Houston Methodist Hospital's research into the gut microbiome as a source of concussion biomarkers has a prominent new benefactor: the National Football League Players' Association.

The union, which has sounded an alarm about the long-term consequences of the league's head-related injuries, is funding a Houston Methodist study looking for signs of concussion in stool samples of Rice University athletes, a project aimed at constructing a detailed gut microbiome profile of mild Traumatic Brain Injury (mTBI). The hope is that such a profile will lead to non-invasive diagnostic tests to guide return-to-play decisions, as well as novel ways to treat concussions.

"We greatly appreciate this support," said Dr. Sonia Villapol, PhD, a Houston Methodist neuroscientist leading the study. "It shows the high level of interest in developing real-time testing pinpointing post-concussion bacterial changes in the gut that will provide a clearer understanding and measurement of the brain injury's severity."

Dr. David Klossner, PhD, director of medical and scientific research for the players' association, said that "by supporting research like Dr. Villapol's team is doing, we believe we can continue to make steady, meaningful advances to better understand the connection between the microbiome and brain health for the betterment of our membership's health, as well as that of the general population."

The funding is the first ever from an NFL entity for a Houston Methodist research effort.

Concussions affect more than just NFL players, of course. There are an estimated 4 million traumatic brain injuries a year in the United States, about 70% of which go unreported. Dr. Villapol emphasized the value of the research to all possible patients.

Concussions are a challenge for modern medicine because there's no definitive, objective test, and the only therapy is rest. Diagnoses are based on self-reported symptoms, such as blurry vision, dizziness, nausea and headaches, but a person can have a brain injury without showing symptoms, then suffer from cognitive health issues years later.

Unraveling how brain injuries change gut bacteria and developing interventions to restore the proper balance represents a new hope for better diagnosis and treatment.

"The study is a first step in demonstrating the link between a concussion and the bacterial changes in the gut," said Dr. Kenneth Podell, PhD, a neuropsychologist, director of the Houston Methodist Concussion Center and co-primary investigator of the study. "Understanding these changes may allow us to develop novel ways of treating the brain after a concussion."

The research builds on the team's smaller 2022 study, also tracking Rice athletes, which was cut short by the COVID-19 pandemic. In football players who suffered a concussion, it found a drop-off of two bacterial species in stool samples normally found in abundance in healthy individuals. The study, published in Brain, Behavior and Immunity - Health, also found a correlation between traumatic-brain-injury-linked proteins in the blood and one brain-injury-linked bacterial species in the stool.

(Related: What the Gut Microbiome Can Tell Us About Concussions)

The new study expands the number of participants — 120 Division 1 athletes are enrolled (up from 33 in the previous study, all football players) — and includes women. Eighty compete in contact sports — football or women's soccer — and 40 compete in non-contact sports.

NFL players would be a logical beneficiary of the research, given the issues that head injuries pose in the league. More than 200 NFL concussions a year have been diagnosed in recent years, despite rule changes and improved helmets meant to reduce the risk.

Moreover, repeated concussions have been linked to chronic traumatic encephalopathy (CTE). Evidence of CTE has been found in the brains of many former football players after death, and more than a third of surveyed former NFL players believe they have chronic traumatic encephalopathy, based on symptoms such as depression and cognitive difficulties, according to a Harvard study published in JAMA Neurology this fall. The study was partly funded by the NFL Players' Association.

Dr. Klossner noted players' health and safety is a critical focus for the association.

That is also a goal of Dr. Villapol's concussion research. In her application for the funding, she wrote that the projects aims to "revolutionize the safety and health management of NFL and college student athletes."

The idea behind the research involves the gut microbiome's reflection of a number of changes in the central nervous system following a concussion:

• Vomiting often occurs due to the direct link between the brain and the stomach via the vagal nerve
• Inflammation initiated in the brain causes certain bacteria to all but evaporate within hours to days
• The resulting gut dysbiosis causes a lack of anti-inflammatory antioxidants that aid recovery and may lead to an overgrowth in harmful bacteria, which release toxins and increase inflammation that can affect the brain again

In the proposal, Dr. Villapol wrote that using her lab's sophisticated analytic methods, including advanced long-read DNA sequencing, the team will analyze extensive data over time to discern patterns or markers involving concussions.

Dr. Villapol emphasized it was important for the new study to include women athletes. She noted that men and women don't have the same immunities or gut microbiomes, and that the team has seen differences in microbiome responses in male and female animals on which they've conducted research.

The grant is for $443,000 over two years. Uses of the money will include the cost of the lab's microbiome metagenomics data analysis, as well as stipends for the participating Rice athletes — $100 loaded onto a debit card for each visit.

Rice athletes participating in the study must be 18 to 30 years old. They will provide blood samples in addition to stool samples and undergo neuropsychological testing if they suffer a concussion.

"What's unique about this study is that we're focusing on the holistic well-being of our student-athletes to contribute to both their academic success and what happens on the field or the court," said Sarah Schodrof, an assistant athletic director for Medical Services and Research at Rice. "This is a study that's going to help their long-term health and their professional pursuits after their athletic careers have ended."

Dr. Villapol said the next step after this study would be a large multi-institutional study involving at least 1,000 athletes. If the research is validated, any gut microbiome profile of mTBI would be available to all and not require any patenting of new technology, Villapol explained.

The NFL Players' Association selected the Houston Methodist study and three other gut microbiome research projects for funding from about 50 applications, said a spokesman for the group. The other recipients were the University of Texas Health Science Center at Houston, the University of Colorado and Uniformed Services University.