A new study adds to what has been emerging in the literature — namely that there appear to be gut microbiome “signatures” for various pain conditions — suggesting that microbiome-based diagnostics and therapeutics may one day be routine for a broad range of pain conditions.
“There is now a whole list of pain conditions that appear to have these signatures, including postoperative pain, arthritis, neuropathy and migraine to name a few,” Robert Bonakdar, MD, director of pain management, Scripps Center for Integrative Medicine, San Diego, told Medscape Medical News.
Fibromyalgia and complex regional pain syndrome (CRPS) are also on the list.
A team led by Amir Minerbi, MD, PhD, director of the Institute for Pain Medicine, Haifa, Israel, and colleagues published one of the first articles on gut changes in fibromyalgia. They noted that the gut microbiome could be utilized to determine which individuals had the condition and which did not — with about a 90% accuracy.
The team went on to show that transplanting gut microbiota from patients with fibromyalgia into germ-free mice was sufficient to induce pain-like behaviors in the animals — “effects that were reversed when healthy human microbiota were transplanted instead,” Minerbi told Medscape Medical News.
Further, in a pilot clinical study, the researchers showed that transplanting microbiota from healthy donors led to a reduction in pain and other symptoms in women with treatment-resistant fibromyalgia.
Most recently, they found significant differences in the composition of the gut microbiome in a cohort of patients with CRPS from Israel, compared to matched pain-free control individuals.
Notably, two species — Dialister succinatiphilus and Phascolarctobacterium faecium – were enriched in patients with CRPS, while three species — Ligilactobacillus salivarius, Bifidobacterium dentium, and Bifidobacterium adolescentis – were increased in control samples, according to their report published last month in Anesthesiology.
“Importantly,” these findings were replicated in an independent cohort of patients with CRPS from Canada, “suggesting that the observed microbiome signature is robust and consistent across different environments,” Minerbi told Medscape Medical News.
Causal Role?
“These findings collectively suggest a causal role for the gut microbiome in at least some chronic pain conditions,” Minerbi said.
However, the co-authors of a linked editorial cautioned that it’s “unclear if D succinatiphilus or P faecium are functionally relevant to CRPS pathophysiology or if the bacteria increased in healthy control samples protect against CRPS development.”
Minerbi and colleagues also observed that fecal concentrations of all measured short chain fatty acids (SCFA) in patients with CRPS were lower on average compared to pain-free control individuals, of which butyric, hexanoic, and valeric acid showed significant depletion.
Additionally, plasma concentrations of acetic acid showed significant depletion in patients with CRPS vs control individuals, while propionate, butyrate, isobutyrate and 2-methyl-butyric acid showed a trend toward lower concentrations.
The quantification of SCFA in patient stool and serum is a “notable advance” in this study, Zulmary Manjarres, PhD; Ashley Plumb, PhD; and Katelyn Sadler, PhD; with the Center for Advanced Pain Studies at The University of Texas at Dallas, wrote in their editorial.
SCFA are produced by bacteria as a byproduct of dietary fiber fermentation and appropriate levels of these compounds are important to maintain low levels of inflammation in the colon and overall gut health, they explained.
This begs the question of whether administering probiotic bacteria — many of which are believed to exert health benefits through SCFA production — can be used to treat CRPS-associated pain. It’s something that needs to be studied, the editorialists wrote.
Yet, in their view, the “most notable achievement” of Minerbi and colleagues is the development of a machine learning model that accurately, specifically and sensitively categorized individuals as patients with CRPS or control individuals based on their fecal microbiome signature.
The model, trained on exact sequence variant data from the Israeli patients, achieved 89.5% accuracy, 90.0% sensitivity, and 88.9% specificity in distinguishing patients with CRPS from control individuals in the Canadian cohort.
Interestingly, in three patients with CRPS who underwent limb amputation and recovered from their pain, their gut microbiome signature remained unchanged, suggesting that microbiome alterations might precede or persist beyond symptomatic phases.
Test and Treat: Are We There Yet?
The gut microbiome link to chronic pain syndromes is a hot area of research, but for now gut microbial testing followed by treatment aimed at “fixing” the microbiome remains largely experimental.
At this point, comprehensive gut-microbiome sequencing is not a routine, guideline-supported part of care for fibromyalgia or any chronic pain condition.
“Unfortunately, even for doctors interested in this area, we are not quite at the state of being able to diagnose and treat pain syndrome based on microbiome data,” Bonakdar told Medscape Medical News.
He said there are many reasons for this including that this type of microbiome analysis is not commonly available at a routine lab. If patients do obtain testing, then the results are quite complex and may not translate to a diagnosis or a simple microbiome intervention.
“I think the closest option we have now is considering supplementing with commonly beneficial probiotic in pain conditions,” Bonakdar said.
One example is a preliminary fibromyalgia trial which found that supplementing with Lactobacillus, Bifidobacterium, and Saccharomyces boulardii appeared to have benefit.
“Unfortunately, this is hit or miss as other trials such as one in low back pain did not find benefit,” Bonakdar said.
Addressing gut microbiome changes will become “more actionable when microbiome analysis is more commonplace as well as is the ability to tailor treatment to the abnormalities seen on testing in a real-world manner,” Bonakdar said.
“Until then, there is no harm in promoting an anti-inflammatory diet for our patients with pain which we know can improve components of the microbiome while also supporting pain management,” he concluded.
Minerbi, Bonakdar, and the editorial writers had no relevant disclosures.