Phase 2 Randomized, Placebo-Controlled Clinical Trial of Recombinant Human Growth Hormone (rhGH) During Rehabilitation From Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of death and disability, but there are currently no therapies with proven efficacy for optimizing regeneration of repair during rehabilitation. Using standard stimulation tests, as many as 40–50% of survivors of severe TBI have deficiency of one or more pituitary hormones. Of these, the somatotropic axis is the most commonly affected, with Growth Hormone (GH) deficiency affecting ~20% of persons with severe TBI. Treatment with recombinant human Growth Hormone (rhGH) is generally effective in reversing the effects of acquired GH deficiency, but there is no evidence documenting functional or neurocognitive improvement after GH replacement in TBI patients. As a consequence, screening for GH deficiency and GH replacement when deficiency is found is not routinely performed as part of the rehabilitation of TBI survivors. Given that most of the recovery after TBI occurs within the first 6–12 months after injury and IGF-1 and GH are part of a coordinated restorative neurotrophic system, we hypothesized that patients will optimally benefit from GH therapy during the window of maximal neuroregenerative activity. We performed a Phase IIa, randomized, double-blind, placebo-controlled feasibility trial of recombinant human Growth Hormone (rhGH), starting at discharge from an inpatient rehabilitation unit, with follow up at 6 and 12 months. Our primary hypothesis was that treatment with rhGH in the subacute period would result in improved functional outcomes 6 months after injury. Our secondary hypothesis proposed that treatment with rhGH would increase IGF-1 levels and be well tolerated. Sixty-three subjects were randomized, and 40 completed the trial. At baseline, there was no correlation between IGF-1 levels and peak GH levels after L-arginine stimulation. IGF-1 levels increased after rhGH treatment, but it took longer than 1 month for levels to be higher than for placebo-treated patients. rhGH therapy was well-tolerated. The rhGH group was no different from placebo in the Disability Rating Scale, Glasgow Outcome Scale-Extended, or neuropsychological function. However, a trend toward greater improvement from baseline in Functional Independence Measure (FIM) was noted in the rhGH treated group. Future studies should include longer treatment periods, faster titration of rhGH, and larger sample sizes

The altered TBI fecal microbiome is stable and functionally distinct

IntroductionPatients who suffer a traumatic brain injury (TBI) often experience chronic and sometimes debilitating sequelae. Recent reports have illustrated both acute and long-term dysbiosis of the gastrointestinal microbiome with significant alterations in composition and predicted functional consequences.MethodsWorking with participants from past research, metagenomic stability of the TBI- associated fecal microbiome (FMB) was evaluated by custom qPCR array comparing a fecal sample from 2015 to one collected in 2020. Metatranscriptomics identified differently expressed bacterial genes and biochemical pathways in the TBI FMB. Microbiota that contributed the largest RNA amounts identified a set of core bacteria most responsible for functional consequences of the TBI FMB.ResultsA remarkably stable FMB metagenome with significant similarity (two-tail Spearman nonparametric correlation p < 0.001) was observed between 2015 and 2020 fecal samples from subjects with TBI. Comparing the 2020 TBI FMB metagenome to FMBs from healthy controls confirmed and extended the dysbiotic genera and species. Abundance differences between average TBI and healthy FMBs revealed Bacteroides caccae, B. uniformis, Blautia spp., Collinsella spp., Dialister spp., and Ordoribacter spp. were significantly different. Functionally, the Parabacteroides genus contributed the highest percentage of RNA sequences in control FMBs followed by the Bacteroides genus as the second highest contributor. In the TBI FMB, the Corynebacterium genus contributed the most RNA followed by the Alistipes genus. Corynebacterium and Pseudomonas were distinct in the top 10 contributing genera in the TBI FMB while Parabacteroides and Ruminococcus were unique to the top 10 in controls. Comparing RNA profiles, TBI samples had ∼1.5 fold more expressed genes with almost 700 differently expressed genes (DEGs) mapped to over 100 bacterial species. Bioinformatic analysis associated DEGs with pathways led identifying 311 functions in the average TBI FMB profile and 264 in the controls. By average profile comparison, 30 pathways had significantly different abundance (p < 0.05, t-test) or were detected in >80% of the samples in only one of the cohorts (binary distinction).DiscussionFunctional differences between TBI and healthy control FMBs included amino acid metabolism, energy and carbon source usage, fatty acid metabolism, bacterial cell wall component production and nucleic acid synthesis and processing pathways. Together these data shed light on the functional consequences of the dysbiotic TBI FMB decades after injury

Table_1_The altered TBI fecal microbiome is stable and functionally distinct.docx

IntroductionPatients who suffer a traumatic brain injury (TBI) often experience chronic and sometimes debilitating sequelae. Recent reports have illustrated both acute and long-term dysbiosis of the gastrointestinal microbiome with significant alterations in composition and predicted functional consequences.MethodsWorking with participants from past research, metagenomic stability of the TBI- associated fecal microbiome (FMB) was evaluated by custom qPCR array comparing a fecal sample from 2015 to one collected in 2020. Metatranscriptomics identified differently expressed bacterial genes and biochemical pathways in the TBI FMB. Microbiota that contributed the largest RNA amounts identified a set of core bacteria most responsible for functional consequences of the TBI FMB.ResultsA remarkably stable FMB metagenome with significant similarity (two-tail Spearman nonparametric correlation p 80% of the samples in only one of the cohorts (binary distinction).DiscussionFunctional differences between TBI and healthy control FMBs included amino acid metabolism, energy and carbon source usage, fatty acid metabolism, bacterial cell wall component production and nucleic acid synthesis and processing pathways. Together these data shed light on the functional consequences of the dysbiotic TBI FMB decades after injury.</p