Q&A: Understanding altered fecal microbiome in chronic TBI may lead to new treatments
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Patients with chronic traumatic brain injury demonstrated “significantly different” fecal microbiome structures compared with controls, according to findings from a two-site trial published in Journal of Neurotrauma.
The fecal microbiome of the chronic TBI cohort had little or no members of several species of Prevotella and Bacteroidies while also demonstrating a higher level of bacteria in the Ruminococcaceae family compared with controls. While “the sequelae of gut-brain axis disruption” following TBI is not fully understood, the researchers noted that characterizing TBI-related changes in the fecal microbiome may produce biomarkers and therapeutic targets related to patient morbidity.
“Mild TBI is associated with alterations in gut metabolism soon after injury with direct impacts upon the intestinal mucosa, including loss of tight junctions, that contribute to increased intestinal permeability, inflammation and malabsorption,” the researchers wrote. “Patients with mild TBI also can develop sequelae years after injury, presenting with profound fatigue and altered cognition. Such mucosal alterations likely foster dysbiotic conditions to which the intestinal microbiota adapt, ultimately establishing an altered bacterial population that propagates the sequelae.”
Randall J. Urban, MD, professor in the department of internal medicine, vice president and chief research officer and vice dean of clinical research at The University of Texas Medical Branch’s School of Medicine, and colleagues examined whether the fecal microbiome was altered among patients with chronic, moderate to severe TBI who resided in permanent care facilities compared with healthy controls who worked at the facilities. Healio Neurology spoke with Urban and Melinda Sheffield-Moore, PhD, Thomas A. & Joan Read Endowed Chair for Disadvantaged Youth, professor and department head, and director of the Aging & Translational Research in Medicine Lab in the department of health & kinesiology at Texas A&M University and adjunct professor of medicine at The University of Texas Medical Branch, about the study results and the implications of the findings for patients with TBI.
Healio Neurology: What prompted this research?
Sheffield-Moore and Urban: TBI is a complex neurological insult that can lead to chronic, progressive deterioration of patient health with increased morbidity. Individuals with a history of TBI are also at increased risk for a number of neurologic disorders, including chronic traumatic encephalopathy, Parkinson’s disease and Alzheimer’s disease. Recently, there has been a lot of attention on the long-term health consequences of sport-, combat-, and other trauma-related brain injuries. This has revealed how little scientists know about the long-term metabolic or inflammatory effects that can present in the years following acute brain injury.
Our most recent study was a natural extension of some intriguing clinical data we published in 2017. In that study, we found unique metabolic and inflammatory signatures in patients with chronic TBI who were approximately 18 years post-TBI. These patients had altered amino acid metabolism, as indicated by lower plasma amino acids than controls following a meal, as well as hormone and cytokine profiles that suggested chronic inflammation. The goal in this new clinical trial published in Journal of Neurotrauma was to investigate why post-meal amino acids might be lower by examining the fecal microbiome of patients with chronic TBI. We also wanted to determine the role of the gut-brain axis in TBI-associated pathologies that often lead to disability in patients with chronic TBI, including fatigue, loss of cognition and brain fog.
The ability to conduct cutting-edge work in patients with TBI and discover therapeutically relevant scientific details was made possible because of the generous support of a local philanthropist who had a son who suffered a severe TBI. He recognized the critical need for clinical research in TBI and opened research avenues for our team that would otherwise not have been possible through traditional funding mechanisms.
Healio Neurology: How much is known about the impact of TBI on the gut-brain axis?
Sheffield-Moore and Urban: As we noted in the article, very little is currently known about the impact of TBI on the gut-brain axis. However, our 2017 study identified a possible metabolic and inflammatory link, suggesting a role for the gut-brain axis in chronic TBI. Notably, it is not clear why certain individuals appear more susceptible than others to developing persistent problems following TBI such as fatigue and brain fog. A growing body of evidence suggests that gut bacterial communities contribute to human physiology, immunity and inflammation, and dysbiosis of these communities can affect cognition, behavior and mood. We and others believe that TBI-induced changes to the gut microbiome lead to alterations in gut metabolism, including altered production of short-chain fatty acids, and intestinal mucosa resulting in potential disruption of the gut-brain axis.
Healio Neurology: Can you provide an overview of the study results?
Sheffield-Moore and Urban: Overall, our two-site clinical trial identified significantly shifted fecal microbiomes in patients with chronic TBI compared with age- and location-matched controls. Notably, the chronic TBI cohort exhibited the absence of, or a reduction in, several species of Prevotella and Bacteroidies, whereas bacteria in the Ruminococcaceae family were found in greater quantities. Our new study also reinforced the previous metabolic link showing correlations between specific microbes and amino acid levels. In particular, we found significantly reduced levels of L-tryptophan, L-sarcosine, B-alanine, and alanine, which were positively correlated with the reduced levels of several species of Prevotella in the chronic TBI cohort. These findings open therapeutic avenues to minimize patient morbidity by offering biomarkers and microbial candidates for potential intervention.
Healio Neurology: Did anything in the results surprise you?
Sheffield-Moore and Urban: We were pleased to find that the significant differences between TBI and controls persisted in both the Bakersfield, Calif., and Galveston, Texas, locations. Specifically, the overall relative abundance of bacterial genera from each clinical site was comparable, and no single genera was found to differ between locations. Digging deeper into the data, we were surprised to yield several immediate therapeutic targets, such as several species of Prevotella and Bacteroidies and bacteria in the Ruminococcaceae family, which now associate with amino acid deficiency and may indicate a microbiota that disrupts nutrient use.
Healio Neurology: How could these results impact the care of patients with TBI?
Sheffield-Moore and Urban: These study results yielded potential therapeutic and mechanistic insights into chronic TBI. A next step in care might include replacement of the dysbiotic intestinal community by fecal microbiome transplant to improve symptoms, but more human, animal and ex vivo studies are needed first. We have also recently published works that give these complex, gut-brain axis linked TBI morbidities a name: Brain Injury Associated Fatigue and Altered Cognition (BIAFAC). Intriguingly, TBI patients with BIAFAC also have altered growth hormone secretion, and treatment of these patients with growth hormone has been shown to relieve the debilitating symptoms of BIAFAC. We hope to continue uncovering more clues to the mechanisms underlying these TBI-related symptoms as we conduct these next-step studies, reflect upon our body of recent evidence and continue to treat patients with TBI.
Reference:
Urban RJ, et al. J Neurotrauma. 2021;doi:10.1089/neu.2019.6688.