'First Evidence' Links Gut Bacteria, Fibromyalgia

Deborah Brauser

July 09, 2019

Patients with fibromyalgia appear to have specific gut microbiome alterations that differ from their healthy peers, new research suggests.

In the "first evidence" to show this connection, investigators found that women with fibromyalgia had significant differences in 19 species of gut bacteria compared with healthy controls. They also had higher serum levels of butyrate and lower levels of propionate.

In addition, machine-learning algorithms showed diagnostic prediction accuracy ratings of 87%–88%.

"To the best of our knowledge, this is the first demonstration of gut microbiome alteration in non-visceral pain," the researchers note.

Dr Amir Minerbi

"Basically, we showed a correlation between the composition and function of the gut microbiome and fibromyalgia, but there are a few questions that still remain," lead author Amir Minerbi, MD, PhD, Alan Edwards Pain Management Unit, McGill University Health Center, Montreal, Canada, told Medscape Medical News.

This includes assessing whether the findings are specific to fibromyalgia or if they can be more widely applied to chronic pain — and if all of this can be used to help with diagnoses, Minerbi said.

"We know that diagnosing fibromyalgia is quite challenging, so a diagnostic tool based on gut microbiota could be a very useful aid to clinicians. This opens the door for future studies and for the future of chronic pain research in general," he added.

The findings were published online June 18 in Pain.

Questionable Pathophysiology

The pathophysiology of fibromyalgia is not well understood, the investigators note. There are "multiple hypotheses being suggested, including impaired central nervous system nociceptive processing, altered peripheral nociception, and systemic inflammation," they add.

In addition, clinicians rely on patients' self-reported symptoms, which often leads to inaccurate diagnoses.

The researchers note that two recent retrospective cohort studies showed a 66% to 73% rate of false-positive diagnoses for fibromyalgia.

"Evidence is mounting on the critical role of the gut microbiota in a variety of pathologies, including, but not limited to, metabolic, cardiovascular, oncologic, neurologic, and psychiatric disorders," they write.

However, "data on the possible role of the gut microbiota in the pathophysiology of chronic pain outside of the gastrointestinal tract is still scarce," which led investigators to assess the possible association between the microbiome and fibromyalgia.

"Some of the circuits that are involved in psychiatric and neurologic conditions are also involved in chronic pain. So that was the rationale to look into changes in the microbiome in patients with chronic pain," Minerbi said.

Between October 2017 and June 2018, the investigators enrolled 77 women in Montreal who had fibromyalgia and were between the ages of 30 and 60 years (mean age, 46 years). The mean time of diagnosis was 12 years prior to recruitment.

Three groups of individuals were also included to serve as healthy controls. This included first-degree female relatives to act as genetic controls (n = 11); household members of the study patients (n = 20); and unrelated healthy women who were the same age as the patients (n = 48).

In addition to clinician interviews and other measures, a dietitian interviewed the participants and supervised administration of the National Institutes of Health Automated Self-Administered 24-hour Canada Dietary Recall questionnaire.

There were no significant between-group differences in intake of vitamins, minerals, alcohol, caffeine, sugar, fatty acids, and fiber. The overall diet quality scores were also not significantly different.

Participants used the Omnigen Gut OM-200 kit (DNA Genotek) to collect and freeze a stool sample at home. The frozen samples were delivered to the study facility within 10 days of collection and DNA was then extracted from the samples.

Using 16S ribosomal RNA (rRNA) gene amplification and whole genome sequencing, the investigators assessed the microbiomes of the 77 women with fibromyalgia and the 79 participants who acted as the total comparator group.

Gut Differences

Results showed "relatively similar" structure and diversity of the gut microbiome between the patients with fibromyalgia and healthy controls. However, they found significant alterations in gut microbiome composition when exploring the data at a "higher resolution."

Nineteen species of taxa were significantly different in patients with fibromyalgia vs the unrelated study participants. Those that were lower in abundance included Faecalibacterium prausnitzii, Bacteroides uniformis, Prevotella copri, and Blautia faecis.

Faecalibacterium prausnitzii is a butyrate-producing bacteria that has been shown in previous research to be depleted in multiple intestinal diseases.

An abundance of Bacteroides uniformis, Prevotella copri, and others have been linked before to inflammatory arthritis. In addition, Bacteroides uniformis has been detected in osteoarthritic joint tissue and Prevotella copri in rheumatoid arthritis synovial fluid.

However, these species were in lower abundance in the patients with fibromyalgia, calling into question past considerations of fibromyalgia as a rheumatologic disease.

Species that were in higher abundance in those with fibromyalgia included Intestinimonas butyriciproducens, Flavonifractor plautii, Butyricoccus desmolans, Eisenbergiella tayi, Eisenbergiella massiliensis, and Parabacteroides merdae.

Serum levels of butyric acid were significantly higher and levels of propionic acid were lower in the fibromyalgia group vs the unrelated-controls group (P = .005 and .006, respectively). They also had a nonsignificant trend toward lower levels of isobutyric acid (P = .056).

There was also a significant correlation between disease-severity measures, including pain intensity and distribution, fatigue, and cognitive symptoms, and an abundance of several taxa (Benjamini-Hochberg FDR, < .05).

Next, a "LASSO machine learning algorithm showed high prediction accuracy of patients from controls, based only on individual microbiome features," the investigators report. This resulted in an overall prediction accuracy, using Area Under the Curve/Receiver-Operating Characteristics (AUC-ROC), of 87.2%.

A Support Vector Machine algorithm yielded a prediction accuracy AUC-ROC of 87.8%.

Paving the Way

The study "paves the way for further studies, elucidating the pathophysiology of [fibromyalgia], developing diagnostic aids, and possibly allowing for new treatment modalities to be explored," the researchers write.

Minerbi noted that both the identity and function of the species of bacteria that differed between the groups were surprising.

"Some of them are actually involved in very interesting processes that could be pertinent in fatigue, sleep problems, cognitive dysfunction, and chronic pain — all of which are symptoms that we find in fibromyalgia," he said.

He added that the investigators now want to map other chronic pain conditions "and see if we can find similar alterations in the gut microbiome."

"Also, most important for patients, is the question of whether we can use what we found to treat fibromyalgia and improve the quality of life," he said.

Minerbi said the current findings are also important for patients on a psychological level.

For many years, because fibromyalgia is so hard to diagnose and has relied on subjective reports and not clinical evaluations, "many people did not believe that fibromyalgia existed and patients were sometimes doubted by family members, friends, and even clinicians. So what we've found is important," he explained.

Dietary Change for Pain?

Dr Robert Bonakdar

Commenting for Medscape Medical News, Robert Bonakdar, MD, director of pain management at Scripps Center for Integrative Medicine, La Jolla, California, said this study "is one of the best I have seen" in evaluating the microbiome and its relation to pain.

It has been known "for some time," Bonakdar said, that alterations in the microbiome can influence different types of pain, including inflammatory arthritis and visceral pain syndromes such as chronic pelvic pain.

"This trial found a significant association between the abundance of several taxa with pain intensity as well as fatigue and cognitive dysfunction commonly found in fibromyalgia. What is especially noteworthy…is that they used machine learning to show that just knowing the state of microbiome or its 'signature' could partially predict those with fibromyalgia vs controls," said Bonakdar, who was not involved with the research.

"These findings may help to partially explain why nutritional approaches such as increasing polyphenols through fruit and vegetable intake may improve fibromyalgia symptoms and quality of life," as noted in a recent preliminary trial, he added.

Bonakdar is a past president of the American Academy of Pain Management (AAPM). In addition, as reported at the time by Medscape Medical News, he spoke at the AAPM 2016 Annual Meeting about how nutrition can affect pain.

Overall, this area is especially important for clinicians "because it may provide a future diagnostic tool that is often elusive in conditions like fibromyalgia. Having a microbiome signature could allow clinicians to understand to what extent the gut is promoting the condition as well as how planned interventions that may alter the microbiome — such as diet, pre-, and probiotics — could be promising tools," he said.

Bonakdar also pointed out that while clinicians are more comfortable with gut interventions, such as stool transplants in GI conditions like inflammatory bowel disease, "it is intriguing to think about using these in the future to potentially address conditions like fibromyalgia that are connected as part of the Gut-Brain axis."

He noted that there are still more questions than answers in using the microbiome in pain management.

"But the main takeaway for clinicians is that for your patients, especially those with more complex refractory pain, think about the gut. While not all the answers reside there, we know that gut is affected in the pain journey through diet, stress, medications, and the disease process itself," he said.

"Beyond this, suggesting a higher fiber, higher polyphenol diet is a win-win to begin to support the gut while additional studies confirm these findings," Bonakdar said.

The study authors and Bonakdar have reported no relevant financial relationships.

Pain. Published online June 18, 2019.

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