Altered Fecal Microbiome Years after Traumatic Brain Injury

Abstract

Patients with chronic traumatic brain injury (TBI) requiring long-term, permanent care suffer a myriad of clinical symptoms (i.e., impaired cognition, fatigue, and other conditions) that persist for years beyond the acute brain injury. In addition to these comorbid clinical symptoms, chronic TBI patients exhibit altered amino acid and hormonal profiles with distinct cytokine patterns suggesting chronic inflammation. This metabolic link suggests a role of the gut-brain axis in chronic TBI. Thus, we utilized a two-site trial to investigate the role of the gut-brain axis in comorbidities of chronic TBI. The fecal microbiome profile of 22 moderate/severe TBI patients residing in permanent care facilities in Texas and California was compared to 18 healthy age-matched control subjects working within the participating facilities. Each fecal microbiome was characterized by 16S(V4) ribosomal RNA (rRNA) gene sequencing and metagenomic genome sequencing approaches followed by confirmatory full 16S rRNA gene sequencing or focused tuf gene speciation and specific quantitative polymerase chain reaction evaluation of selected genera or species. The average chronic TBI patient fecal microbiome structure was significantly different compared to the control cohort, and these differences persisted after group stratification analysis to identify any unexpected confounders. Notably, the fecal microbiome of the chronic TBI cohort had absent or reduced Prevotella spp. and Bacteroidies spp. Conversely, bacteria in the Ruminococcaceae family were higher in abundance in TBI compared to control profiles. Previously reported hypoaminoacidemia, including significantly reduced levels of l-tryptophan, l-sarcosine, ß-alanine, and alanine, positively correlated with the reduced levels of Prevotella spp. in the TBI cohort samples compared to controls. Although the sequelae of gut-brain axis disruption after TBI is not fully understood, characterizing TBI-related alterations in the fecal microbiome may provide biomarkers and therapeutic targets to address patient morbidity.

Repetitive, mild traumatic brain injury results in a progressive white matter pathology, cognitive deterioration, and a transient gut microbiota dysbiosis

“…With regard to the second goal, and based on emerging literature showing acute and chronic gut microbiota dysbiosis after TBI in humans 30 and rodents [26][27][28][29] , it was hypothesized that rmTBI would also cause significant alterations in the gut microbiota that would parallel the emergence of neuropathological alterations. The results did reveal minor alterations in community diversity (α-and β-) that were influenced more by time than by treatment.…”

“…In fact, Nicholson and colleagues 29 noted that changes in the gut microbiota in their studies were significantly positively correlated with lesion volume. Humans with chronic dysbiosis had experienced severe TBI as well 30 . The one study that exposed rats to repeated heat impacts (N = 5) used our rmTBI method [31][32][33] and reported alterations in microbial diversity out to 30 days after the last head impact 55 .…”

“…Emerging preclinical studies are associating alterations in the gut microbiota with TBI but the majority of these imparted single, very severe head injuries and used relatively short survival times post-impact [26][27][28][29] . In light of the fact that the majority of military and sports-related TBIs are repeated and mild in nature, and considering that the fecal microbiota is altered for more than 20 years in humans after TBI 30 , we have evaluated the gut microbiota response to rmTBI involving 20 mild head impacts and longer survival times post-injury. The results show a progressive emergence of white matter damage, cognitive deterioration and a mild, transient gut dysbiosis.…”

Alterations to the gut microbiome after sport-related concussion and subconcussive impacts in a collegiate football players cohort

“…Changes in the gut microbiota in response to the inflammatory stage have been previously observed in severe TBI patients 39,40 . Furthermore, the gut microbiome may be a valuable biomarker of repetitive exposure to concussions in athletes.…”

Antagonism of Macrophage Migration Inhibitory Factory (MIF) after Traumatic Brain Injury Ameliorates Astrocytosis and Peripheral Lymphocyte Activation and Expansion

“…TBI is known to affect the brain–gut axis [ 63 ]. Γδ T cells represent a key immune component in the gut that regulates intestinal homeostasis and inflammation [ 64 , 65 ], including after CNS injury [ 66 ].…”