A five-year, $3.4 million grant from the National Institutes of Health is powering work by an interdisciplinary team of researchers at The University of Texas at Dallas investigating potential causes of endometriosis pain.
Principal investigator Dr. Katelyn Sadler , an assistant professor of neuroscience in the School of Behavioral and Brain Sciences , and her colleagues are analyzing the relationship between endometriosis pain and the community of microorganisms found in the vagina.
Endometriosis is a condition in which tissue like the kind that lines the uterus is discovered outside of the uterus. An estimated 10% of reproductive-age women worldwide have endometriosis, which causes many patients pain and infertility. Although treatments can help some patients, there is no known cure.
“We are exploring how endometriosis pain begins,” Sadler said. “Not only do we not know what causes this pain, but we also don’t know why or how endometrial tissue forms outside of the uterus. Surgically removing those endometrial lesions relieves the pain in some patients but not all. The surgery actually leaves some patients in worse pain.”
Sadler has allied with Dr. Nicole De Nisco , an associate professor of biological sciences in the School of Natural Sciences and Mathematics , to attack the problem from microbiology and neuroscience perspectives. Their research could help pave the way for both a treatment for endometriosis pain and a diagnostic test for the condition, which currently requires surgery to identify with certainty.
“The premise is that specific interactions between the microbiota and pain-sensing neurons precipitates endometriosis pain,” said De Nisco, who is also a Fellow, Eugene McDermott Distinguished Professor. “We hope to find specific microbes that we can connect to this incidence of pain.”
Sadler’s previous work with mice showed that the vaginal microorganisms present with endometriosis are sufficient and required for pain neuron sensitization, and that introducing probiotic bacteria decreased that sensitization.
“The microbiome found in mice that have endometriosis differs from that of healthy animals,” Sadler said. “Transferring the microbiome from mice with endometriosis into healthy animals transfers that pain.”
Sadler and De Nisco hope to observe this same effect using human tissues. De Nisco’s lab team will use vaginal microbial communities from healthy individuals in existing studies and will also synthesize microbial communities that reflect those found in humans.
In De Nisco’s lab , the researchers will introduce those communities onto dorsal root ganglia (DRG) cells, specialized nerve cells clustered near the base of the spine. These DRG neurons will come from mice and from humans — a rare resource provided by Dr. Ted Price BS’97, Ashbel Smith Professor of neuroscience and director of the Center for Advanced Pain Studies . This procedure will help determine whether the endometriosis microbiome alone is sufficient to induce pain-neuron sprouting and activity.
“Over the past eight years, we’ve isolated more than a thousand different urogenital microbiota strains,” De Nisco said. “It’s exciting to have the chance to put these microbes onto human DRG neurons and see what kind of impact they have on the nervous system.”
Researchers hope that the endometriosis microbiomes they test will have similar compositions that could constitute a signature for the disease.
“Today, a definitive endometriosis diagnosis requires laparoscopic surgery where a surgeon sees lesions in the abdominal cavity,” Sadler said. “We hope the planned experiments enable successful detection of painful endometriosis based on one’s specific microbiome. That would be an incredible outcome — a diagnosis from a swab rather than surgery.”
Researchers also hope to determine if an abnormal microbiome is present because of the condition or if it has helped cause the condition — a chicken-and-egg problem, as Sadler explained.
“My hypothesis is that your microbiome isn’t necessarily the thing that causes endometriosis, but, if you have endometrial lesions, that changes the entire immune profile of your abdominal cavity, thus creating a feedforward disease cycle between the changed microbiome and the immune system,” Sadler said.
To break this cycle, Sadler’s team is focusing on the protein calcitonin gene-related peptide (CGRP). Several CGRP antagonist drugs have been approved by the Food and Drug Administration for the treatment of chronic migraine.
“Our preliminary data show increased CGRP activity in both mice and people that have endometriosis,” Sadler said. “We hypothesize that introduction of the endometriosis-associated microbiome could increase the release of CGRP from sensory nerve fibers, perpetuating endometriosis pain.”
The scientists hope that an improved understanding of the biochemical signals that pass between the microbiome and host in the reproductive tract can lay the groundwork for new therapies.
“Endometriosis is an important, common problem affecting so many people,” De Nisco said. “Even if we don’t find a magic bullet in this project, we are building a research network and community around this and other women’s health problems that will eventually make impactful progress. It’s such an important starting point.”
The research is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development ( R01HD121726 ).