Alterations of the GH/IGF-I Axis and Gut Microbiome after Traumatic Brain Injury: A New Clinical Syndrome?

Abstract

Context

Pituitary dysfunction with abnormal growth hormone (GH) secretion and neurocognitive deficits are common consequences of traumatic brain injury (TBI). Recognizing the comorbidity of these symptoms is of clinical importance; however, efficacious treatment is currently lacking.

Evidence Acquisition

A review of studies in PubMed published between January 1980 to March 2020 and ongoing clinical trials was conducted using the search terms “growth hormone,” “traumatic brain injury,” and “gut microbiome.”

Evidence Synthesis

Increasing evidence has implicated the effects of TBI in promoting an interplay of ischemia, cytotoxicity, and inflammation that renders a subset of patients to develop postinjury hypopituitarism, severe fatigue, and impaired cognition and behavioral processes. Recent data have suggested an association between abnormal GH secretion and altered gut microbiome in TBI patients, thus prompting the description of a hypothesized new clinical syndrome called “brain injury associated fatigue and altered cognition.” Notably, these patients demonstrate distinct characteristics from those with GH deficiency from other non-TBI causes in that their symptom complex improves significantly with recombinant human GH treatment, but does not reverse the underlying mechanistic cause as symptoms typically recur upon treatment cessation.

Conclusion

The reviewed data describe the importance of alterations of the GH/insulin-like growth factor I axis and gut microbiome after brain injury and its influence in promoting neurocognitive and behavioral deficits in a bidirectional relationship, and highlight a new clinical syndrome that may exist in a subset of TBI patients in whom recombinant human GH therapy could significantly improve symptomatology. More studies are needed to further characterize this clinical syndrome.

traumatic brain injury, BIAFAC, growth hormone, insulin-like growth factor-I, growth hormone secretion, gut microbiome

Traumatic brain injury (TBI) is arguably one of the most complex and common types of brain injury (1) and frequently leads to impairment of quality of life (QoL) and increased morbidity (2). The sequelae of TBI are not well understood and are the result of not only direct mechanical damage sustained from the initial injury (primary), but also to cellular and molecular damage that is exacerbated in the following hours, days, weeks, months, and years post injury (secondary) (3, 4). The etiology of secondary injury can be multifaceted and may be related to altered cerebral blood flow, excitotoxicity, inflammation, microglial activation, metabolic anomalies, mitochondrial dysfunction, and oxidative stress resulting in transient or lifelong neurocognitive and behavioral deficits (4-7). The clinical severity of TBI is often assessed based on the Glasgow Coma Scale, and the type and degree of structural damage by imaging and prognostic models (8). Overall, TBI complexity occurs on a spectrum ranging from mild to severe, diffuse to focal, and single to repeated exposures in brain versus multiple organs, which leads to injury-specific heterogeneous pathobiological responses that cannot be regarded as a single entity.

Previous studies have suggested that post-TBI hypopituitarism is a common sequelae, reportedly affecting 40% to 50% of survivors of severe TBI (9). Growth hormone (GH) and gonadotropin deficiencies are the most commonly observed pituitary hormone deficits (with rates of approximately 13% and 10%, respectively), whereas adrenocorticotrophic and thyroid-stimulating hormone deficiencies are less common (with rates of 4-12%) (10). Conversely, Klose et al. (11) demonstrated that the true prevalence of GH deficiency (GHD) may actually be lower than other published studies when stringent criteria including confirmatory testing is applied suggesting a high risk of bias in diagnostic testing of these patients, whereas Emelifeonwu et al. (12) reported that the severity of TBI does not influence the prevalence and severity of post-TBI hypopituitarism.

The clinical consequences of adult GHD syndrome are variable and include decreased muscle strength, decreased lean body mass, increased central fat mass, and altered metabolic profile (13). Notably, impaired QoL is the characteristic feature in patients with GHD post TBI manifesting as neuropsychiatric symptoms (eg, fatigue, depression, sleep disturbances, impaired memory, and altered cognition and executive functioning) (14-16). While previous studies have demonstrated the development of GHD post TBI (10), to date there has been no clinical study specifically investigating the effects of recombinant human GH (rhGH) therapy in the acute phase of TBI in patients with GHD, and only a few studies have demonstrated improvement in symptoms related to neurocognitive performance, fatigue, sleep disturbance, depression, and anxiety with rhGH therapy in patients with chronic TBI and abnormal GH secretion (17-19).

GH has long been known to modulate gastrointestinal (GI) function (20). A number of studies have implicated its role in maintaining gut integrity (eg, decreasing intestinal permeability and bacterial translocation) and improving gut function (eg, macronutrient absorption and immune function) (21, 22). Recent studies have further supported this notion by demonstrating that the microbial impact on growth is mediated through the GH/insulin-like growth factor (IGF)-I axis, indicating an intricate interplay between GH and the gut microbiome on the regulation of growth (23-25). Because GH and IGF-I can also exert neurotrophic and neuroregenerative effects after brain injury (26), a bidirectional relationship between the altered GH/IGF-I axis and the gut microbiome has been postulated (27). This has led to the description of a hypothesized new clinical syndrome called “brain injury associated fatigue and altered cognition” (BIAFAC) (19, 28, 29), which refers to a subset of TBI patients who go on to develop postinjury hypopituitarism and other metabolic abnormalities, namely altered gut microbiome and impaired amino acid utilization.

This review aims to provide an overview of the dynamic relationship between the GH/IGF-I axis and the gut microbiome after brain injury, and to explore the possible role of rhGH therapy in modulating the neurocognitive consequences of brain injury via the gut microbiome. By developing a better understanding of the role of the microbiota–gut–brain axis in either potentiating inflammation or protecting against secondary injury, future therapeutic targets for neuroprotection and neurorehabilitation can be identified to reduce morbidity, and potentially improve the clinical outcomes of BIAFAC patients.

In preparation for this review, we conducted an electronic database search of PubMed of studies published between January 1980 to March 2020, and also reviewed ongoing clinical trials. The search terms used were “growth hormone,” “traumatic brain injury,” and “gut microbiome.”

GH/IGF-I Axis and the Brain

The GH/IGF-1 axis plays an integral role not only on brain growth, development, and myelination, but also on neuroprotection and neuroregeneration (26). It is also one of the key regulator hormones of appetite, neurocognitive function, energy metabolism, memory, mood, sleep, and wellbeing (30). By binding to the GH receptor at target tissues, GH stimulates IGF-I synthesis and secretion, primarily by the liver (31) and locally by the brain (32). Brain cells such as neurons, glia, and oligodendrocytes actively respond to GH and IGF-I signaling due to the high expression of GH and IGF-I receptors in the central nervous system (CNS) (33, 34).

In embryonic cultures from cerebral cortex, GH stimulates neuronal precursor and glial cells (35, 36), and increases neurogenesis, myelination, and synaptogenesis (37). In animal studies, GH has been shown to stimulate neuronal proliferation and differentiation, improve neurocognitive function (26, 38), and confer protection against neuronal hypoxic/ischemic injury (39). These data suggest that rhGH therapy may exert neuroprotective effects against hypoxic–ischemic brain injury, and promote the proliferation of progenitor neural stem cells in the human fetal cortex (40).

Compared to GH, IGF-I exerts more potent trophic effects in the motor and sensory neurons, and on neuronal development and regeneration (41-44). IGF-I promotes neurite outgrowth (45), protects cells from apoptotic stimuli at the mitochondrial level (46), and is active in Schwann cell survival, maturation, and myelination in vitro (42). In rat studies, IGF-I is the restorative molecule for increasing hippocampal neurogenesis and memory accuracy (47), and confers protective effects on neurons acting on both the MAPK and PI-3K/Akt pathways to promote survival of motor neurons and regulation of skeletal muscle growth (48). Conversely, declining serum GH and IGF-I levels associated with physiological aging has been shown to be responsible for alterations in brain structures and functions (49).

Pathophysiology of GHD after TBI

The pathophysiology of TBI-induced hypopituitarism is complex. The primary event of direct mechanical trauma to the brain at the time of initial impact is followed by a series of secondary events, resulting in secondary brain injury (50). During this secondary phase, ischemia to the hypothalamus and pituitary due to vascular injury, cytotoxicity, and inflammatory changes may all occur contributing to the delayed worsening of the brain injury (51) (Fig. 1).

Figure 1.

Effects of traumatic brain injury on growth hormone secretion and the microbiota–gut–brain axis. Brain injury causes an interplay of ischemia, cytotoxicity, and inflammation that results in delayed worsening of symptom complex. The resulting perturbations to endogenous growth hormone secretion and gut dysbiosis contributes to the development of impaired amino acid utilization, neurocognitive dysfunction, and changes in behavioral processes. The changes may occur in the brain first that then affects the gut or vice versa (a bidirectional relationship). Recombinant human growth hormone therapy has been hypothesized to break this cycle (dashed green arrows) by directly reducing the impact of secondary injury pathology thereby inducing eubiosis and improving symptom complex.

Vascular injury is frequently implicated as the inciting mechanism responsible for post-TBI hypopituitarism, as autopsy studies have shown a high prevalence of necrosis or hemorrhage into the pituitary gland in up to 43% of all fatal TBI cases (52). The degree and severity of post-TBI hypopituitarism is related to the anatomy and blood supply to the hypothalamic–pituitary region. The pituitary gland is located in the skull base within the sella turcica, separated from the suprasellar cistern by the diaphragma sella and tethered to the hypothalamus by the infundibulum. About 70% to 90% of blood supply to the anterior lobe of the pituitary gland is supplied by branches from the long hypophyseal portal vessels that arise from the superior hypophyseal artery (53); however, the anatomic extension of the long hypophyseal vessels makes them more vulnerable to damage. Shearing forces, direct compression by raised intracranial pressure, brain edema, and brain shift causes ischemic changes to the pituitary gland. The short hypophyseal portal vessels arise from branches of the intracavernous internal carotid artery (ie, the inferior hypophyseal arteries), which enter the sella from below the diaphragma sella and supply the anterior gland with less than 30% of its vascular supply, predominantly in the medial portion of the gland that includes the pars intermedia (53). Because the somatotroph cells, located in the lateral wedge of the pituitary gland, are supplied by a long hypophyseal portal system, it might explain the increased frequency of GHD post TBI (10). Other factors associated with trauma in general (eg, hypotension and hypoxia) may also contribute to the acute effects of primary brain injury resulting in worsening of the ischemia to the pituitary at this time. Conversely, the secondary phase of TBI has a slower progression that could range from hours to years after the initial direct mechanical trauma causing free radical generation, excitotoxicity from excess glutamate, and systemic and CNS immune activation (7) that could lead to cell swelling, necrosis, and ultimately apoptosis of distal brain tissue (54, 55).

By comparison with reports in adults, there is limited literature and research on longer-term endocrine dysfunction after TBI in children. In fact, pediatric patients may have more complex mechanisms involved in neuroplasticity as the CNS matures. The most prevalent mechanisms of TBI in pediatric population are those among 0 to 4-year-olds who suffer from the shaken baby syndrome, and teenagers due to motor vehicle accidents (56). After long-term follow-up of children after TBI, dysfunction of hypothalamic and/or anterior pituitary deficiency can cause significant impairment in QoL, poor growth, precocious puberty, failure to enter or progress through puberty, chronic fatigue, amenorrhea, and a variety of neurocognitive symptoms (57, 58). Onset of these symptoms may be insidious and confused with the postconcussive syndrome, and hence hypopituitarism may go unrecognized for long periods in children after TBI (56). Therefore, it is possible that these patients may suffer even greater severity of long-term consequences after TBI and greater alterations in the relationship between the GH/IGF-I axis and gut microbiome.

Genetic predisposition has also been implicated in the development of post-TBI hypopituitarism. Apolipoprotein E (ApoE) is the major apolipoprotein responsible for enhancing lipid transport and metabolism within the CNS (59), and may play a role in neuronal repair mechanisms. In the setting of TBI, ApoE regulates amyloid deposition, lipid distribution, mitochondrial energy production, and oxidative stress (60, 61), and increases intracellular calcium in response to injury (62). Previous studies have indicated that the ApoE genotype may influence post-TBI endocrine outcomes (59), and patients with the ApoE3/E3 genotype appear to have a lower risk of developing post-TBI hypopituitarism than patients with other genotypes (63). Another possible explanation to the development of post-TBI hypopituitarism is autoimmunity that may trigger an ongoing process of neuroinflammation (64), especially in those with elevated antipituitary and antihypothalamic antibodies (65). Finally, the possibility of regeneration of injured portal vessels has long been proposed by Daniel et al. (66) to explain the recovery of pituitary function in some patients over time after TBI, as this phenomenon may be related to the direct mechanical injury that did not result in pituitary infarction, edema formation, and raised intracranial pressure.

Rationale for rhGH Therapy in Patients with Post-TBI GHD

Traumatic brain injury is associated with a wide variety of symptoms that impact cognition and emotional health, namely fatigue, sleep disturbances, subjective memory problems, poor concentration, impaired information processing, irritability, depression, anxiety, impulsivity, irritability, emotional lability, and apathy (67). The level of fatigue that patients report after TBI appears to correlate with other QoL-related symptoms such as anxiety, sleep disturbances, and neurocognitive impairment that persist in a large subset of patients (19). Although many of the symptoms are likely multifactorial, in a study by Mossberg et al. (18), these investigators reported that TBI-related fatigue is distinct from that reported by GH-sufficient individuals as it is often more severe, originates centrally within the brain, and is not limited to peripheral fatigue.

Evidence to support the role of CNS dysfunction after TBI has also been established using magnetic resonance imaging (MRI) studies. Following mild TBI, resting state functional connectivity in the brain is altered (68, 69) with widespread alterations in canonical network connectivity, including the default mode network and thalamocortical pathways (70, 71). Although the underlying mechanisms are not well understood, numerous studies have shown that rhGH therapy has been linked to neuroprotection and neural repair following injury (72). Table 1 summarizes a series of clinical studies that evaluated the effects of rhGH administration in TBI patients of varying severity on QoL and neurocognitive function in patients with TBI. It is noteworthy that 3 out of the 10 clinical studies included patients without established GHD per se, as defined by the criteria set forth by the Endocrine Society (73) and American Association of Clinical Endocrinologist (74) Clinical Practice Guidelines, and yet positive results were obtained implying neuroprotective and neurorehabilitative effects of rhGH therapy in such patients. Studies by Reimunde et al. (75) and Devesa et al. (76) included patients with peak GH levels ≥7 mg/dL following testing with the GH releasing hormone-arginine test, whereas Wright et al. (19) assessed patients with peak GH levels <8 mg/dL after being tested using the glucagon stimulation test (GST) (Table 1). Furthermore, there are also published case reports reiterating the positive effects of rhGH therapy on neurorehabilitation, neurocognitive function, and cerebral metabolism in a young man (77), a young female (78), and an elderly patient (79) respectively; all of whom were not GH deficient. However, in these case reports, a placebo effect cannot be excluded.

Table 1.

Sample studies of the effects of rhGH therapy on quality of life and neurocognitive function in patients with TBI

Investigators	N	Age (years)	GH stimulation test	Study design	Treatment duration	Recombinant human GH dose (mg/day)	Salient clinical outcomes
Wright et al., 2020 (19)	18	48.0 males 21.2 females	GST	Double-blind, placebo-controlled crossover clinical study followed by open rhGH treatment in both arms	1 year	0.4 mg/day first month, 0.6 mg/day for remainder	Decreased fatigue, sleep disturbance and anxiety, and changes in brain connectivity and morphology
Dubiel et al., 2018 (105)	63	31.1	Arginine in 38% of patients	Phase 2 randomized, placebo-controlled clinical study	1 year	0.4 mg/day titrated according to serum IGF-I, not exceeding 1.0 mg/day	Trend towards improved functional independence measure
Mossberg et al., 2017 (18)	15	45.5	GST	Clinical open-label study	1 year	Started at 0.2 mg/day, increased to 0.4 mg/day and then to 0.6 mg/day	Improved depression and reduced fatigue
Gardner et al., 2015 (106)	161	42.6	ITT, GST or GHRH-arginine	Retrospective, database analysis	1 year	0.37 mg/day	Long-term improvement in quality of life
Moreau et al., 2013 (17)	23	37.9	ITT or GHRH-arginine	Open, prospective clinical study	1 year	0.3 to 0.6 mg/day	Improved cognition and quality of life
Devesa et al., 2013 (76)	13	24.6	GHRH-arginine	Open, prospective clinical study	8 months	0.8-1.0 mg/day for 5 days/week, no treatment 15 days every 2 months	Improved cognition and motor skills
Reimunde et al., 2011 (75)	11	53.3	GHRH-arginine	Prospective placebo-controlled pilot study	3 months	0.5 mg/day for 20 days, then 1 mg/day for 5 days/week	Improved cognition
High et al., 2010 (16)	23	39.1	GST	Randomized controlled study	1 year	0.2 mg/day, uptitrated to 0.6 mg/day	Improved cognition
Maric et al., 2010 (108)	4	39.3	GHRH + GHRP-6	Open, prospective clinical study	6 months	0.3 mg/day in males, 0.4 mg/day in females	Improved cognition and psychiatric functioning
Kreitschmann-Andermahr et al., 2008 (109)	84	36.7	Arginine, ITT, GHRH or GHRH-arginine	Retrospective, database analysis	1 year	0.3 mg/day starting dose	Improved quality of life

Abbreviations: GHRH, growth hormone releasing hormone; GST, glucagon stimulation test; ITT, insulin tolerance test; rhGH, recombinant human growth hormone.

Interestingly, the study by Wright et al. (19) demonstrated that rhGH therapy over 12 months in patients with mild TBI decreased fatigue, sleep disturbance, and anxiety, increased resting energy expenditure, and improved altered perception of submaximal effort when performing exercise testing. On MRI assessments, associated brain changes were found, such as increased frontal cortical thickness and gray matter volume, and resting state connectivity changes in regions associated with somatosensory networks. Nonetheless, rhGH therapy did not reverse the underlying condition in this subset of patients, as symptoms returned after treatment ceased. Thus, it remains unclear if the benefits of rhGH therapy in TBI patients were due to the correction of underlying GH dysfunction or via an alternative mechanism.

Alterations in the Gut Microbiome after TBI

The rapidly expanding field of assessing the interactions between the GI tract, immune system, endocrine system, and brain has led to the suggestion that the gut microbiome plays a significant role in influencing each of these systems (80-82). This relationship is referred to as the microbiota–gut–brain axis (27, 83), with communication between the gut microbiota and the CNS occurring through a neuroendocrino-immunological network (84). Recent next-generation sequencing analyses have further demonstrated a link between altered gut microbiomes and altered neurocognition, behavior, and mood disorders associated with several other neuropathological diseases, including Parkinson’s disease (85), Alzheimer’s disease (86), autism (87), depression (88), and anxiety (89). Bacteroidetes and Firmicutes phyla are the dominant gut microbiota, with Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia in lesser numbers, although gut microbial composition may differ among individuals depending on diet, age, gender, environment, and genetics (90).

Studies have also shown that acute TBI is associated with alterations in GI metabolism and loss of tight junctions contributing to increased intestinal permeability, inflammation, and malabsorption, consequently leading to neuroinflammation and changes in intestinal contractility (91, 92). In the long term, reductions in gut mobility disrupt the existing balance of microflora and promote small intestinal bacterial overgrowth contributing to gut dysbiosis (27). Furthermore, neurocognitive and behavioral changes can alter gut microbiota composition suggesting a bidirectional relationship between TBI-associated perturbations of the GH/IGF-I axis and gut microbiome (27) (Fig. 1).

In a controlled cortical impact rodent model, gut microbiota changes were found 2 hours after injury and persisted out to 7 days post injury, with decreased Firmicutes and increased bacterial families within the Bacteroidetes and Proteobacteria phyla (93). In another study of controlled cortical impact mice model, Treangen et al. (94) demonstrated the development of gut dysbiosis with decreased Lactobacillus gasseri, Ruminococcus flavefaciens, and Eubacterium ventriosum and increased Eubacterium sulci and Marvinbryantia formatexigens after 24 hours. Human studies of TBI-induced gut dysbiosis, however, have been scarce until recently. Howard et al. (95) found in severe TBI patients a decrease in Bacteroidales, Fusobacteriales, Verrucomicrobiales, and an increase in Clostridiales and Enterococcus within 72 hours of the injury. More recently, Urban et al. (29) reported alterations in fecal microbiome community structures, namely decreased Prevotella, Bacteroidetes and several amino acids, and increased Ruminococcaceae that were present more than 27 months in patients with moderate-to-severe TBI. Furthermore, following TBI-induced physical disruptions to the blood–brain barrier (96), intestinal contents and the associated upregulation of the proinflammatory immune response can permeate the CNS, resulting in increased microglial activity, neuroinflammation, and neuropathology (97). Therefore, it is possible that TBI-induced gut dysbiosis may play a role in decreasing GH secretion and increasing microglial activation following the injury (98). Overall, these studies demonstrate the complex relationships within the microbiota–gut–brain axis, revealing that the altered bacterial populations can persist even years after TBI and may influence the degree of neuropathology and functional impairment in TBI patients.

Implications of Recent Studies and Proposal of a Hypothesized New Clinical Syndrome

There is now emerging evidence suggesting a link between the GH/IGF-I axis and the gut microbiome (99, 100). These data were further corroborated by a recent elegant study that characterized the gut microbiome in mouse lines with states of GHD and GH excess and implicated the role of GH in promoting microbial maturation and metabolic functions such as short-chain fatty acid, folate, and heme B biosynthesis (101). Because of the evidence indicating that TBI induces a cascade of neuropathological events that renders a subset of the patients with hypopituitarism and other metabolic abnormalities (eg, impaired gut microbiome and impaired amino acid utilization), a group of investigators has recently proposed a hypothesized new clinical syndrome called BIAFAC (19, 28, 29). This syndrome includes patients who achieve peak GH levels <8 ng/mL after a GST (19) that are classified as having abnormal GH secretion, and includes patients with GHD and those without GHD, according to the GST GH cutpoint criteria to diagnose adult GHD (74). It remains unclear whether BIAFAC is caused by GHD per se or whether the abnormal GH secretion is a direct result of the disease itself. Many of the symptoms of BIAFAC overlap with those of postconcussive syndrome, specifically profound fatigue, behavioral processes, and neurocognitive dysfunction related to executive function, short-term memory, and processing speed index (Fig. 1). However, genetic predisposition and history of multiple TBIs may be at play as not every post-TBI patient develops BIAFAC and that this clinical syndrome can occur across the range of TBI severity from very mild to severe cases. The factors that differentiate BIAFAC from those with postconcussive syndrome include (1) that symptom onset may not occur for at least 6 months after the initial trauma and manifest months or years later, (2) that patients display peak serum GH levels <8 ng/dL after being tested with the GST, (3) that patients respond very favorably to rhGH therapy, and (4) that patients demonstrate MRI changes of increased gray matter volume and cortical thickness in frontal regions and altered connectivity in somatosensory brain networks (19). Additionally, BIAFAC symptoms are different in severity compared with patients with GHD from other causes, such as pituitary tumors and/or after pituitary surgery and radiation, and respond with significant improvements in fatigue after a minimum of 3 months of rhGH therapy, and in cognition between 4 and 5 months. When symptom improvement is achieved using a series of assessments that included physical performance and fatigue, resting energy expenditure, brain morphometry and connectivity, and neuropsychological tests, BIAFAC patients report that the improvement is highly profound to the point that some of them have been able to resume their normal physical activities. When there is disruption of rhGH therapy, either from a drug holiday or from insurance coverage refusal, the symptoms recur (ie, fatigue and neurocognitive impairment returns in 3 months and 4-5 months, respectively) suggesting that rhGH therapy can only improve BIAFAC symptoms while on treatment, but cannot reverse the underlying cause. Additionally, because altered postmeal amino acid profiles were also observed in post-TBI patients (102), a further study by Urban et al. (29) exploring the fecal microbiome in chronic TBI patients in permanent care facilities compared with controls working at these facilities found that chronic TBI patients displayed different fecal microbiome community structures compared with the controls.

With these findings, many follow-on questions have since arisen. Are some patients more susceptible to develop chronic inflammation of the brain post TBI? Why do some patients develop symptoms much sooner after injury than others? Does BIAFAC truly exist in a subset of TBI patients, and, if so, what are the mechanisms that cause the symptom complex in BIAFAC patients that differ from those with GHD due to non-TBI causes? Is there a role for fecal microbiome transplant or specific foods in altering the gut microbiome in BIAFAC patients? It is noteworthy that altering the gut microbiome through administration of fecal microbiome transplant or probiotics has been previously studied as a means to treat various intestinal diseases, metabolic disorders, endocrine diseases, and growth failure secondary to malnutrition (99, 103, 104). One intriguing therapeutic potential would be to administer rhGH to TBI patients in order to assess whether this therapy could mitigate gut dysbiosis, restore the gut microbiome to a healthy profile, and promote neurocognitive symptom improvement that correlates with changes in the gut microbiome. This clinical trial is currently being conducted at the University of Texas Medical Branch in Galveston (clinicaltrials.gov identifier: NCT03554265). In this study, fecal sampling for characterization of the gut microbiome will occur monthly while on rhGH treatment, and each subject will enroll with an eligible control from their household that will also provide fecal samples so that the gut microbiomes can be compared between the 2 cohorts.

Concluding Remarks

Abnormal GH secretion that occurs after TBI in both the adult and the pediatric population is associated with negative neurocognitive and behavioral consequences that frequently impair neurorehabilitation and recovery. Positive effects of rhGH therapy in post-TBI patients on fatigue, behavioral processes, and neurocognitive outcomes have been demonstrated in some, but not all, studies. Because of the scarcity of clinical studies of rhGH therapy in human subjects together with the evolution of symptoms of TBI over time post injury, drawing firm conclusions on the efficacy of rhGH therapy in these patients cannot be made. Recent studies, however, have suggested that in a subset of TBI patients, a hypothesized new clinical syndrome called BIAFAC might exist. These patients are characterized by perturbations to endogenous GH secretion and altered gut microbiome that derived significant clinical benefit while treated with rhGH, but with recurrence of negative clinical symptoms when treatment is discontinued. The mechanisms involved are unclear, although an interesting hypothesis (and currently being studied by a group of investigators) is to evaluate the effects of rhGH therapy in improving the symptom complex and mediating the resolution of gut dysbiosis in such patients. More clinical trials are needed to further confirm and characterize BIAFAC in a subset of TBI patients, to assess changes to the gut microbiota following different types and severities of TBI, and to evaluate optimal rhGH doses that can be used without inducing rhGH-related adverse effects and duration of treatment. Ultimately, this information will help improve our understanding of the pathophysiology of the symptom complex, mechanism of symptom improvement, and to better identify TBI patients that will derive most therapeutic benefit from exogenous rhGH administration.

Abbreviations

Abbreviations
 
• ApoE

  apolipoprotein E

 
• BIAFAC

  brain injury associated fatigue and altered cognition

 
• CNS

  central nervous system

 
• GH

  growth hormone

 
• GHD

  GH deficiency

 
• GI

  gastrointestinal

 
• GST

  glucagon stimulation test

 
• IGF

  insulin-like growth

 
• MRI

  magnetic resonance imaging

 
• QoL

  quality of life

 
• TBI

  traumatic brain injury

Acknowledgments

Financial Support: The authors did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Additional Information

Disclosure Summary: K.C.J.Y. has received research grants to Barrow Neurological Institute for clinical research studies from Ionis, Crinetics, Millendo, Corcept, and Novartis, and has served on advisory boards for Pfizer, Novo Nordisk, Ipsen, and Corcept. B.E.M. has served on an advisory board for Novo Nordisk. K.R. has served on advisory boards for AbbVie and Endo Pharm, and is a board member of the nonprofit Human Growth Foundation. M.S.-M. and R.B.P. have no conflicts to disclose. R.J.U. has received research grants from the Moody Endowment and TIRR Foundation, and has served on advisory boards for Novo Nordisk and Sandoz.

Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.