MS is increasingly recognized, presenting a vast potential for leveraging its capabilities as a potential diagnostic, prognostic, and therapeutic tool.” Nonetheless, the gut microbiome is probably not the sole path to addressing MS. For one thing, genetic factors contribute to the risk of developing MS. Moreover, microbiota beyond the gut might matter. As Mangalam and his colleagues explained: “While the gut microbiome has garnered significant attention in the context of MS, it is crucial to acknowledge that other host microbiomes, such as the oral and nasal microbiota, may also play a role in the development and progression of this neurological disorder.”

Is precision possible?

From a patient perspective, all this information is little more than a collection of clinical and biological gobbledygook unless it impacts the efficacy of treatments. For now, autoimmune diseases “are increasing in prevalence, but selecting the best therapy for each patient proceeds in trial-and-error fashion,” wrote Renuka Nayak, MD, PhD, assistant professor of medicine at the University of California, San Francisco, and Diego Orellana, a graduate student at Washington University in St. Louis. “This strategy can lead to ineffective therapy resulting in irreversible damage and suffering; thus, there is a need to bring the promise of precision medicine to patients with autoimmune disease.” Nayak and Orellana suggested that “the gut microbiome can be manipulated to improve therapy and to derive greater benefit from existing therapies.”

As scientists learn more about autoimmunity, molecular targets might be identified. When the gut microbiome increases the activation or decreases the suppression of particular components of the immune system, that can trigger autoimmunity. For example, CD40L is a protein that can be expressed on various cells, including activated T cells. Recently, Jon Laman, PhD, professor of immune physiology at the University Medical Center Groningen in the Netherlands, and his colleagues showed that too much expression of CD40L can lead to autoimmunity. Consequently, inhibitors of CD40L might treat a range of autoimmune diseases.

“A number of CD40L antagonists have entered clinical trials and have demonstrated therapeutic benefit in organ-specific and systemic autoimmune diseases,” noted Laman and his colleagues. “The use of CD40L antagonists will expand to a wider spectrum of human immune–mediated inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis owing to the newfound ability to control disease progression.”

Study humans, not mice

Even as scientists and clinicians learn more about the connection between the gut microbiome and autoimmune diseases, they realize that they are just starting to explore this area of biomedicine.

“Our current understanding of how the microbiome impacts the immune system is based mostly on experimental findings from animal studies,” said Takeuchi. “However, it has been increasingly recognized that the human gut microbiome is substantially different from the mouse microbiome, as well as the way it impacts the immune system.”

Much more work lies ahead. As Takeuchi noted: “It would be important to study the human gut microbiome and immune system in the context of autoimmunity through clinical trials and deep phenotyping, such as multi-omics, in the future.” Such work, he said, “would provide new mechanistic insights into how gut bacteria modulate host immunity and autoimmunity in a manner that is relevant to humans.”

 

Read more:

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2. National Institute of Environmental Health Sciences. Microbiome. (Last reviewed March 22, 2024). niehs.nih.gov/health/topics/science/microbiome
3. Sung, J., Rajendraprasad, S.S., Philbrick, K.L., et al. The human gut microbiome in critical illness: disruptions, consequences, and therapeutic frontiers. Journal of Critical Care 79: 154436 (2024).
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9. Ludgate, M.E., Masetti, G., Soares, P. The relationship between the gut microbiota and thyroid disorders. Nature Reviews Endocrinology 20:511–525. (2024).
10. Heidari, H., Lawrence, D.A. An integrative exploration of environmental stressors on the microbiome-gut-brain axis and immune mechanisms promoting neurological disorders. Journal of Toxicology and Environmental Health. (2024). org/10.1080/10937404.2024.2378406.
11. Tuner, T-A., Lehman, P., Ghimire, S., et al. Game of microbes: the battle within – gut microbiota and multiple sclerosis. Gut Microbes 16(1): 2387794. (2024).
12. Nayak, R.R,. Orellana, D.A. The impact of the human gut microbiome on the treatment of autoimmune disease. Immunological Reviews 325(1):107–130. (2024).
13. Laman, J.D., Molloy, M., Noelle, R.J. Switching off autoimmunity. Science 385:827–829. (2024).

 

Mike May is a freelance writer and editor with more than 30 years of experience. He earned an MS in biological engineering from the University of Connecticut and a PhD in neurobiology and behavior from Cornell University. He worked as an associate editor at American Scientist, and he is the author of more than 1,000 articles for clients that include GEN, Nature, Science, Scientific American, and many others. In addition, he served as the editorial director of many publications, including several Nature Outlooks and Scientific American Worldview.