‘On the cusp’ of something big: New insights into the microbiome’s role in immunity
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As of just a few years ago, early enthusiasm over the apparent interplay between the gut microbiome and the immune system, and that it was driving or exacerbating certain rheumatic diseases, seemed to have all but dried up.
The data at the time had failed to move the bar beyond correlation, and the potential for any sort of clinical utility or therapy seemed scant.
Source: Renuka Nayak, MD, PhD
However, these attitudes have been steadily changing, as recent findings increasingly suggest not just correlation between gut microbes and rheumatic diseases, but causation. There is now evidence for disease modulation through the microbiome, and more rheumatologists are taking notice of the evolving data.
“Perhaps the most important point is that there is a move away from the idea that the wrong bacteria in the gut are causing illness or injury,” Renuka Nayak, MD, PhD, assistant professor at the University of California, San Francisco, told Healio Rheumatology. “We are moving away from the basic idea that there are good guys and bad guys.”
Rather than indulge in simplistic renditions of “good vs. bad,” experts like Nayak use words like “interplay” and “crosstalk” to describe how microbes in the gut interact with each other, with human cells, with the immune system and, potentially, with medications.
According to Gregg Silverman, MD, of the New York University Grossman School of Medicine, studies assessing these relationships within the last decade have pushed the field into a new, unprecedented realm.
“Right now, the research in the microbiome in rheumatology is getting beyond the phase when we are seeing correlation,” he said. “We are starting to understand the mechanisms. We are starting to figure out what the bacteria are doing and what this has to do with the immune system.”
However, “starting” to figure it out and arriving at answers that can lead to therapeutic interventions are two different animals, according to John M. Davis, III, MD, a rheumatologist at the Mayo Clinic.
“We are thinking about how to modulate the microbiome, but this is an area of uncertainty,” he said.
Although it may be possible to alter the microbiome to restore general gut health, doing so to improve complex conditions like rheumatoid arthritis, lupus, psoriatic arthritis or various spondyloarthropathies is another matter.
“There are host genetics to consider,” Davis said.
Environmental and lifestyle factors also play a role in the microbiome. Diet, smoking, alcohol consumption and history of illness can impact an individual’s microbes, as can the region of the country or world in which they live.
Another challenge lies in understanding the role of the microbiome in metabolizing medications.
“If a drug is being metabolized by the microbiome, what does that look like in the patient?” Nayak said. “What does that mean for response to the drug, and what does it mean for adverse events?”
In short, it remains unclear whether, for example, diarrhea or liver toxicity experienced by a patient is due to a poor response by the human cells or the microbial cells, according to Nayak.
“If we can understand this, then maybe we can use therapies in a more targeted way and improve the efficacy of our medications,” she said.
Sorting and analyzing all these relationships is painstaking work, but researchers have made significant strides in recent years.
Human Cells, Microbes Evolve ‘In Parallel’
The factors that impact the interplay between the microbiome and the human immune system begin at birth, according to Kristi Kuhn, MD, PhD, head of the division of rheumatology at the University of Colorado School of Medicine.
“The route of delivery, the method of feeding and the timing of natural foods being introduced all impact how an individual’s immune system develops,” she said. “All of this also will impact the microbiome and how the immune system develops and interacts with it. This all happens in parallel.”
When the parallel lines remain parallel, the delicate homeostasis also remains. However, if the immune system responds to something it should not respond to, problems can arise.
In a 2019 paper published in Best Practice & Research: Clinical Rheumatology, Kuhn and colleagues explored the role of mucosal surfaces in this interplay between the microbiome and host.
“Indeed, the mucosal immune system strikes a delicate balance between tolerance of commensal organisms and overt inflammation to ward off pathogens,” the researchers wrote. “Disruptions of the microbial ecology at mucosal surfaces has been described in a vast number of different human disease processes, including many forms of arthritis, and the resulting implications are still being understood to their fullest.”
According to Kuhn and colleagues, bacterial translocation may be involved, along with bacterial metabolite production, education of the immune response and molecular mimicry.
“It is normal for the immune system to recognize the bacteria that evolved with us and not respond,” Kuhn told Healio Rheumatology. “It is also normal for the immune system to recognize a pathogen like salmonella and form a response. However, if it is a commensal bacterium that is supposed to be there, and the immune system forms a response, this is when the problem can occur.”
According to Nayak, the reason this problem can occur may be rooted in molecular mimicry.
“Microbes have proteins. We have proteins. Those proteins may sometimes look similar to one another,” she said, adding that the immune system will occasionally respond to the wrong protein at the wrong moment. “By accident, this normal immune response becomes autoimmune.”
Despite this advanced understanding, Kuhn stressed that it remains unclear exactly how the dysbiosis in the interplay between host and microbiome can lead to a specific condition like RA or systemic lupus erythematosus.
It is also unclear whether this represents a single event or a series of steps that lead to disease development.
“It may be additive, meaning there is an exposure in the periodontium, which then leads to a response in the gut, which then leads to some manifestation in the joints,” Kuhn said. “It may be A plus B plus C, or maybe any one of these exposures is sufficient to cause disease.”
According to Nayak, there are microbes in the gut that can modulate — essentially “ramp up or ramp down” — the immune system.
“They may also produce proteins that the immune system is targeting,” she said.
Genetic factors may also apply, Nayak added.
“The story is evolving, because we now understand that the production of metabolites and molecular mimicry contribute to these processes,” she said. “It is not just that microbes translocate from the gut into the bloodstream and into the joints.”
As the knowledge base continues to grow, Kuhn said she encourages the rheumatology community to be “open-minded” about all of these possible avenues of disease pathogenesis.
“All of these things are on the table and may contribute,” she said.
Meanwhile, research into the microbiome’s impact on specific conditions, like RA, has begun to validate the idea that this is a multifactorial process that leads to disease.
Microbe-Immune ‘Crosstalk’ in RA
In a 2016 paper published in Genome Medicine, in which Davis was a researcher, Chen and colleagues sequenced the 16S ribosomal DNA of fecal samples from patients with RA, their first-degree relatives and a random cohort of healthy controls. The results demonstrated lower microbial diversity in the RA cohort compared with the control cohort. In addition, certain bacterial lineages were identified that carry associations with high levels of alpha-aminoadipic acid and asparagine, along with interleukin-17A, according to the researchers. Ultimately, they concluded that an association between the intestinal microbiota and metabolic signatures may “determine a predictive profile” for causation and progression of disease.
Later, in a 2021 paper also published in Genome Medicine, Gupta and colleagues investigated the gut microbiome of 32 patients with RA to determine whether it contained an association with minimal clinically important improvement (MCII) in disease activity.
“We showed that the gut microbial profile at baseline could predict activity of the disease 6 to 12 months down the road,” Davis, who was one of the researchers of the Gupta study, told Healio Rheumatology. “This is evidence that gut health does influence the course of disease and response to treatment.”
Davis described the findings as “fairly provocative” because they could help rheumatologists not only predict disease course, but, possibly, response to therapy.
“It may also be possible to differentiate responses to certain therapies, but that is a more challenging question,” he said.
According to Gupta, Davis and colleagues, baseline microbiome traits were different between patients who demonstrated MCII and those who did not. In addition, patients with higher microbial diversity were more likely to experience clinical improvement. The researchers also reported identifying several microbial taxa and biochemical pathways of MCII response. They concluded that modifying the gut microbiome to improve clinical outcomes “may hold promise” as a treatment for RA in the future.
“There is strong evidence that something is happening in the mucosal surfaces,” Kuhn said, adding that these sites range from the sinus and lung to the gut and vaginal canal. “Something is happening at that level leading to the development of anti-CCP antibodies, which we use to diagnose RA.”
According to Davis, the relationship between gut microbes and the immune system in RA could be defined by this “crosstalk.”
“In some cases, there is evidence that gut microbes might influence or educate different immune cells that mediate the disease,” he said.
This information will be useful not only in understanding RA, but also the role of the microbiome in other conditions, including lupus.
‘Paradigm-Shifting Results’
Perhaps the most convincing data demonstrating causality between the microbiome and a disease state can be found in lupus.
In a 2021 paper published in Frontiers in Immunology, Xiang and colleagues aimed to determine whether the association between the gut microbiome and lupus was, in fact, causal. According to the researchers, two distinct microbial populations demonstrated a positive correlation with SLE risk, while three other populations demonstrated a negative correlation.
“This study supports that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk,” Xiang and colleagues wrote.
According to Silverman, the terms that most accurately describe the process of how the microbiome impacts lupus are “homeostasis” and “shifts back-and-forth.”
“The barrier between the microbes in the gut and the rest of the body is not impervious,” Silverman said. “In a setting of local gut inflammation, large molecules and pieces of bacteria pass through, and some types of whole bacteria can translocate to draining lymph nodes without causing infection, and there are many other processes that may be triggered. The bacteria form these complex biochemical pathways, sometimes from one bacterium to the other and sometimes between bacteria and human cells.”
This likely explains the conclusion that the effects of the microbiome on lupus could be “beneficial or detrimental,” he added.
Further research in lupus builds on these conclusions.
In a paper published this year in the Annals of the Rheumatic Diseases, on which Silverman was a researcher, Azzouz and colleagues wanted to know whether the gut microbiome in a patient with lupus changes over time. They conducted a taxonomic analysis of the gut microbiome of patients with SLE in serial samples obtained over months and years. According to the researchers, there was a “significant temporal community-wide ecological microbiota instability.” In addition, one particular species of microbe was associated with lupus nephritis disease flares and high levels of serum IgG2 antibodies to this gut bacterium, called Ruminococcus gnavus (RG).
“Our findings rationalize how blooms of the RG pathobiont may be common drivers of clinical flares of lupus, which is often a remitting-relapsing disease, and highlight the potential pathogenic properties of specific strains of RG isolated from active LN patients,” the researchers wrote.
According to Silverman, this was the first longitudinal survey focused on the microbiome in patients with lupus.
“What we discovered in terms of drivers of flares is paradigm shifting,” he said.
Silverman added that certain strains of bacteria that are pathogenic expanded, often 10-fold, in approximately 40% of the patients with lupus nephritis flares.
“With this information, it may be possible to anticipate what will happen in the patient based on shifts in the microbiome,” he said. “It may impact how we treat the disease in the future as well.”
However, Silverman acknowledged that more research is required if causality is to be proven definitively. Despite the growing body of evidence, research pertaining to the causality of individual species in the microbiome in lupus is hard to establish for multiple reasons, he said.
One reason is that the bacteria in the gut are “hidden from view” unless they are specifically sampled and then categorized, according to Silverman.
“We speculate that the association of autoimmune disease flares with RG bacteria blooms may be more akin to post-streptococcal autoimmune states like rheumatic fever,” he said. “Here, the autoimmune disease in a genetically predisposed individual is also somehow triggered by certain strains of bacteria. Also, the stage for these blooms may be set in lupus patients who we found have a very unstable microbiome.”
The other question that still requires an answer is whether an unstable microbiome is pathogenic in general.
“Is it the microbiome itself or is it really something that knocks it out of whack?” Silverman said.
According to Kuhn, there are several possibilities that could explain how bacteria in the gut might contribute to disease.
First, bacteria that are supposed to be in the gut may ultimately travel to a joint, driving the inflammatory process.
Yet another theory pertains to the mucosal barriers.
“It may be that cells from the mucosal immune system circulate,” Kuhn said. “If a T cell that is prone to inflammation goes into the joint and there is not enough regulation, you can end up with a disease state.”
However, Silverman’s work suggests a third possibility, specifically regarding rheumatic fever, Kuhn said.
“Gut bacteria may trigger pathogenic immune responses that cross-react with the host,” she said.
According to Kuhn, data from the Silverman study represent critical step in the direction of understanding how the microbiome connects to disease.
“Trying to understand the specific way in which RG triggers IgG2 and ultimately nephritis will be the next step in our understanding of the specific mechanisms by which the microbiome contributes to disease,” she said.
The next question is what to do with the microbiome if, in fact, that is the issue. Research into psoriatic disease and spondyloarthritides may shed light on therapeutic interventions in the microbiome moving forward.
‘Selective Smart Bombs’
In a paper published this year in Arthritis & Rheumatology, Essex and colleagues conducted rRNA sequencing of stool samples from 277 patients with spondyloarthritis, as well as a cohort of healthy control individuals. According to the researchers, there were certain microbial populations involved in mediating serum C-reactive protein present in the SpA population, compared with controls. In addition, other microbes associated with HLA-B27 positivity were identified in the SpA group.
“Our work supports the existence of a common gut dysbiosis in SpA and related inflammatory pathologies,” Essex and colleagues wrote. “We reveal shared and disease-specific microbial associations and suggest potential mediators of disease activity.”
Findings like these raise the question of whether a complete transplant of the gut microbiota can be curative. According to Nayak, a small 2021 study from Kragsnaes and colleagues published in the Annals of the Rheumatic Diseases evaluated this approach.
“Unfortunately, the trial had to stop early because it was during the pandemic,” she said. “But they found that people who got the transplant actually did worse.”
Despite the negative result, there may be a silver lining, Nayak said.
“Although it was not what we were hoping for, it did show you could have an impact on disease activity with microbiota transplant,” she said. “It is useful to have that information for humans, because most of the previous data were mouse models.”
As researchers continue to explore the impacts of wholesale replacement of the microbiome, some experts believe that such extreme measures may not be suitable for most patients.
“We should target certain bacteria rather than dismantling the entire microbiome or the immune system,” Silverman said.
In a paper published this year in Nature Reviews Bioengineering, Bai and colleagues noted that there are several possible strategies for genetically engineering the gut microbiome, in addition to complementary approaches, such as “encapsulation, coupling with electronic devices, orthogonal diet engineering and fecal microbiota transplantation.”
According to Silverman, the question of whether it is possible to “engineer” the microbiome in the setting of rheumatic diseases remains complicated, as different microbiome communities may be required for each patient.
“Dysbiosis is a response to inflammation,” he said. “If you put a new coat of paint over an imbalanced microbiome but don’t do anything about inflammation, it is likely just going to revert to the pre-existing disturbed state.”
Like with total fecal replacement, broad-spectrum antibiotics also may not be the long-term solution, Silverman added.
“Maybe a better approach is to knock down a specific species and replace it with benign strains,” he said. “Selective smart bombs to eliminate one species and cause replacement by others might be feasible in the future in our patients, particularly those with lupus.”
Although excitement surrounding the potential to alter the microbiome to mitigate specific disease states is growing, experts understand that significant challenges remain. Not least among these challenges is the way the microbiome metabolizes medications.
‘On the Cusp’ of Therapeutic Interventions
Further findings from the Essex study suggest that other microbial populations may predict good response to conventional synthetic DMARDs in patients with RA. In addition, a 2020 study published in Arthritis & Rheumatology by Artacho and colleagues, on which Nayak was a researcher, suggested significant links between the abundance of gut bacterial taxa, as well as their genes, and clinical response, including “orthologs related to purine and methotrexate metabolism,” they wrote.
“There has been some evidence that methotrexate may be differentially metabolized by gut microbes in patients with RA,” Davis said. “This may influence response in those patients.”
According to Davis, it has been “long suspected” that the gut microbiome modifies metabolization of sulfasalazine.
“That is part of how the drug works,” he said. “However, patients with different microbiomes might handle it differently.”
Davis added that it is worth considering that metabolites may be impacting the immune system directly, rather than acting on the medication itself.
“Different bacteria in the gut may lead to different metabolites, which may then impact immune cells in the gut,” he said.
Although Nayak acknowledged a substantial body of research demonstrating different gut populations in patients on treatment vs. no treatment, it is difficult to “tease out” the actual impact of this metabolism on disease activity like pain and inflammation, she said.
“The drugs may be impacting the microbiome,” Nayak said. “Or it may be interplay between the drugs, the microbiome and the immune system.”
This interplay may explain adverse effects to medications like methotrexate, she added.
With all of this in mind, the stage for the next generation of studies in this area appears set.
“In the near term, it may be possible to develop biomarkers based on gut microbial profiles or gut metabolite profiles to see if a certain drug could be effective in a patient with RA,” Davis said.
According to Nayak, most of the current research in this space is concerned with oral medications, as opposed to injections or infusions.
“So many patients are taking biologics, but I have not seen any data to suggest that biologics are metabolized by bacteria,” she said.
However, that could soon change. Understanding the way next-generation medications are metabolized by the gut is just one direction for future consideration in rheumatology research.
According to Kuhn, the next step will be targeting those microbes therapeutically.
“This could be the next phase of the pipeline for the rheumatology armamentarium,” she said.
As this research develops, Silverman said he believes the microbiome will emerge as a key factor in clinical practice among rheumatologists.
“Early enthusiasm about the microbiome waned a few years ago because we did not really move beyond correlation,” he said. “But with more research showing disease modulation, we are starting to have evidence that could be explored for clinical utility. We may be on the cusp of doing something deeply beneficial about specific diseases.”
- References:
- Artacho A, et al. Arth & Rheum. 2020;doi:10.1002/art.41622.
- Azzouz DF, et al. Ann Rheum Dis. 2023;doi:10.1136/ard-2023-223929.
- Bai X, et al. Nat Rev Bioeng. 2023;doi:10.1038/s44222-023-00072-2.
- Chen J, et al. Genome Med. 2016;doi:10.1186/s13073-016-0299-7.
- Chriswell ME, Kuhn K. Best Pract Res Clin Rheumatol. 2019;doi:10.1016/j.berh.2020.101492.
- Essex M, et al. Arth & Rheum. 2023;doi:10.1002/art.42658.
- Gupta VK, et al. Genome Med. 2020;doi:10.1186/s13073-021-00957-0.
- Kragsnaes MS, et al. Ann Rhuem Dis. 2021;doi:10.1136/annrheumdis-2020-219511.
- Xiang K, et al. Front Immunol. 2021;doi:10.3389/fimmu.2021.667097.
- For more information:
- John M. Davis, III, MD, can be reached at 200 1st St. SW, Rochester, MN 55905; email: davis.john4@mayo.edu.
- Kristine Kuhn, MD, PhD, can be reached at 1635 Aurora Ct., 4th Floor, Aurora, CO 80045; email: kristine.kuhn@cuanschutz.edu.
- Renuka Nayak, MD, PhD, can be reached at 400 Parnassus Ave., San Francisco, CA, 94143; email: renuka.nayak@ucsf.edu; jaida.johnson@cuanschutz.edu.
- Gregg Silverman, MD, can be reached at Science Building, 5th Floor, Rm 517, 435 E. 30th St., New York, NY, 10016; email: gregg.silverman@nyulangone.org.
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