The gut bacteria boost pain in fibromyalgia - part I

Not all chronic pain has a clear cause. Some people experience persistent pain without any visible damage or disease. 

A leading example of unexplained pain is fibromyalgia, which impacts around 2% to 4% of the population, mostly women. Fibromyalgia causes widespread pain, fatigue, sleep problems, and memory issues. Many people with fibromyalgia also experience depression and digestive troubles. 

Despite its high frequency in the population, researchers still do not fully understand why fibromyalgia develops, and current treatments often fail to provide full relief. 

Studies suggest that the central nervous system becomes overactive in fibromyalgia, but changes also occur throughout the body, including in the immune system and even in the skin’s nerve fibers.

The gut microbiota's role in pain
Recently, researchers have turned their attention to the gut microbiota—the community of bacteria living in the digestive system—as a possible factor in chronic pain conditions like fibromyalgia. 

Previous studies have shown that people with fibromyalgia have a different gut microbiota compared to healthy individuals. Since the gut microbiota is already known to influence even distant parts of our body (like the brain), scientists questioned whether it could also play a role in fibromyalgia symptoms. 

To find out, researchers transplanted fecal samples from women with fibromyalgia into germ-free mice. 

The study
These mice had no previous exposure to any microbes, making them perfect models to study new bacterial communities.

After the transplantation, the mice that received microbiota from fibromyalgia patients developed long-lasting pain sensitivity, while mice that received microbiota from healthy donors did not. 

Importantly, when the sick mice later received microbiota from healthy donors, their pain symptoms improved, suggesting that gut bacteria can influence chronic pain development.

The pain relief was only seen when the original gut bacteria were removed before the transplant; skipping the antibiotics prevented the treatment from working. Antibiotics alone had only a small effect on pain. 

Depression, and long-term effects of pain
The mice that received microbiota from fibromyalgia patients developed various types of pain. They also showed signs of spontaneous pain without any obvious injury. 

Mice that had received fibromyalgia microbiota began to show signs of depression-like behavior, though not at the four-week mark.

Interestingly, in the mouse model, depression-like behavior appeared only after months of chronic pain.

Since the human donors in this study did not have depression or anxiety, and the depressive symptoms appeared gradually, the scientists suspect that the prolonged pain may have triggered the mood changes over time. Rather than being directly transferred through the microbiota.

This pattern is consistent with other studies showing that long-term pain can lead to anxiety and depression in animals. So, changes in gut bacteria could cause long-term effects on mood as well, not just on pain. 

Changes in metabolism and the immune system
The gut barrier, the protective lining that prevents bacteria and toxins from leaking into the body, was intact. There were no signs of major inflammation or damage, which means the changes and the pain were not due to gut injury. Still, the gut microbiota strongly influences the body's metabolism. 

In this study, the mice that received fibromyalgia-associated microbiota showed important changes in their metabolic profiles. Levels of certain amino acids, such as glutamate, rose in the brain and spinal cord. 

Glutamate plays a key role in pain by sending signals between brain and spinal cord nerve cells. When glutamate levels rise, it can lead to heightened sensitivity and chronic pain if the system stays overactive.

Changes in lipid metabolism were also observed, including a reduction in fatty acids important for nerve function. Additionally, specific bile acids that usually help control pain were reduced. 

When researchers treated the mice with a bile acid supplement, their pain symptoms improved slightly. This finding matched previous research showing that bile acid disruptions could predict fibromyalgia pain in patients. 

Immune system changes were also clear. The blood of mice with fibromyalgia microbiota had more inflammatory monocytes and other signs of immune activation. 

Inside the spinal cord, the microglia—the brain's immune cells—became reactive. When researchers blocked the activation of microglia before transplanting the microbiota, the mice experienced less pain. This confirmed that microglia play a direct role in pain hypersensitivity triggered by gut bacteria.

Nerve changes linked to pain sensitivity
The mice’s peripheral nervous systems were also affected. Sensory neurons in the dorsal root ganglia, which transmit signals from the body to the spinal cord, became overly sensitive to touch and heat.

Reduced nerve fiber density could contribute to abnormal pain perception. Skin samples showed that these mice had fewer nerve fibers, a change that mirrors findings in some people with fibromyalgia. 

Taken together, these results show that gut bacteria from fibromyalgia patients can create a widespread set of problems in the body: they alter metabolism, activate the immune system, make sensory neurons more excitable, and reduce nerve fiber density. 

All these factors together can explain the persistent nature of fibromyalgia symptoms.

Perhaps this distressing disease is actually rooted in the digestive system, rather than the nervous system?

About the paper that inspired:

First Author: Weihua Cai, Israel
Published: Neuron, July 2025
Link to paper: https://www.cell.com/neuron/fulltext/S0896-6273(25)00252-1