Inulin Supplementation Mitigates Gut Dysbiosis and Brain Impairment Induced by Mild Traumatic Brain Injury during Chronic Phase

Abstract

Mild traumatic brain injury (mTBI) has been shown to acutely alter the gut microbiome diversity and composition, known as dysbiosis, which can further exacerbate metabolic and vascular changes in the brain in both humans and rodents. However, it remains unknown how mTBI affects the gut microbiome in the chronic phase recovery (past one week post injury). It is also unknown if injury recovery can be improved by mitigating dysbiosis. The goal of the study is to fill the knowledge gap. First, we aim to understand how mTBI alters the gut microbiome through the chronic period of recovery (3 months post injury). In addition, as the gut microbiome can be modulated by diet, we also investigated if prebiotic inulin, a fermentable fiber that promotes growth of beneficial bacteria and metabolites, would mitigate dysbiosis, improve systemic metabolism, and protect brain structural and vascular integrity when administered after 3 months post closed head injury (CHI). We found that CHI given to male mice at 4 months of age induced gut dysbiosis which peaked at 1.5 months post injury, reduced cerebral blood flow (CBF) and altered brain white matter integrity. Interestingly, we also found that Sham mice had transient dysbiosis, which peaked 24 hours after injury and then normalized. After 8 weeks of inulin feeding, CHI mice had increased abundance of beneficial/anti-inflammatory bacteria, reduced abundance of pathogenic bacteria, enriched levels of short-chain fatty acids, and restored CBF in both hippocampi and left thalamus, compared to the CHI-control fed and Sham groups. Using machine learning, we further identified top bacterial species that separate Sham and CHI mice with and without the diet. Our results indicate that there is an injury- and time-dependent dysbiosis between CHI and Sham mice; inulin is effective to mitigate dysbiosis and improve brain injury recovery in the CHI mice. As there are currently no effective treatments for mTBI, the study may have profound implications for developing therapeutics or preventive interventions in the future.

Inulin supplementation prior to mild traumatic brain injury mitigates gut dysbiosis, and brain vascular and white matter deficits in mice

“…In contrast, we found higher levels of butyrate ( Figure 4B ) in inulin-fed Naïve (p < 0.0001), Sham (p < 0.0001) and CHI (p = 0.0001) mice compared to controls, as well as higher levels of propionate ( Figure 4C ) in inulin fed Sham (p = 0.0432) and CHI (p = 0.0482) mice compared to controls. This is consistent with our previous findings ( Yanckello et al, 2022 ).…”

“…Pairwise comparisons in the right hippocampus showed a significant increase in CBF in the CHI-inulin compared to the CHI-control in the right hippocampus (p = 0.0390) ( Figure 5E ). This is consistent with our previous study that showed inulin increased CBF even when administered during the chronic recovery period of CHI ( Yanckello et al, 2022 ). Other regional CBF values can be found in Table 4 .…”

“…It is interesting to note that Sham mice also experienced gut microbiome changes in diversity and composition despite without having CHI. We had a similar observation in our previous study (Yanckello et al, 2022) and were therefore suggested to include a Naïve cohort in the current study as a negative control. It will also be important for other CHI-related studies to include a Naïve cohort in the future, especially those related to microbiome research.…”

“…The microbiome-gut-brain axis has emerged as a topic of interest in mTBI research ( Treangen et al, 2018 ; Yanckello et al, 2022 ). Considerable evidence demonstrates that mTBI with a closed head injury (CHI) in animal models increased intestinal permeability and gut dysbiosis as early as 24 hours post-injury, which persists for as long as 3 months ( Treangen et al, 2018 ; Yanckello et al, 2022 ). CHI disrupts microbiome diversity, increases pathobiont bacteria and decreases putatively beneficial bacteria ( Treangen et al, 2018 ; Nicholson et al, 2019 ).…”

“…Emerging evidence shows that manipulation of the gut microbiome through dietary intervention may be actionable in reducing long-term symptoms after mTBI ( Yu et al, 2019 ). In a recent study, we showed that prebiotic inulin, a non-digestible dietary fiber, increased the level of beneficial bacteria, reduced pathobiont bacteria, and elevated SCFAs in the cecal contents and plasma during the chronic phase of TBI-recovery ( Yanckello et al, 2022 ). In another study, we also showed that increased in beneficial bacteria was associated with increased CBF ( Ma et al, 2018 ).…”