Scientists at the University of Texas at Dallas say microbes in the gut could be a key to reducing pain from sickle cell disease.
In a study published last month in Cell Host & Microbe, the UT Dallas researchers found resetting the gut microbiome eased chronic pain in mice with sickle cell disease by boosting a probiotic bacterium.
The researchers also observed the reverse: Transferring a sickle cell–like microbiome into healthy mice triggered lasting pain, likely through signals traveling along the vagus nerve, the information highway between the gut and the brain.
The study emphasizes a need to examine the gut microbiome in cases of sickle cell, pinpointing targets that could ease pain on their own or work alongside treatments, said Dr. James Taylor, director of the Center for Sickle Cell Disease at Howard University in Washington, D.C., who was not involved in the study.
Bacteria fighting the good fight
First described in 1910, sickle cell disease stems from an inherited gene mutation that warps red blood cells into rigid sickles. Those misshapen cells clog tiny vessels and cut off oxygen, causing bouts of severe pain.
In the United States, roughly 100,000 Americans live with sickle cell disease. In Texas, about one in every 2,000 babies is born with it. It is most common among African Americans.
Examining how the gut microbiome is impacted by sickle cell disease is a relatively new area of study, said Taylor and Katelyn Sadler, an assistant professor of neuroscience at UT Dallas who led the study.
Recent studies suggest people with sickle cell disease can develop “gut leakiness,” where low oxygen damages the intestinal lining and weakens its barrier, Sadler said. The damage keeps the immune system in a heightened state.
That raised a question for Sadler and co-author Dr. Amanda Brandow, a pediatric hematologist-oncologist at the Medical College of Wisconsin: Does sickle cell disease reshape the gut microbiome?
To answer their question, the team compared the gut microbes of mice engineered to have sickle cell disease to those of healthy mice. They noticed a microbe lacking in the sickle cell mice: Akkermansia muciniphila, a bacterium discovered two decades ago and often linked to a sturdy gut barrier and metabolic health.
When the researchers restored the bacterium in the sickle cell mice via a fecal transplant, the animals stopped showing signs of or responses to pain for 48 hours. In separate experiments, they fed the mice daily supplements of the bacterium bought online and a lab-grown strain, also daily. The lab-grown strain produced longer relief than did the supplements.
In a reverse test, the team transplanted gut microbes from sickle cell mice into healthy mice. Those recipients showed signs of pain.
Analyzing the animals’ stool, the researchers saw a buildup of chemicals tied to bilirubin breakdown, the yellowish byproduct of red blood cell turnover. Sadler said gut bacteria normally break down bilirubin, but in sickle cell disease, there may not be enough of these microbes to handle the extra load.
That excess, the team found, appears to trigger stress signals in the gut that travel to the brain along the vagus nerve.
The gut microbiome may help ease other pain conditions
Mice offer a practical starting point, but they can’t capture the complexity of sickle cell disease in people, Taylor said. Human studies are needed to sort out the details. For instance, bilirubin accumulation may contribute to pain in some patients but not others — a distinction that could reflect individual microbiomes or other biological factors.
People with sickle cell disease often receive antibiotics in the hospital to prevent severe infection, Taylor said. Children with the condition are typically placed on daily penicillin during their first five years to reduce their risk of invasive bacterial diseases. While adults usually experience pain crises, and not kids, Taylor said the study underscores a familiar tension: Antibiotics can be lifesaving, yet overuse may disrupt the gut microbiome.
Taylor added the new work highlights a blind spot. Scientists don’t know what sickle cell drugs do to the microbiome. Whether a therapy activates fetal hemoglobin, the oxygen-delivering protein that is turned off after birth, or prevents red blood cells from clumping, its effects on gut microbes are largely unknown.
Next, Sadler’s lab wants to learn whether the bacterium used in the study eases pain on its own or by teaming up with other gut bacteria that help break down bilirubin. Whatever the researchers learn might also be applicable to other pain conditions where there are shifts in the microbiome. Their findings, then, could one day lead to better relief for those conditions as well.
Miriam Fauzia is a science reporting fellow at The Dallas Morning News. Her fellowship is supported by the University of Texas at Dallas. The News makes all editorial decisions.