Traumatic stress is often followed by adverse post-traumatic neuropsychiatric sequelae (APNS), including post-traumatic stress disorder (PTSD), depression, and somatic or physical symptoms.
The underlying pathways remain unclear. A recent study published in Translational Psychiatry examined the potential role of the microbiome-gut-brain axis in this interaction.
Study: Association between microbiome and the development of adverse posttraumatic neuropsychiatric sequelae after traumatic stress exposure. Image Credit: Chanintorn.v/Shutterstock.com
Background
The influence of this axis on the brain’s functioning has been demonstrated in individuals with neuropsychiatric disorders. This is partly because of the metabolites released by the gut microbes. These include physiologically active chemicals and neurotransmitters.
Some microbes produce short-chain fatty acids (SCFAs) like butyrate that help protect the gut epithelial barrier and cross the blood-brain barrier (BBB), producing an anti-inflammatory effect on the brain.
Others, notably Enterobacteriaceae, release lipopolysaccharides (LPS), potent endotoxins that activate the Toll-like receptor (TLR) 4 pathway, unleashing a storm of inflammation.
In support of the theory that the microbiome-gut-brain axis may underlie APNS, earlier research shows differences at the microbiome level between PTSD and non-PTSD individuals, such as lower diversity and enrichment in opportunistic pathogens.
Animal models demonstrated a shift in microbial profile with stress, associated with higher levels of inflammation at local and systemic levels.
What did the study show?
The study examined stool samples from 51 trauma patients in the Advancing Understanding of RecOvery afteR traumA (AURORA) study. The mean age of the participants was 52 years, and the samples were collected at a mean of 45 days from their visit to the emergency department (ED) after a traumatic incident.
Over 60% were White, mostly non-Hispanic, and a quarter were Black. The participants were assessed for post-traumatic stress disorder (PTSD), depression, and somatic symptoms using the appropriate tools.
These were then analyzed for associations between demographic features, microbial profile, and APNS. Both microbial abundances and microbial metagenomics were considered in this analysis.
The results showed that the profile of the gut microbiome explained about half the variation in PTSD vs a quarter for depression and 44% for somatic symptoms. For PTSD, three microbes showed a linear increase in abundance with symptom severity, while one of them was also correlated with increasing depression severity. Two other species were enriched in association with somatic symptom severity.
In addition, the researchers identified important highly prevalent commensal microbial species like Flavonifractor plautii, Ruminococcus gnavus, and Bifidobacterium species as predictors of APNS outcomes depending on the abundance data. B. adolescentis, B. longum, and Flavonifractor plautii were part of the top five predictors for all three APNS outcomes.
Conversely, metagenomics data showed shifts in the amino acid biosynthetic pathways with all three APNS outcomes. In humans, L-ornithine can be synthesized de novo or converted to arginine, making the L-arginine, ornithine, and citrulline pathways interconvertible.
The citrulline biosynthesis pathway was inversely associated with poorer outcomes in all three areas. Meanwhile, L-arginine and polyamine biosynthesis was the best predictor of PTSD and third among depression predictors, varying negatively with PTSD and depression scores.
The bacterium E. coli participated at a higher level in all arginine-ornithine biosynthetic pathways but produced a smaller fraction of the total L-citrulline in people with PTSD vs more in those with depression.
Conversely, Ruminococcus contributed less to L-arginine production through both pathways. Other microbes from the genera Flavonifractor and Faecalibacterium were more active in converting ornithine to L-arginine in people with PTSD or depression.
What are the implications?
The findings suggest that APNS is more likely to occur in people with higher abundances of certain commonly occurring microbial species.
Demonstrated differences in the microbial abundances contributed from a fifth to a half of the observed variations in APNS outcomes, matching that which is accounted for by clinical and demographic profile differences.
The models identified two important predictors for all APNS outcomes: Bifidobacterium species and Flavonifractor plautii.
Though this does not corroborate all earlier studies, it underlines the need to construct more comprehensive microbiome models when assessing possible associations beyond the species level.
The association of APNS with microbiome changes may be mediated by lower arginine availability for the body due to the gut microbiome activity, reflecting a metabolic shift that has been shown likewise in plasma samples from PTSD patients.
This is seen in the altered contributions to pathways for the biosynthesis of the linked amino acids arginine, citrulline, and ornithine.
The global arginine bioavailability ratio (GABR) is measured as the ratio of arginine to ornithine and citrulline, which are its breakdown products. Changes in arginine metabolism could alter arginine vasopressin or nitric oxide (NO) levels, affecting multiple neuropsychiatric pathways. Further research will help identify how exactly different microbial species contribute to these shifts.
“Ours is the first study to longitudinally evaluate the link between the gut microbiome and APNS outcomes while providing mechanistic links along the microbiome-gut-brain axis.”
This may provide some evidence of an underlying APNS link mechanism owing to its origin in the gut microbiota via microbial metabolites. It may open novel research routes for managing and preventing such outcomes in the future.
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