Study Links Chronic Sickle Cell Pain to Gut Microbial Imbalance

A research collaboration involving scientists and students at The University of Texas at Dallas has found a clear connection between the chronic sickle cell disease pain and the bacteria present in their gastrointestinal tracts.

Dr. Katelyn Sadler, assistant professor of neuroscience in the School of Behavioral and Brain Sciences, is the corresponding author of the study, which was conducted in mice and human tissue and published online Sept. 16 in the journal Cell Host & Microbe.

The researchers from UT Dallas and the Medical College of Wisconsin (MCW) focused on Akkermansia muciniphila, a bacterium commonly found in the human gut but known to be less prevalent in individuals with sickle cell disease. In the study, the team alleviated chronic pain in mice engineered to have sickle cell disease by transplanting bacteria from the feces of healthy mice into the digestive tract of the sickle cell animals.

"Our results are strong evidence that the contents of the microbiome in individuals with sickle cell might drive chronic pain," Sadler said.

Sickle cell disease is a genetic disorder in which red blood cells become abnormally shaped, like sickles, and rigid. Individuals with sickle cell can experience sudden, acute pain due to the misshapen cells blocking blood flow and depriving areas of the body of oxygen. For reasons that are unclear, at least 50% of individuals with sickle cell disease also experience chronic pain.

The two types of pain have separate pathologies, Sadler said, with the gut microbiome thought to play a role in chronic pain.

"The bacteria and other compounds in your digestive system have diverse, pervasive effects beyond what people might anticipate," she said. "Your immune system can become more activated based on gut bacteria, and that can have wide-ranging implications in your body. The idea of gut microbiomes driving chronic pain elsewhere in the body is becoming more prevalent, including in recent fibromyalgia research."

A. muciniphila is available over-the-counter as a probiotic supplement. Sadler said the group's study is the first to identify the bacterium as a target for sickle cell disease pain.

"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. Interestingly, 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 that changing the contents of the gut can activate nerve endings in the intestine that send signals to the central nervous system.

"What we think happens specifically in these sickle cell experiments is central sensitization," she said. "Everything becomes more sensitive because of a change in the brain or spinal cord."

The human gut microbiome is constantly changing, not only in the short term due to daily diet fluctuations, but also in the long term related to factors such as age, lifestyle, medications and environment.

"Probiotics like Akkermansia can be very helpful in light of this frequent evolution," Sadler said, "although we believe one would have to switch probiotics eventually as the bacteria in your gut adapt to kill off Akkermansia."

The study's lead author is Dr. Amanda Brandow, professor of pediatrics and a pediatric hematologist at MCW who treats children with sickle cell disease pain. She and Sadler have collaborated since 2017.

"Chronic sickle cell disease pain has a profound negative impact on the quality of life of individuals living with the disease," Brandow said. "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."

Sadler described the potential development of a therapeutic drug for chronic sickle cell pain as "life-changing."

"These patients don't have many symptom-management options right now," she said. "Gene therapy is new and cost-prohibitive for most, and individuals who receive the therapy have to undergo chemotherapy. Even then, in the new gene therapy studies, chronic pain was not assessed, just acute pain.

"This idea is a type of therapy that hasn't really been explored before. It could be relatively inexpensive for people who, right now, are often turned away when seeking pain-relief medications."

Dr. Kelli Palmer, an author of the study and professor of biological sciences at UT Dallas, enlisted her students to grow the A. muciniphila bacteria required for the study using an anaerobic incubator, which cultures cells in a low-oxygen environment.

"We recruited a team of master's students from my graduate biochemistry class to brainstorm on experiments about how the gut microbiome impacts pain," said Palmer, a Cecil H. and Ida Green Distinguished Chair in Systems Biology Science in the School of Natural Sciences and Mathematics. "We had students from our master's programs do the Akkermansia work in my lab, creating this opportunity for biology students to work on interdisciplinary research."

Sadler said the teamwork with Palmer and her students was "amazing" and touted the environment at the University for nurturing that kind of cooperation.

"At UT Dallas, you can find like-minded people in your department, across your school and across the University, which makes everything easier," she said. "The experts available right here allow for our science to be even more impactful. This is a collaborative, translational story that you couldn't tell in many places."

UT Dallas faculty who are authors of the paper also include Dr. Ted Price BS'97, Ashbel Smith Professor of neuroscience and Center for Advanced Pain Studies (CAPS) director; Dr. Gregory Dussor, department head of neuroscience and the James Bartlett Chair in Behavioral and Brain Sciences; Dr. Diana Tavares Ferreira, assistant professor of neuroscience; and Dr. Iti Mehta, assistant professor of instruction in biological sciences.

Other UT Dallas-affiliated authors include Dr. Zulmary Manjarres Farias, Stephanie Shiers PhD'19, Mackenzie Simms BS'24 and Ishwarya Sankaranarayanan, neuroscience researchers in CAPS; McKenna Pratt, Khadijah Mazhar and Mandee Schaub, neuroscience and cognition doctoral students; Sruthi Mudunuri, Aishwarya Kappagantu and Anagha Sheshadri, molecular and cell biology graduate students; and Sahar Alhendi, bioinformatics and computational biology graduate student.

Additional authors are from the Southwest Transplant Alliance and from MCW, including Dr. Cheryl Stucky, professor of cell biology, neurobiology and anatomy.

The work was funded in part by grants from the National Heart, Lung, and Blood Institute (R00HL155791, R01HL142657, K23HL114636), the National Institute of Neurological Disorders and Stroke (R33NS114954, U19NS130608, R01NS070711, R37NS108278) and the National Institute of General Medical Sciences (R35GM122503) - all components of the National Institutes of Health. Additional support was provided by the Rita Allen Foundation and the Advancing a Healthier Wisconsin Endowment.

Media Contact: Stephen Fontenot, UT Dallas, 972-883-4405, [email protected], or the Office of Media Relations, UT Dallas, (972) 883-2155, [email protected].