Abstract
Purpose of Review
Early enteral nutrition improves outcomes following traumatic brain injury (TBI). This can prove difficult due to TBI-induced feeding intolerance secondary to disruption of the brain-gut axis, a network composed of central nervous system (CNS) input, autonomic signaling, and immunologic regulation that controls gut and CNS homeostasis. Here, we discuss the pathophysiology of brain–gut axis dysregulation and outline nutrition strategies in patients with TBI.
Recent Findings
Feeding intolerance following TBI is multifactorial; complex signaling between the CNS, sympathetic nervous system, parasympathetic nervous system, and enteric nervous system that controls gut homeostasis is disrupted within hours post-injury. This has profound effects on the immune system and gut microbiome, further complicating post-TBI recovery. Despite this disruption, calorie and protein requirements increase considerably following TBI, and early nutritional supplementation improves survival following TBI. Enteral nutrition has proven more efficacious than parenteral nutrition in TBI patients and should be initiated within 48 hours following admission. Immune-fortified nutrition reduces CNS and gut inflammation and may improve outcomes in TBI patients.
Summary
Although autonomic dysregulation of the brain–gut axis results in feeding intolerance following TBI, early enteral nutrition is of paramount importance. Enteral nutrition reduces post-TBI inflammation and enhances immunologic and gut function. When feasible, enteral nutrition should be initiated within 48 hours following injury.
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Introduction
Traumatic brain injury (TBI) remains a major source of disability and mortality in the injured patient [1, 2]. Despite over 50 million TBIs diagnosed annually and decades of research, outcomes remain highly variable, as clinicians still understand little regarding the complexities and multi-system nature of TBI [3]. For years, the tenets of TBI management have focused on prevention of secondary injury, as there are currently very few therapies to treat damage to the brain tissue itself [4]. Billions of healthcare dollars are utilized annually to discover novel therapies targeted against intrinsic central nervous system (CNS) dysfunction seen in TBI, such as coma, seizures, and paralysis, as well as extra-anatomic neurophysiologic dysfunction [5].
TBI results in dysregulation and disruption of multiple organ systems, most notably the gastrointestinal (GI) tract. Our comprehension of the GI manifestations of TBI coincides with our increased understanding of the brain-gut axis, a biochemical signaling cascade between the CNS and digestive system involving bidirectional immunological and neurohormonal inputs that help facilitate gut motility, intestinal mucosal integrity, and immunologic homeostasis [6]. Dysregulation of the brain–gut axis has been implicated in various illness processes, including inflammatory bowel disease, depression, dementia, and other various neuropsychiatric conditions [7•, 8]. More recently, brain–gut axis dysfunction has been implicated in the pathogenesis of both the acute and chronic sequelae of TBI, as many of the major tenets of TBI-related symptoms are at least in part the result of impaired brain-gut signaling [9•].
For the injured patient, dysregulation of the brain–gut axis in the setting of concomitant TBI has profound downstream effects on nutritional supplementation [10•]. As caloric requirements precipitously increase following trauma, clinicians are often forced to reconcile a patient’s caloric needs with GI dysregulation often encountered in the setting of TBI [11]. In this review, we will discuss the imbalances and dysregulation of the brain–gut axis in TBI patients as it pertains to nutritional support, and we will highlight strategies to manage the nutritional needs of these patients during their hospitalization.
Brain–Gut Axis Disruption Following TBI
Baseline gut homeostasis relies on complex bidirectional signaling through the brain-gut axis, a network composed of multiple systems that execute complex functions within the GI tract and CNS [12••]. The CNS exerts its effects on the gut through branches of the autonomic nervous system, which include the sympathetic (SNS), parasympathetic (PNS), and enteric nervous systems (ENS). In turn, the CNS receives input from the GI tract through efferent peripheral autonomic fibers as well as neuropeptide signaling [13•]. Inputs from these three branches affect multitudes of complex physiologic processes, including GI motility and peristalsis, gut microbiome symbiosis, mucosal integrity, and systemic inflammatory and immunologic function. As is frequently seen in TBI, the hierarchical control of gut physiology by the autonomic nervous system is dramatically altered following a traumatic insult to the brain, as afferent and efferent signaling become impaired in as little as 24 hours post-injury [14]. Dysregulation of the brain–gut axis following TBI manifests itself as acute feeding intolerance, diarrhea, and gastroparesis, all occurring at a time where nutritional support is of paramount importance.
TBI has profound effects on both the afferent and efferent sympathetic pathways of the brain–gut axis [15•]. Preganglionic sympathetic fibers arising from the sympathetic chain synapse in one of three visceral ganglia (celiac, superior, or inferior mesenteric) before providing postganglionic fibers to several different cell types, including sphincter smooth muscle, vascular smooth muscle, and other neural cells of the enteric nervous system [16, 17]. In contrast, afferent fibers become activated by gut inflammation and injury, and TBI has been shown to markedly increase sympathetic tone early on following injury, culminating in a “fight or flight” catecholamine storm in multiple organ systems, including the GI tract [18, 19]. This process results in splanchnic vasoconstriction, shunting blood flow away from the gut and altering GI motility, contributing to diarrhea and gastroparesis classically seen in TBI patients [20••].
The parasympathetic innervation of the GI tract is also dramatically altered following TBI [21]. Most parasympathetic gut innervation arises from the vagus nerve, descending from the CNS and providing postganglionic efferent neurons that regulate secretomotor function in the GI tract. Normal vagus nerve input is bidirectional, and it assists in reflexive arcs following meal-related gut distention and facilitates neuropeptide release, among other various processes. Furthermore, the vagus nerve is pivotal in maintaining intestinal mucosal integrity in times of physiologic stress and inflammation [22•]. In concert with the ENS, efferent parasympathetic activation through a cholinergic-mediated reflex has been demonstrated to inhibit pro-inflammatory cytokines, and murine models have shown that complete absence of vagal input results worsens gut injury and inflammation following TBI [23, 24, 25•]. Dysregulation of this bidirectional parasympathetic input in the setting of TBI results in gut dysmotility and gut inflammation that negatively impacts CNS function.
The enteric nervous system is composed of sensory and motor components of the GI tract and functions to integrate these stimuli with external signaling inputs from both the SNS and the PNS [26]. Like other autonomic components of the GI tract, the bidirectional signaling between the ENS and CNS is paramount to the functionality of a healthy brain-gut axis; likewise, dysregulation of the ENS is a hallmark of both short- and long-term GI pathology following TBI. Catecholamine pre-dominance following TBI has been shown to inhibit normal ENS signaling, which is heavily reliant on acetylcholine neurotransmission [27, 28]. Furthermore, acute CNS inflammation witnessed following TBI appears to have a pro-inflammatory effect on enteric glial cells, a predominant component of the ENS [29•, 30••]. Reactive astrogliosis within the CNS following injury appears to promote gliosis within the gut and alter cytokine expression within enteric glial cells [31]. Although the effects of GI gliosis appear neuroprotective in the short term, this process has been implicated in many of the chronic GI changes observed following TBI, including feeding intolerance, gastroparesis, neurogenic bowel, impaired sphincter function, and chronic diarrhea [30].
Microbiome and Immunologic Disruption Following TBI
The immunologic cell lines within the Peyer’s patches and intestinal linings of the GI tract are a key factor in brain-gut homeostasis. CNS signaling has profound effects on both the innate and adaptive immune system within the GI tract, and conversely, normal immunologic GI function exerts retrograde effects on CNS activity [32]. GI macrophage half-life and mast cell degranulation are both dependent on neuropeptide release by the CNS; in turn, cytokine release by macrophages exerts a pro-motility effect on the ENS and ANS, and histamine and serotonin release by mast cells exert a regulatory effect on higher CNS function [33, 34]. Similar bidirectional effects have been observed in B-cells and T-cells, as normal adaptive immunity within the GI tract is dependent on acetylcholine-mediated and catecholamine-mediated signaling from the CNS [35]. In turn, immunoglobulin production by B cells appear to be neuroprotective, and, although the mechanism is poorly understood, normal T-cell function within the GI tract promotes gut motility and provides input to the CNS regarding gut distention and visceral nociception [36, 37•, 38]. Following TBI, increased levels of glucocorticoids exert negative effects on the efficacy of nearly all immune system cell types, and catecholamine surges due to acute neuroinflammation result in increased levels of pro-inflammatory cytokines that impair mucosal and cellular immunity within the GI tract [17, 39••]. As such, this CNS-mediated inflammation reduces GI motility and exacerbates feeding intolerance often seen in TBI patients [17]. Overall, dysregulation of the immune system’s bidirectional relationship with the CNS results in a state of immunocompromise following TBI, predisposing these patients to opportunistic enteric pathogens secondary to impaired mucosal immunity and bacterial translocation [40, 41•].
The relationship between the gut microbiome and CNS has become an increasingly important clinical factor in TBI [42]. Metabolites from gut flora affect CNS gene expression, alter blood–brain barrier permeability, and promote neurotransmitter release within the CNS in both mice models and in various human disease processes, lending validity to the assumption that the microbiome plays a pivotal role in normal brain–gut axis homeostasis [43, 44]. In addition, native gut flora have been shown to affect cytokine levels and T-cell differentiation, and as such, alterations in the gut microbiome could result in bidirectional dysregulation of the components of the brain–gut axis [45, 46]. Following TBI, cellular changes to the microbiome have been observed within hours following injury, which in turn can result in increased neuroinflammation and worsened neurologic recovery [47••, 48, 49]. In addition, through interactions with the ENS and ANS, functional gut microbiota are pivotal to maintenance of gut motility and mucosal integrity and absence of a competent microbiome in the setting of TBI results in impaired villous absorption and increased feeding intolerance [50, 51•].
Nutritional Requirements Following TBI
The increased nutritional requirements of TBI patients are well documented, with most clinical guidelines recommending initiation of enteral nutrition ideally within the first 24–48 hours of admission [10, 52]. TBI has been shown to increase global metabolic activity, and several studies have demonstrated a target nutritional goal of 25–30 kcal/kg/day in addition to 1.0–1.5 g/kg/day of protein to meet increased metabolic requirements and maintain positive nitrogen balance [53, 54]. Early nutrition has been shown to limit CNS inflammation following TBI; a recent systematic review of 13 randomized controlled trials confirmed the beneficial outcomes associated with early nutrition supplementation, including decreased mortality, reduced infection rate, and improved functional outcomes [55]. Conversely, multiple studies have demonstrated that patients who did not receive enteral nutrition within five days following TBI had up to a fourfold increase in the likelihood of in-hospital mortality [55].
Patients with TBI often present with concomitant injuries, such as abdominal trauma, that preclude early initiation of enteral feeding. In this setting, it has been proposed that early initiation of parenteral nutrition should be considered to maintain skeletal muscle mass and positive nitrogen balance in the acute phase of TBI. Generally, parenteral nutrition is associated with hepatic steatosis and increased incidence of nosocomial infections and bacteremia [56, 57]. Additionally, parenteral nutrition can result in fluid and electrolyte imbalances, which predisposes patients with intracranial hypertension who require hyperosmolarity therapy to deleterious side effects [58, 59]. In addition, hyperglycemia known predictor of poor outcomes following TBI and continuous infusion of dextrose-rich parenteral nutrition with resultant hyperglycemia may confer increased risk following TBI [60•, 61, 62••]. Conversely, whereas the lack of villous stimulation in parenteral nutrition lead to mucosal sloughing and wasting, enteral nutrition has been shown to enhance mucosal blood flow, and it is widely accepted that enteral nutrition is a more effective method of delivery of metabolic substrates, such as medium-chain fatty acids, fiber, complex carbohydrates, vitamins, and minerals [55, 63].
As such, enteral nutrition is widely accepted as the preferred modality of nutritional support in TBI patients. Parenteral nutrition should be considered in patients with TBI who have concomitant traumatic injuries that preclude enteral feeding initiation, such as in the setting of abdominal trauma. In addition, parenteral nutrition should be considered in patients with TBI who cannot undergo enteral feeding within 3–5 days following admission. In both instances, parenteral nutrition should be transitioned to enteral nutrition once enteral access is established and concomitant injuries are addressed.
Route of Feeding in TBI Patients
Patients with moderate or severe TBI present several challenges when considering their increased nutritional requirements post-injury, as many of these patients cannot perform self-feeding due to their injuries. These patients often require mechanical ventilation, thus precluding voluntary oral intake, and many TBI patients exhibit impaired swallowing mechanisms or reduced consciousness that predispose them to aspiration events and pneumonia, complicating their recovery. As such, these patients are reliant on naso-enteral feeding access early within their hospital course, but due to impaired brain–gut axis signaling, TBI patients frequently experience gastroparesis and feeding intolerance in the acute phase of injury, and tolerance of gastric feedings must be assessed daily.
Because of this early feeding intolerance, post-pyloric feeding is frequently implemented in critically ill TBI patients. As injury-related gastroparesis can lead to high gastric residuals in the acute phase, post-pyloric feeding bypasses the atonic stomach, reducing the incidence of transient tube feeding interruption for elevated gastric residual volume. Furthermore, recent evidence supports that post-pyloric enteral nutrition reduces the risk of aspiration pneumonia and increases the total volume of caloric intake when compared to conventional nasogastric feeding in TBI patients [55, 64•]. Transpyloric feeding tube placement can be achieved almost universally in any ICU setting, and as such, early tube feeding initiation through post-pyloric feeding access is recommended in absence of any concomitant injury [65]. In clinical settings where post-pyloric access cannot be established, nasogastric feeding should be administered within the first 24–48 hours of admission with increased surveillance toward gastric feeding intolerance.
Novel Nutritional Therapies in TBI Patients
Central nervous system inflammation following TBI has deleterious effects on immunologic and microbiome homeostasis within the GI tract. Increased sympathetic tone and cytokine release due to CNS damage results in impaired mucosal protection and increased permeability of the intestinal wall, which in turn results in bidirectional imbalances through brain–gut interactions and incites secondary damage on the CNS, perhaps contributing toward long-term sequelae of TBI [66]. Given these alterations, it has been proposed that supplementation of substrates that promote healthy immunologic function, which include arginine, omega-3 fatty acids, and glutamine, could decrease this secondary inflammatory effect and promote early neurologic recovery and minimize secondary CNS damage [66, 67, 68•]. Several studies have compared experimental immune-enhancing tube feeding formulas and conventional tube feeding formulas in TBI patients who require enteral nutrition. Overall, immune-enhancing nutrition decreases the inflammatory response in the acute phase of TBI as demonstrated by reductions in circulating cytokine levels [69, 70••]. Reversal of impaired immunologic function was also observed, as patients who received immune-enhancing nutrition demonstrated reduced bacteremia during inpatient hospitalization, although the incidence of other nosocomial infections was uniform across both arms [71•]. Ultimately, immune-enhanced nutrition has shown promise as a brain–gut axis modulator in acute TBI, although more prospective studies will be required to determine whether its usage should be uniform in this patient population.
Vitamin and mineral supplementation have shown promise in TBI patient populations, although their beneficial effects on neuronal recovery and brain-gut homeostasis are still largely hypothetical. Vitamin D deficiency has been shown to worsen TBI outcomes in animal models, suggesting that routine vitamin D supplementation should improve neuronal recovery post-injury [72, 73]. Similarly, vitamin E, a free radical scavenger, has improved neuronal recovery in concussed mice, although its effect on TBI recovery in humans remains unclear [74]. Zinc and magnesium depletion have been observed following TBI as well as neuropsychiatric illnesses, suggesting that routine supplementation of these minerals could improve TBI outcomes. Zinc supplementation has shown promise in animal models following TBI, although prospective data in human populations are currently not available [75]. Similarly, although magnesium supplementation has been studied in humans with TBI, more prospective trials will be recovered to prove the efficacy of routine supplementation in this population [76, 77]. While the benefits of routine supplementation of vitamins and trace metals are still unclear, we strongly advocate for routine electrolyte surveillance and aggressive repletion of all electrolyte derangements in TBI patients.
Conclusion
Disruption of the brain–gut axis contributes greatly to feeding tolerance witnessed in patients with TBI. These disruptions occur at the cellular level within the CNS, ANS, and gut microbiome within hours following injury, and neuroinflammation from the initial CNS insult has marked downstream effects within the GI tract. Early enteral nutrition is a hallmark of TBI management that has been shown to augment brain–gut axis activity and reduce acute and chronic sequelae of TBI. Enteral nutrition is likely superior to parenteral nutrition in this patient population, and post-pyloric enteral feeding access is preferred over traditional gastric feeding. Immune-enhanced tube feeds and routine vitamin and mineral supplementation are promising therapies to reduce neuroinflammation and improve recovery following TBI.
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Marshall, W.A., Adams, L.M. & Weaver, J.L. The Brain–Gut Axis in Traumatic Brain Injury: Implications for Nutrition Support. Curr Surg Rep 10, 172–179 (2022). https://doi.org/10.1007/s40137-022-00325-w
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DOI: https://doi.org/10.1007/s40137-022-00325-w