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

Abstract

IntroductionMild traumatic brain injury (mTBI) has been shown to negatively alter bacterial diversity and composition within the gut, known as dysbiosis, in rodents and humans. These changes cause secondary consequences systemically through decreased bacterial metabolites such as short chain fatty acids (SCFAs) which play a role in inflammation and metabolism. The goal of the study was to identify if giving prebiotic inulin prior to closed head injury (CHI) could mitigate gut dysbiosis, increase SCFAs, and improve recovery outcomes, including protecting cerebral blood flow (CBF) and white matter integrity (WMI) in young mice.MethodsWe fed mice at 2 months of age with either inulin or control diet (with cellulose as fiber source) for two months before the CHI and continued till the end of the study. We analyzed gut microbiome composition and diversity, determined SCFAs levels, and measured CBF and WMI using MRI. We compared the results with Naïve and Sham-injury mice at 24 hours, 1.5 months, and 3-4 months post-injury.ResultsWe found that both CHI and Sham mice had time-dependent changes in gut composition and diversity after surgery. Inulin significantly reduced the abundance of pathobiont bacteria, such as E. coli, Desulfovibrio spp and Pseudomonas aeruginosa, in Sham and CHI mice compared to mice fed with control diet. On the other hand, inulin increased SCFAs-producing bacteria, such as Bifidobacterium spp and Lactobacillus spp, increased levels of SCFAs, including butyrate and propionate, and significantly altered beta diversity as early as 24 hours post-injury, which lasted up to 3-4 months post-injury. The mitigation of dysbiosis is associated with protection of WMI in fimbria, internal and external capsule, and CBF in the right hippocampus of CHI mice, suggesting protection of memory and cognitive functions.DiscussionThe results indicate that giving inulin prior to CHI could promote recovery outcome through gut microbiome modulation. As inulin, microbiome analysis, and MRI are readily to be used in humans, the findings from the study may pave a way for a cost-effective, accessible intervention for those at risk of sustaining a head injury, such as military personnel or athletes in contact sports.

Prebiotic inulin enhances gut microbial metabolism and anti-inflammation in apolipoprotein E4 mice with sex-specific implications

“…Interestingly, inulin was able to reduce and normalize the α-diversity of the E4 -F mice to the level similar to other three groups. The finding aligns with previous studies demonstrating that inulin can reduce α-diversity in mice with APOE4 genotype and with traumatic brain injury (TBI) 12 , 13 , 46 .…”

“…Another major finding from the E4 -F mice was the reduced in the abundance of E. coli. Elevated E. coli levels have also been linked to diseases such as stroke, TBI, and AD 3 , 46 , 47 . In this study, inulin decreased the abundance of E. coli , which might reduce the Lipopolysaccharide (LPS)-induced inflammatory pathways 48 – 50 .…”

The altered TBI fecal microbiome is stable and functionally distinct

“…Pyruvate fermentation to SCFAs and nucleotide levels (potentially contributed by commensal bacteria) have both been connected to improved outcomes for TBI recovery ( Lusardi, 2009 ; Yanckello et al, 2022a , b ; Zhao et al, 2023 ). Interestingly, as reviewed by Gomes et al (2011) , work on extracellular adenosine in a variety of brain disorders has led to recognition that adenosine receptor antagonists positively promote synaptic plasticity that may ultimately involve control of glutamatergic transmission or a variety of other brain homeostasis pathways.…”

“…Translationally, completion of these studies will not only help to elucidate the impacts of the dysbiotic TBI FMB but should identify novel targets for prebiotic, probiotic, and molecular approaches targeted to the bacteria in the GI tract. There are a number of studies that tested general probiotics or FMB transplants in the context of TBI or other neurotrauma that showed mixed results ( Kigerl et al, 2016 ; Brenner et al, 2017 ; Rice et al, 2019 ; Yi et al, 2019 ; Yanckello et al, 2022a , b ) supporting a need for greater specificity in targeting. Based on the observed SCFA metabolism differences in the TBI FMB, we recently completed a trial of a prebiotic fructooligosaccharide dietary supplement in subjects who have moderate to severe TBI (NCT04949607).…”

Gut microbiome association with brain imaging markers, APOE genotype, calcium and vegetable intakes, and obesity in healthy aging adults

“…Accumulating evidence has implicated the gut microbiome in brain health ( Cox and Weiner, 2018 ). Gut dysbiosis is associated with many neurological disorders, including Alzheimer’s disease, stroke, and traumatic brain injury ( Vogt et al, 2017 ; Borsom et al, 2020 ; Yanckello et al, 2022a ; Hammond et al, 2022b ). Aging is associated with significant alterations in the gut microbiome ( Hoffman et al, 2017 ).…”