Gut Microbes Cause Fibromyalgia-Like Symptoms in Mice

Many people suffer from chronic pain due to various medical conditions. In some ailments, like arthritis or multiple sclerosis, tissue or nerve damage causes this pain. In fibromyalgia, though, this pain isn’t associated with any obvious infection or injury, complicating treatment efforts.

Previously, researchers showed that changes in the gut microbiome influenced chronic pain in irritable bowel syndrome.¹ Subsequently, a team showed that patients with fibromyalgia had distinct gut microbiomes from people without this condition.² According to neuroscientist Kate Sadler at the University of Texas at Dallas, an outstanding question in the field is, “Are the changes that we see in these conditions just a symptom of the condition…or do the changes in the microbiome actually contribute to the pain in these conditions?”

A team of researchers at McGill University and the Israel Institute of Technology tackled this dilemma using germ-free mice. They demonstrated that fecal microbiome transplantation (FMT) of samples from patients with fibromyalgia induced chronic pain in the animals, while replacing it with microbiota from healthy people reduced the pain.³ The findings, published in Neuron, demonstrate a causative role of the gut microbiome in fibromyalgia and pave the way for potential therapeutic interventions for the condition.

Weihua Cai, a postdoctoral fellow in Arkady Khoutorsky’s group at McGill University and study coauthor, studied chronic pain with different animal models, but said that working with germ-free mice and the gut microbiome was new. She admitted she was uncertain about the gut microbiota inducing systemic pain and recalled wondering, “How can you feed the feces and…cause pain?”

Even so, Cai mastered working with the new mice and giving oral gavages of fecal samples from healthy people or those with fibromyalgia. The team wanted to focus on the impacts of chronic pain, so despite fibromyalgia also causing symptoms like fatigue and depression, the researchers restricted their samples to individuals who only reported severe pain.

Cai and her colleagues delivered FMTs to the mice once per week for four weeks, and assessed their sensitivity to mechanical stimulation, heat, and cold and also monitored them for pained facial expressions. Over the four weeks, mice given FMTs from people with fibromyalgia demonstrated increased sensitivity to all stimuli and more expressions related to pain. Cai said that she was stunned when she analyzed the data and saw the results. “This [was] so surprising for me.”

Wanting to determine the long-term effects from the FMT, the team transplanted another group of mice with feces from people with fibromyalgia and monitored the animals over four months. They saw that not only did the mice continue to experience hypersensitivity and pain, but the animals also showed depression-like symptoms in behavioral tests.

“I thought that was really impressive that the changes in the microbiome are changing behavior that long. That's really, really, really cool,” said Sadler, who was not involved with the study. She added that she was impressed by the thoroughness of the study to evaluate pain and other fibromyalgia symptoms.

The next question that Cai and her team wanted to answer was whether they could reverse the fibromyalgia symptoms that the FMT induced. After the initial FMT with samples from people with fibromyalgia, the team treated the mice with antibiotics to deplete the microbiota and retransplanted them with fecal samples from healthy people.

The second FMT reversed the chronic pain symptoms in the mice. “It's quite fascinating that if you feed the mice with the feces sample from the human, you can mimic the human's disease phenotype,” Cai said.

The promising results from in vivo experiments spurred the researchers’ interest in trying a small trial in people with fibromyalgia. After removing their existing microbiomes with antibiotic treatment and bowel cleansing, 14 participants orally ingested capsules containing healthy donors’ microbiomes. Of the 11 who completed the full trial, most of the patients experienced decreased pain intensity, depression, and interrupted sleep.

Although the findings will need to be repeated in randomized controlled trials, Cai said that seeing the results from basic science research be translated into the clinic to help patients was inspiring. She added that currently, people in the lab are exploring the exact bacteria or bacterial products responsible for causing fibromyalgia or protecting against it.

Sadler echoed the need for larger, controlled trials, and added that an unresolved question is what causes the changes to the microbiota. However, she said, “This study is a beautiful example and a convincing example of the fact that changes in the gut microbiome can affect pain in other areas of the body that are not just the gut.”