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Functional recovery following traumatic brain injury in rats is enhanced by bovine thymus nuclear extract supplementation

ABSTRACT: Traumatic brain injury (TBI) is one of the leading causes of death worldwide. Due to complex etiology, there are currently no effective treatments for TBI, and trauma survivors suffer from a variety of long-lasting health consequences. One of the pathological manifestations of TBI is neuroinflammation, which is thought to delay tissue repair and patient recovery. With nutritional support recently emerging as a vital step in improving TBI patients’ outcomes, we sought to evaluate the potential therapeutic benefits of nutritional supplements derived from bovine glandular tissues, which can deliver a variety of nutrients and bioactive molecules. We show that bovine thymus-derived extracts contain antigens found in neural tissues and are relevant to neuroinflammation, and supplementation of rats with thymus extracts induces production of IgG antibodies against neuronal and glial antigens. In a rat model of controlled cortical impact (CCI) we determined that animals supplemented with a nuclear extract of bovine thymus (TNF) display greatly improved performance on beam balance and spatial memory tests following CCI. Using RNA-Seq, we identified an array of signaling pathways that are modulated by TNF supplementation in rat hippocampus, including those involved in the process of autophagy. Finally, we demonstrate that TNF supplement-induced increase in blood levels of IgG autoantibodies against nervous system antigens correlates with better animal performance on behavioral tests. Together, our data show, for the first time, that a nutritional supplement containing nuclear fraction of bovine thymus is potent at enhancing the functional recovery from TBI in a rat model, modulates signaling pathways implicated in TBI pathology and recovery at gene and protein levels, and may be beneficial for reducing neuroinflammation and improving tissue repair.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE240927 | GEO | 2023/11/06

REPOSITORIES: GEO

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Project description:Traumatic brain injury (TBI) initiates not only complex neurovascular and glial changes within the brain but also pathophysiological responses that extend beyond the central nervous system. The peripheral response to TBI has become an intensive area of research, as these systemic perturbations can induce dysfunction in multiple organ systems. As there are no approved therapeutics for TBI, it is imperative that we investigate the peripheral response to TBI to identify targets for future intervention. Of particular interest is the gastrointestinal (GI) system. Even in the absence of polytrauma, brain-injured individuals are at increased risk of suffering from GI-related morbidity and mortality. Symptoms such as intestinal dysmotility, inflammation, ulceration, and fecal incontinence can drastically diminish quality of life. The GI tract is inhabited by trillions of microbes that have been implicated as modulators of many neurological disorders. Clinical and preclinical studies implicate gut dysbiosis, a pathological imbalance in the normally symbiotic microbiota, as both a consequence of TBI as well as a contributing factor to brain damage. However, our understanding of this interplay is still limited. While relatively little is known about the effects of TBI on the structure and function of the GI tract, prior studies report that experimental TBI induces intestinal barrier dysfunction and morphological changes. To confirm these findings in the current model of TBI, male C57BL/6J mice underwent a sham control or a controlled cortical impact (CCI) procedure to induce a contusive brain injury, and intestinal permeability was assessed at 4 h, 8 h, 1 d, and 3 d post-injury. An acute, transient increase in permeability was observed at 4 h after CCI. Histological analyses of the ileum and colon at multiple time points from 4 h to 4 wks revealed no overt morphological changes, suggesting that CCI induced a short-lived physiologic dysfunction without major structural alterations to the GI tract. As the microbiome is a modulator of GI physiology, we performed 16s gene sequencing on fecal samples collected prior to and over the first month after CCI or sham injury. Microbial community diversity was assessed using common metrics of alpha and beta diversity. Alpha diversity was lower in the CCI injury group and beta diversity differed among groups, although these effects were not observed in all metrics. Subsequent differential abundance analysis revealed that the phylum Verrucamicrobiota was increased in CCI mice at 1, 2, and 3 d post-injury when compared to sham mice. Subsequent qPCR identified the Verrucamicrobiota species as Akkermansia Muciniphila, an obligate anaerobe that resides in and helps regulate the intestinal mucus layer and barrier. To determine whether TBI promotes changes to the GI tract favorable for the proliferation of A. muciniphila, mucus-producing goblet cells and the level of GI hypoxia were evaluated. Goblet cell density in the medial colon was significantly increased at 1 d, while colon hypoxia was significantly increased at 3 d. Taken together, these studies show that CCI induces transient intestinal barrier dysfunction followed by increased goblet cell density and hypoxia in the colon with a concomitant increase in A. muciniphila that may suggest a compensatory response to systemic stress after TBI.

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Functional recovery following traumatic brain injury in rats is enhanced by bovine thymus nuclear extract supplementation

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