Imbalance in gut bacteria, microbes may drive chronic pain in SCD
Findings from mouse study support clinical trial to test probiotic supplements
Changes in the gut microbiome, the group of bacteria and other microbes living in the digestive tract, may drive chronic pain in people with sickle cell disease (SCD), a new study reveals.
In a study using mice and human tissues, a team of U.S. researchers investigated how such changes, and possible imbalances, in the gut may be managed to alleviate pain in SCD.
Chronic pain in an SCD mouse model was eased by a transplant of feces from healthy mice, according to the researchers. Meanwhile, healthy mice transplanted with SCD mouse feces developed persistent pain.
Moreover, data showed that treatment with an over-the-counter probiotic supplement containing the bacteria Akkermansia muciniphila alleviated chronic pain in SCD mice.
“These findings are extremely exciting as this work provides preclinical data to support a clinical trial using probiotics or fecal microbiota transplantation as a novel treatment for chronic sickle cell disease pain,” Amanda Brandow, a professor of pediatrics and a hematologist at the Medical College of Wisconsin, who served as the study’s lead author, said in a university news story.
The study, “Gut microbiota and metabolites drive chronic sickle cell disease pain in mice,” was published in the journal Cell Host & Microbe.
In SCD, its hallmark sickle-shaped red blood cells break down easily, resulting in symptoms of anemia. These abnormally shaped cells can also become stuck in small blood vessels, blocking blood flow and triggering episodes of sudden and acute pain, referred to as vaso-occlusive crises.
However, for unknown reasons, at least half of SCD patients also experience persistent, or chronic, pain.
“Chronic sickle cell disease pain has a profound negative impact on the quality of life of individuals living with the disease,” said Brandow, who also treats children with SCD pain.
Researchers treated SCD mice with supplements containing A. muciniphila
An earlier study found differences in the number and types of bacteria present in stool samples collected from individuals with SCD compared with healthy, matched controls. Still, it’s unclear whether these changes contribute to chronic SCD pain.
Katelyn Sadler, PhD, an assistant professor of neuroscience at the University of Texas at Dallas and the study’s corresponding author, noted that, among patients, “your immune system can become more activated based on gut bacteria, and that can have wide-ranging implications in your body.”
“The bacteria and other compounds in your digestive system have diverse, pervasive effects beyond what people might anticipate,” Sadler said, adding that “the idea of gut microbiomes driving chronic pain elsewhere in the body is becoming more prevalent.”
To further explore the relationship between the gut microbiome and chronic SCD pain, researchers from the two universities conducted a series of experiments in an SCD mouse model.
When the team transplanted the feces of healthy mice into the digestive tract of SCD mice, chronic pain was alleviated, as indicated by reduced sensitivity to touch and cold.
The bacteria and other compounds in your digestive system have diverse, pervasive effects beyond what people might anticipate. … Your immune system can become more activated based on gut bacteria, and that can have wide-ranging implications in your body.
An examination of SCD mouse feces revealed low numbers of bacteria belonging to the genus Akkermansia, similar to those found in stool samples collected from SCD patients in a previous study.
The researchers then treated the SCD mice with supplements containing Akkermansia muciniphila — a bacterium that has been shown to have beneficial effects on gut health and release anti-inflammatory molecules known as short-chain fatty acids.
Treatment with both live and commercially available freeze-dried A. muciniphila alleviated chronic pain in SCD mice, according to the team.
“We identified Akkermansia because it makes short chain fatty acids, which appear crucial for alleviating sickle cell pain,” Sadler said. “Transplanting it into our sickle cell mice almost completely reversed their chronic pain.”
Healthy mice were given a feces transplant from mice with SCD. These animals then experienced persistent pain, the data showed.
“When we transplanted all bacteria from sickle cell mice to animals without sickle cell disease we transferred the pain with it — not the genetic blood disorder, but the touch and cold hypersensitivity,” Sadler said.
Results are ‘strong evidence’ of link between gut, chronic pain
Looking more closely, the team determined that the persistent pain experienced by healthy mice with transplanted SCD mouse feces was driven by the activation of the vagus nerve. That nerve sends sensory information from the body’s organs, including those of the digestive tract, to the brain.
When SCD mouse feces were examined for molecules responsible for vagus nerve activation, the scientists found elevated levels of heme breakdown products, particularly bilirubin. Heme is an iron-containing molecule that’s part of hemoglobin, the oxygen-carrying protein inside red blood cells.
Accordingly, healthy mice treated with oral bilirubin exhibited signs of vagus nerve activation and central sensitization, a condition in which the nervous system becomes hypersensitive, resulting in heightened pain.
The researchers then discovered that bilirubin drives vagus nerve hyperexcitability by binding to a protein receptor known as TRPM2. This receptor may be a novel target for chronic SCD pain relief, the team noted.
“What we think happens specifically in these sickle cell experiments is central sensitization,” Sadler said. “Everything becomes more sensitive because of a change in the brain or spinal cord.”
Lastly, experiments to confirm whether the SCD mouse model findings would translate to human patients showed that bilirubin and related heme breakdown products were persistently elevated in the blood of SCD patients. They also had lower levels of gut bacteria that produce an enzyme responsible for metabolizing, or breaking down, bilirubin than healthy, pain-free individuals.
“Our results are strong evidence that the contents of the microbiome in individuals with sickle cell might drive chronic pain,” said Sadler, who noted that the development of a treatment for chronic SCD pain could be “life-changing” for patients.
“This idea is a type of therapy that hasn’t really been explored before,” Sadler said, adding that “it could be relatively inexpensive for people who, right now, are often turned away when seeking pain-relief medications.”
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