Sarah Danehower
  1. Drexel University College of Medicine, Philadelphia, Pennsylvania, United States.


Copyright: © 2021 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Sarah Danehower. Targeting gut dysbiosis as a means to enhance recovery from surgical brain injury. 03-May-2021;12:210

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Background: Surgical brain injury (SBI) impacts roughly 800,000 people who undergo neurosurgical procedures each year. SBI is the result of unavoidable parenchymal damage, vessel disruption, and thermal injury that is an inherent part of all neurosurgical procedures. Clinically, SBI has been associated with postoperative seizures and long-term neurobehavioral deficits. Current therapies are aimed at providing symptom relief by reducing swelling and preventing seizures. However, there are no therapies aimed at reducing the extent of SBI preoperatively. The microbiome-gut-brain axis may serve as a potential target for the development of new preventative therapies due to its extensive involvement in central nervous system function.

Methods: An extensive literature review was conducted to determine whether there is a potential role for dysbiosis treatment in reducing the extent of SBI.

Results: Treatment of gut dysbiosis deserves further exploration as a potential means of reducing the extent of unavoidable SBI. Dysbiosis has been correlated with increased neuroinflammation through impaired immune regulation, increased blood-brain barrier permeability, and increased production of reactive metabolites. Recently, dysbiosis has also been linked to acute neurological dysfunction in the postoperative state. Importantly, treatment of dysbiosis has been correlated with better patient outcomes and decreased length of stay in surgical patients.

Conclusion: Current literature supports the role of dysbiosis treatment in the preoperative setting as a means of optimizing neurological recovery following unavoidable SBI that results from all neurosurgical procedures.

Keywords: Dysbiosis, Microbiome gut-brain axis, Neuroinflammation, Surgical brain injury, Traumatic brain injury


The human microbiota contains over 100 trillion cells and is comprised of a diverse array of bacteria, fungi, archaea, and viruses.[ 34 ] These organisms outnumber our own cells ten-fold and produce over 99% of the genes in our bodies.[ 25 , 27 , 28 , 38 , 58 , 71 ] Given the sheer volume and genetic potential of these organisms, research investigating the role of the microbiome in human health and disease has increased exponentially over the last two decades. One area that has garnered much attention recently is the microbiota-gut-brain axis (MGBA). The MGBA is a bidirectional communication system that enables the central nervous system (CNS) to communicate with the gut and vice versa. The communication between the gut and the CNS is controlled mainly through the direct and indirect connection of the CNS and vagus nerve with the gastrointestinal tract’s enteric nervous system (ENS). The ENS modulates gut motility, absorption, secretion, and blood flow, thereby providing an environment that is suitable for some organisms and incompatible for others. Conversely, the microbiota produces neurotransmitters and metabolites capable of affecting ENS and vagus nerve signaling.[ 10 , 52 , 74 ]

While the complexities of the MGBA are still being discovered, it has become clear that the relative diversity and abundance of certain species of organisms play a role in human health and disease. Disruption of the microbiota, so-termed dysbiosis, is the result of environmental disturbances from several factors. To date, stress, age, host environment, diet, medications (not limited to antibiotics), and maternal factors[ 46 ] have been shown to impact the gut environment through changes in motility, gut wall permeability, and nutrient abundance.[ 24 ] As such, each of these factors represents a potential source through which dysbiosis can develop.

The clinical impact of dysbiosis is extensive. Not only has chronic dysbiosis been linked to obesity, diabetes, IBS, and IBD, but more recently, it has also been correlated with numerous neurological disorders, including but not limited to autism spectrum disorder (ASD), Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis, depression, and anxiety.[ 24 ] More recently, research has shown that acute dysbiosis due to neurological injury and resulting MGBA disruption is associated with negative recovery outcomes following traumatic brain injury (TBI) in mouse models.[ 43 , 96 ] Therefore, preventing dysbiosis may serve to protect against acute and chronic neurological dysfunction following neurological injury.

Despite the evidence highlighting the important role of the MGBA in neurological function, there has been little investigation into the role of the MGBA in outcomes following surgical brain. The purpose of this review is to summarize the current evidence supporting the role of dysbiosis treatment in reducing the extent of surgical brain injury (SBI) and enhancing patient recovery from it.


SBI may result from neurosurgery due to unavoidable parenchymal tissue incisions, small vessel damage, tissue retraction, and burn injury due to electrocautery. Although efforts have been made to reduce SBI through the development of minimally invasive techniques, tissue injury is inevitable in the over 800,000 neurological procedures performed per year.[ 45 ] Because of this damage, neurosurgical patients may experience prolonged surgical complications and lifelong neurobehavioral deficits. The current postsurgical treatment encompasses neuroprotective strategies aimed at reducing edema, ischemia, and dysfunction through the use of osmotic agents, steroids, diuretics, and anti-seizure medications. Unfortunately, none of these agents have definitively been shown to decrease postoperative complications.

Numerous in vivo mouse models have concluded that SBI results in neuronal cell death, apoptotic changes, increased oxidative stress, and blood-brain barrier (BBB) disruption at the surrounding surgical site.[ 45 ] Ultimately, these pathological processes result in the activation of microglia, astrocytes, and macrophages, which deposit collagen in the formation of glial scars in the surrounding areas.[ 87 ] This scarring continues to undergo remodeling and reconstruction for years afterward, resulting in further neurological damage. These results support findings of long-term human studies which show progressive atrophy of brain structures following TBI, stroke, therapeutic lobectomies, and surgical treatment of subarachnoid hemorrhages.[ 9 , 12 , 30 , 31 , 39 , 78 , 84 ]

Current research has been directed at identifying specific therapeutic targets that may prevent SBI. Due to the nervous system’s inability to regenerate tissue in a significant manner, to truly offer a clinical benefit for patients, therapies need to reduce the extent of SBI. Current investigational treatments for SBI have been identified based on two modes of thought: activation of neuroprotective mechanisms or inhibition of neuroinflammatory signaling before damage.

One promising therapy involves Slit2, which may play an important role in neurological recovery. Slit2 is a protein involved in neuronal and axonal development that is expressed at increased levels in the brain following SBI.[ 79 ] Treatment with recombinant Slit2 in a mouse model reduced SBI-induced BBB permeability due to an increased expression of BBB tight junction proteins, occludin, and claudin 3.[ 79 ] Another potential neuroprotective treatment being investigated is preoperative exposure to milk fat globule-epidermal growth factor B (MFGE8). MFGE8 is a neuroprotective signal that promotes phagocytosis, thereby eliminating apoptotic cells before the release of toxic signals. This attenuation of SBI-induced toxic signaling has been associated with decreased brain water content, cell death, inflammation, and neurological dysfunction.[ 79 , 101 ] Conversely, some investigators are looking at preconditioning with toxic substances as a potential means of decreasing neuroinflammation from SBI. Preconditioning with brief exposure to minor amounts of deleterious stimuli has been shown to stimulate tolerance toward future uncontrolled exposures of the same molecule.[ 1 , 70 ] In mouse models, preconditioning with PLA2 resulted in reduced edema, intra-operative bleeding, and improved neurological function following SBI.[ 94 ]

While these therapies show promise, their clinical utility is limited by several factors, including GI absorption, ability to reach the CNS, off-target effects, cost, and general availability. Therefore, other therapeutic targets need to be explored.


The role of the MGBA in disease has become a focus in the neuroscience community within the last decade. Beginning in 2011, investigators showed that compared to control mice, germ-free mice grown in specific-pathogen-free conditions had less anxiety-like behavior.[ 57 ] Since that time, microbiota composition and dysregulation have been linked to the development of a wide range of neurologic conditions. The exact mechanism of interaction between the gut microbiota and the CNS and how this interaction contributes to disease has yet to be revealed. Nevertheless, research has identified several mechanisms in which this bidirectional communicating system may impact neurological function and disease development.

Modulation of autonomic nervous system (ANS)

Signaling within the MGBA is multifaceted, including direct and indirect signaling between the ENS and the vagus nerve part of the ANS. While the ENS is considered a branch of the ANS, it is also capable of functioning independently. The ENS is composed of over 20 different types of neurons (each with their own function) that interact to form the myenteric and submucosal plexuses.[ 92 ] Each plexus represents a complex network of glia, motor neurons, intrinsic sensory neurons, and interneurons that extend throughout the length of the GI tract to control all aspects of digestion, including peristalsis, sphincter tone, and enzymatic secretions.

The interaction of the ENS and ANS is achieved through a combination of direct and indirect mechanisms. ENS sensory and motor neurons provide direct innervation to the vagus nerve, thereby allowing the ENS to provide constant feedback on microbiota structure and function to the CNS. Furthermore, our microbiota may exert direct influence over CNS function. In vivo mouse models showed that anxiolytic Lactobacillus treatment was rendered ineffective in animals who underwent vagotomy.[ 35 ] In addition, introducing microbiota in a germ-free mouse model and/or altering the microbiota in antibiotic-treated control mice have demonstrated how the gut microbiota directly influences the levels of neuromodulators such as plasma levels of serotonin, tryptophan, and kynurenine and hypothalamic levels of vasopressin and oxytocin;[ 54 , 65 , 80 ] neurogenesis in the adult hippocampus;[ 62 ] normal myelination in the prefrontal cortex during early development;[ 42 ] and changes in neuronal excitability and action potentials in enteric neurons.[ 56 ]

These observed structural and functional changes are correlated with different clinical outcomes. First, dysbiosis at an early age leads to dysregulated stress responses through the prevention of hypothalamic-pituitary-adrenal axis maturation.[ 86 ] This manifests as increased anxiety, elevated ACTH and cortisol levels.[ 14 , 57 ] Second, vagal input to the CNS can initiate anti-inflammatory responses which are vital for the regulation of mood and cognitive function.[ 60 ] Dysbiosis may modulate this input, resulting in inhibition of anti-inflammatory processes and leading to mood changes. In addition, several CNS disorders such as PD, AD, and ASD are characterized by ENS dysfunction. The role of ENS dysfunction in the development and progression of these diseases is not well understood, but there is little doubt that the MGBA plays a contributing role. Based on the multitudes of study data that establish the importance of MGBA in neurologic disease, many researchers are now beginning to investigate how best to manipulate the microbiota to combat disease.

Modulation of neuroinflammation

The microbiota plays an important role in immune system development and regulation of neuroinflammation later in life. Increased neuroinflammation has been linked to the development and progression of several neurodegenerative disorders, including AD, PD, AIDS-induced dementia, and TBI.[ 32 ] Dysbiosis leads to disruption of the BBB and activation of microglial cells in the CNS, resulting in increased neuroinflammation, thereby furthering disease burden.

One of the most devastating impacts of neuroinflammation is its disruption of the BBB. Pro-inflammatory cytokines enter the brain through active transport, diffusion through permeable circumventricular organs, or through generation at the BBB in response to a peripheral signal.[ 55 ] Once in the brain, inflammatory cytokines can regulate the loss of BBB integrity.[ 61 ] In one study, researchers showed increased BBB permeability in germ-free mouse models.[ 13 ] This alteration in BBB permeability resulted in the ability of bacterial and cellular metabolites and bacteria themselves to access to the CNS and influence neurological function.[ 37 ] However, treatment of dysbiosis may be able to reverse BBB damage and restore its protective function. When researchers provided the germ-free mice with pathogen-free gut flora, BBB permeability was reduced.[ 13 ]

Notably, TBI also results in increased BBB permeability through unknown mechanisms.[ 32 ] This increase in BBB permeability is one of the main determinants of secondary brain injury characterized by edema, microglial activation, and inflammation. To date, no studies have been conducted to investigate whether treating dysbiosis in TBI patients results in restoration of BBB integrity and decreased secondary brain injury. Nonetheless, dysbiosis treatment has been shown to play an important role in restoring the BBB to its preperturbation status.[ 13 ] Therefore, it stands to reason that dysbiosis treatment may also help prevent secondary brain injury following TBI, which has similar pathophysiological mechanisms with SBI.

Dysbiosis treatment may also prevent SBI-induced damage through mitigation of microglial activation. Microglia serves several important functions in the CNS. First, during development, they modulate neuronal development and synaptic connections to establish CNS circuitry.[ 2 ] Following the development, microglial plays an important role in CNS homeostasis. Microglia cells monitor the environment through their dendritic processes and respond accordingly when exposed to pro-inflammatory or anti-inflammatory cytokines. As such, disruptions in BBB permeability can result in microglial activation. Enhanced microglial activation due to neuroinflammation has been linked with numerous neurological disorders, including ASD, schizophrenia, major depressive disorder, PD, AD, and MS.

While a direct link between dysbiosis, microglial activation, and disease development has not been clearly established, there are numerous studies which support such a relationship. In one study, when PD mouse models were treated with fecal transplants from healthy mice, researchers observed decreased microglial activation and decreased motor deficits.[ 88 ] Similarly, when amyloid precursor protein (APP) transgenic germ-free mice undergo fecal transplants collected from control APP mice, the germ-free mice develop significant CNS accumulation of amyloid plaques.[ 94 ] β-amyloid is produced by Escherichia coli, Salmonella enterica, Salmonella typhimurium, Bacillus subtilis, Mycobacterium tuberculosis, and Staphylococcus aureus in clinically significant amounts. This exogenous β-amyloid crosses into the CNS, where it activates microglia resulting in increased production of ROS.[ 6 ]

Treatment of dysbiosis may act to decrease neuroinflammation through increased regulation of inflammation. Through investigations comparing germ-free mice to controls, researchers have shown the importance of the microbiota in the activation of and development of tolerance in T cells,[ 8 ] the development of antigen-presenting cells, neutrophil production and function, and natural killer cell differentiation.[ 97 ] Furthermore, research has revealed that certain bacterial populations can favor anti-inflammatory or pro-inflammatory states.[ 41 ] Colonization of the gut with segmented filamentous bacteria leads to increased production of Th17 cells, which produce IL-17, a pro-inflammatory cytokine.[ 77 ] Dysbiosis-induced alterations in cell populations and their resulting activity can result in increased production of cytokines. Clinically, this increase in pro-inflammatory cytokines has been linked with increased disease burden in MS mouse models.[ 19 ]

Conversely, treatment of dysbiosis can reduce inflammation and disease burden. Investigators showed that increasing the gut population of Bacteroides fragilis led to increased Treg cell regulation, which ultimately led to the suppression of pro-inflammatory IL-17 production.[ 77 ] In addition, oral administration of Polysaccharide A, a metabolite of B. fragilis, induced anti-inflammatory IL-10 and Treg cell activation resulting in decreased IL-17 cytokine production and improved clinical function for MS mouse models.[ 19 ] Nullification of IL-17 signaling has also been correlated with decreased neuroinflammation and increased neurocognitive outcomes in AD.[ 23 ] Similarly, a randomized, blinded study tested the use of specific probiotics (Lactobacillus salivarius UCC4331 and Bifidobacterium infantis 35624) versus placebo in 77 patients for 8 weeks. At baseline, these patients had a systemic IL-10/IL-12 ratio indicative of Th1 pro-inflammatory state. Of these patients, those who received Bifidobacteria decreased their pro-inflammatory state and had improvement of symptoms. Thus, these patients demonstrate that a specific change in the microbiota not only reduces inflammatory signaling but also contributes to improved clinical outcomes.[ 20 ]

Oxidative and nitrosative stress

Oxidative stress

Several in vivo studies have suggested a role for dysbiosis in increased OS and resulting CNS dysfunction. PD has long been linked with GI disturbances that precede neurological symptoms by years. When researchers analyzed the microbiome of PD patients, they found that there were significantly less H2 producing bacteria.[ 63 , 66 ] Similarly, PD patients with high concentrations of H2 due to overgrowth of H2 producing bacteria had decreased neurologic symptoms.[ 75 ] H2 functions as an antioxidant capable of reducing hydroxyl radicals. These results suggest that dysbiosis may lead to neuronal destruction through decreased H2 production, which results in the increased presence of ROS. This was further supported by a study in rat models of PD, which showed treatment with oral solutions containing 50% saturated H2 resulted in nigrostriatal degeneration was prevented or delayed.[ 36 ]

Based on the above results and the characteristic nature of the CNS which makes it more susceptible to damage by OS, treatment of dysbiosis may serve a critical role in preventing CNS damage from resulting SBI-generated OS. There are several characteristics of the CNS that makes it vulnerable to damage from ROS. First, the CNS has a high oxygen demand due to its almost complete dependability on oxygen phosphorylation for ATP production. Unlike other organ systems, the CNS is incapable of storing large quantities of energy due to its near-constant demand. As such, the CNS is always producing large quantities of ROS through continuous utilization of oxidative phosphorylation for energy requirements.[ 29 , 72 ] Second, the CNS contains numerous molecules that perpetuate the formation of ROS, including iron, copper, and neurotransmitters capable of self-oxidation.[ 21 , 29 , 50 ] Third, the CNS contains reduced levels of glutathione which is needed for detoxification, cellular homeostasis, cellular signaling cascades, and cell differentiation and proliferation.[ 5 ] Fourth, the brain contains a high concentration of lipids which are extremely susceptible to oxidative damage.[ 3 , 7 ] When ROS reacts with lipids, it disrupts cellular signaling, cell membranes and leads to the formation of metabolites capable of disrupting protein structure and function.

Nitrosative stress

Dysbiosis directly and indirectly causes increased production of nitrosative stress through several different mechanisms. Reactive nitrogen species (RNS) production is linked directly to nitric oxide (NO) synthesis.[ 22 ] At physiologic levels, NO acts as an important intracellular signal in neuroprotective pathways such as cell proliferation, differentiation, and survival. However, high levels of NO can interact with ROS to form peroxynitrite, a highly reactive molecule that is capable of posttranslational modification of numerous proteins and inhibition of the electron transport chain. As a result, RNS can lead to decreased production of ATP, ultimately causing mitochondrial fragmentation and apoptotic cell death.

NO is produced by three different types of NO synthases (NOS) through the conversion of L-arginine to L-citrulline.[ 85 ] These enzymes are neuronal-NOS, inducible-NOS (iNOS), and endothelial-NOS. Bacteria directly and indirectly affect the production of NO in three main ways: (1) bacteria-induced inflammation activates iNOS,[ 64 , 85 ] (2) some bacterial species such as Streptomycetes, Bacilli,[ 91 ] and Nocardia[ 18 ] contain their own NOS and can produce exogenous NO, and (3) bacteria such as E. coli and Lactobacillus plantarum can metabolize nitrate and ammonium to nitrite, which is further metabolized by E. coli to produce NO.

Increased peroxynitrite production in microglial cells has been correlated with dysbiosis characterized by colonization of the gut by E. coli, S. enterica, Salmonella typhimurium, Bacillus subtilis, and S. aureus.[ 91 ] Furthermore, peroxynitrite provoked mitochondrial fragmentation has been correlated with the development of PD, AD, Huntington’s disease, and amyotrophic lateral sclerosis.[ 69 , 91 ] When mouse models of PD (induced with methyl-4phenyl-1,2,3,6-terahydropyridine [MPTP] treatment) were treated with NOS antagonists, there was delayed substantia nigra compromise due to decreased formation of ROS and RNS[ 75 ] and inhibition of MPTP-mediated destruction of dopamine-containing neurons.[ 100 ]


Dysbiosis is defined as the persistent imbalance in gut microbial communities. This imbalance has been linked to increased systemic inflammation and dysregulation. From a neurological perspective, dysbiosis results in dysregulation of the MGBA, leading to increased BBB permeability, increased ROS/RNS, neuronal conduction abnormalities, and neuroinflammation. Thus, treating dysbiosis may prevent or slow the progression of numerous neurological disorders. Probiotics, prebiotics, and dietary modifications have all been shown to treat dysbiosis and restore the gut to its predisturbed state. However, determining which treatment works best is still a point of debate within the scientific community.

Dietary modification

The composition of the microbiome is dependent on many factors, one of the most important being diet. From the time of our birth, our diet impacts our microbiome and consequently our health. Breast milk is rich in carbohydrates, nucleotides, cytokines, and immunoglobulins that are important for infant growth.[ 51 ] When compared to infants who were formula-fed, breast milk-fed infants had decreased gut colonization by pathological species such as E. coli, C. difficile, and Bacteroides fragilis and increased presence of beneficial species.[ 67 ] As we transition to solid food, our choice of sustenance and the amount of dietary intake guides the establishment of our microbiome. If dietary intake is not sufficient at a young age, it can cause disease. One study found altered bone morphology, stunted growth, and altered brain metabolism in mice who received microbiota transplants from malnourished children.[ 11 ]

Older individuals are also at increased risk of dysbiosis. Aging leads to natural immunosuppression and senescence, resulting in increased systemic inflammation and the development of disease. Furthermore, changes in digestion and motility affect microbiota communities. Unfortunately, many factors of dysbiosis in the elderly are irreversible. However, diet is an important modifiable determinant of dysbiosis and may serve as a potential treatment for those with or at risk for dysbiosis. One study analyzed the microbiota of 178 elderly individuals and found that there was a significantly decreased diversity of bacterial species.[ 76 ] Further analysis revealed that the severity of dysbiosis in these patients was dependent on diet. Fortunately, changes in diet have been linked with changes in microbiota. Researchers found that even if patients only change their diet for a short period of time (<24 h), it can lead to tremendous changes in microbiota composition.[ 26 ] Current investigation is centered on determining which diets may provide the most benefit for patients.

Diets high in unhealthy fats, protein, salts, and simplex sugars, so-called the western diet (WD), result in elevated levels of Firmicutes and Collinsella and decreased levels of Bacteroides.[ 73 ] These changes in microbiota composition have been linked to increased risk of obesity, depression, anxiety, and cognitive dysfunction.[ 59 , 73 ] One study revealed that consumption of a WD for only 3 days resulted in impaired spatial memory in rodents.[ 59 ] It has been suggested that through changes in microbiota composition, the WD can cause increased gut permeability, BBB dysfunction, and neuroinflammation.[ 47 , 59 ] In one prominent study, the decreased presence of Bacteroides that resulted from WD was associated with decreased conjugation of bile acids.[ 15 ] These unconjugated bile acids become charged in the distal colon and are capable of inflicting damage to the gut lining. This damage results in increased gut permeability, which has been linked with increased neuroinflammation.

Conversely, diets like a Mediterranean diet (MD) that consist mainly of fruits, vegetables, legumes, and whole grains have been linked to decreased systemic and neurological inflammation through changes in microbiota composition.[ 22 , 47 , 53 ] Namely, MD results in increased concentrations of Bacteroides, Prevotella, and Bifidobacteria, some of which have shown to play important roles in the development of neuropsychiatric diseases.[ 22 , 73 ] MD consists of high levels of omega 3 and omega 6 PUFAs which have been linked with decreased risk of developing depression.[ 17 ] When microbiota analysis was performed on patients consuming diets heavy in omega 3 and omega 6 PUFAs, researchers found increased concentrations of Bifidobacterium and Lactobacillus.[ 73 ] This change in bacterial population suggests that Bifidobacterium and Lactobacillus may play a major role in neuropsychiatric disease development.[ 73 ] This is further supported by studies that show the administration of probiotics containing Lactobacillus to patients with depression results in decreased symptoms of depression. In addition, Bacteroides, Prevotella, and Bifidobacteria are critical for the fermentation of carbohydrates into active metabolites and short-chain fatty acids (SCFAs). In vitro studies have shown that through activation of AMPK kinase, SCFAs play a crucial role in the regulation of lipid and cholesterol metabolism[ 83 ] which has been correlated with reduced incidence of neurodegenerative diseases.[ 81 ] Importantly, MDs are also high in many important prebiotics, which play an important role in the treatment of dysbiosis.


Prebiotics are insoluble dietary fibers that serve to stimulate the growth of commensal bacteria to promote a healthy microbiota. Studies have revealed that decreased intake of insoluble fibers leads to a restricted microbiota, thereby inducing dysbiosis.[ 82 ] Clinically, prebiotics have been linked with several health benefits, including decreased body mass index and immune modification leading to decreased systemic inflammation.[ 40 ] More recently, the role of prebiotics in treating neurocognitive disorders has garnered interest.

Numerous prebiotics are being investigated for potential use in disease treatment; however, galactooligosaccharides (GOS) have become the focus of many investigators. GOSs are fermented mainly by Bifidobacteria and Lactobacilli bacteria in the gut.[ 73 ] As such, when used as a prebiotic, GOS induces increased gut colonization of these species. Clinically, administration of GOS has been linked with numerous health benefits, including an observed decrease in anxiety and depression-linked behaviors in mouse models.[ 93 ] Similarly, in healthy human volunteers, GOS led to decreased serum cortisol levels and decreased vigilance when presented with negative stimuli.[ 16 ] In another study, 10-week treatment with GOS in the elderly resulted in decreased inflammation revealed by fecal analysis.[ 99 ]

Importantly, GOS has been shown to reduced surgery-induced cognitive disfunction.[ 99 ] Mice were pretreated with GOS for 18 days before abdominal surgery. Compared to control animals, GOS animals had decreased neuroinflammation (decreased IL-6 and Il-4 in hippocampus) and cognitive impairment as revealed through object recognition tasks. When the microbiomes of these animals were analyzed, it was discovered that GOS treated animals had increased Bifidobacteria.[ 49 ] These results suggest that pretreatment of dysbiosis with prebiotics confers neuroprotection through the prevention of neuroinflammation.


Probiotics are living microorganisms that, when consumed, can provide many health benefits to the host such as antibacterial and antiviral effects,[ 44 ] reducing inflammation,[ 60 ] and restoring a healthy gut flora balance.

In addition, probiotics have been shown to have a beneficial impact on brain function and behavior. In one study, healthy women were randomly assigned to receive a fermented milk product probiotic (FMPP) containing a mix of Bifidobacterium animalis subsp. Lactis, Streptococcus thermophilus, Lactobacillus bulgaricus, and Lactococcus lactis subsp. Lacti in a placebo-controlled study.[ 90 ] The treated subjects then underwent emotional attention task testing and brain activity was measured using functional MRI analysis. A 4-week treatment with FMPP was associated with a significant change in the insula, periaqueductal gray, and somatosensory cortex regions compared with either no intervention or control-treated women, indicating that probiotic treatment in humans can result in modified brain activity. In another placebo-controlled study, healthy human adults treated with Bifidobacterium longum 1714 had reduced stress and improved memory as measured by EEG changes during rapid information processing and cortisol levels.[ 4 ] These effects appear to be probiotic specific as Lactobacillus casei strain Shirota (LcS) relieved stress-associated symptoms in mouse and human models,[ 89 ] whereas Lactobacillus rhamnosus (JB-1) did not improve these measures.[ 48 ]

More importantly, mice with spinal cord injuries that were treated with VSL#3 (a commercially available probiotic) starting on the day of injury and lasting through 35-day postinjury demonstrated reduced neuropathology, improved locomotor recovery, and triggered a protective immune response through an increase in the number of Treg cells.[ 49 ] Similarly, a 10-day treatment with L. bulgaricus (10 trillion CFU/cp plus activated charcoal) was assessed in 64 patients aged 19–78 years old with severe TBI in a prospective, randomized, and placebo-controlled trial. Treatment with the probiotic was associated with a statistically significant decrease in diarrhea and length of stay in the ICU as compared to the control group. Another study also revealed that L. bulgaricus treatment led to a decrease in ventilator-associated pneumonia infection rate and duration of mechanical ventilation.[ 68 ]


SBI is an unavoidable outcome of all neurosurgeries and can potentially have long-term neurofunctional consequences for patients. Even with the development of minimally invasive procedures, neuronal tissue is damaged due to physical manipulation and this damage is often irreparable due to the nature of neuronal cells. Therefore, the only way to treat SBI is to limit the extent of injury while also preventing the progression of injury. There are a couple of therapeutics being investigated that may decrease the extent of SBI through activation of neuroprotective mechanisms or inhibition neuroinflammation.[ 79 , 94 , 98 ] These therapies involve the use of exogenous compounds that may have varying degrees of success based on absorption and ability to penetrate the BBB. One unexplored avenue for SBI prevention and limitation is the utilization and regulation of the MGBA. Unlike other therapies currently under investigation, treatment of dysbiosis has the potential to activate neuroprotective mechanisms while also inhibiting neuroinflammation.

Recent research reveals that treatment of dysbiosis with dietary modifications, prebiotics or probiotics, decreases disease progression and severity in patients with depression and anxiety. Therefore, treatment of dysbiosis before surgery may limit the extent of SBI intraoperative and prevent progression in the postoperative setting. In addition, treatment of dysbiosis through dietary modification, introduction of naturally occurring prebiotics or probiotics represents an easily accessible, more cost-effective option compared to the exogenous compounds such as Slit2 and MFGE8, currently being investigated.

The current evidence supporting the role of MBGA in limiting acute brain injuries is minimal. This is in part due to the fact that the majority of research has focused on the role of chronic dysbiosis in the development of chronic neurological diseases. However, investigations of dysbiosis treatment in acute brain injuries from trauma or surgery are promising and suggest a role of dysbiosis in acute neurological dysfunction. In one study, researchers showed that when mice were pretreated with GOS for 18 days, they had better cognitive recovery following abdominal surgery compared to controls.[ 99 ] In addition, in a 2004 study, researchers found that human brain injury patients had decreased length of stay in the ICU and length of mechanical ventilation when treated with probiotics.[ 33 ]

We recognize that there are many caveats to the evidence supporting the role of dysbiosis treatment and SBI presented in this paper. For one, most research has been conducted in animal models; therefore, the true impact on human health is not well understood. Second, the pathophysiology of SBI is not well understood and may vary between patients. In addition, we currently do not know which treatment methodology for dysbiosis is best or how much treatment is necessary or sufficient. Nevertheless, a therapy to limit and prevent the progression of SBI is greatly needed as SBI affects all 800,000 patients undergoing neurosurgical procedures each year. Treating dysbiosis with dietary modification, prebiotics, or probiotics to limit SBI may represent a cost-effective, non-harmful solution and deserves to be further explored.

Declaration of patient consent

Patient’s consent not required as there are no patients in this study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1. Abd-Elfattah AS, Wechsler AS. Myocardial preconditioning: A model or a phenomenon?. J Card Surg. 1995. 10: 381-8

2. Abdel-Haq R, Schlachetzki JCM, Glass CK, Mazmanian SK. Microbiome-microglia connections via the gut-brain axis. J Exp Med. 2019. 216: 41-59

3. Adibhatla RM, Hatcher JF. Role of lipids in brain injury and diseases. Future Lipidol. 2007. 2: 403-22

4. Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A, Boylan G. Bifidobacterium longum 1714 as a translational psychobiotic: Modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl Psychiatry. 2016. 6: e939

5. Aoyama K, Nakaki T. Impaired glutathione synthesis in neurodegeneration. Int J Mol Sci. 2013. 14: 21021-44

6. Asiimwe N, Yeo SG, Kim MS, Jung J, Jeong NY. Nitric oxide: Exploring the contextual link with Alzheimer’s disease. Oxid Med Cell Longev. 2016. 2016: 7205747

7. Bazinet RP, Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci. 2014. 15: 771-85

8. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014. 157: 121-41

9. Bendel P, Koivisto T, Niskanen E, Könönen M, Aikiä M, Hänninen T. Brain atrophy and neuropsychological outcome after treatment of ruptured anterior cerebral artery aneurysms: A voxel-based morphometric study. Neuroradiology. 2009. 51: 711-22

10. Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011. 23: 1132-9

11. Blanton LV, Charbonneau MR, Salih T, Barratt MJ, Venkatesh S, Ilkaveya O. Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science. 2016. 351: 1-18

12. Bramlett HM, Dietrich WD. Progressive damage after brain and spinal cord injury: Pathomechanisms and treatment strategies. Prog Brain Res. 2007. 161: 125-41

13. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014. 6: 263-ra158

14. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011. 108: 16050-5

15. Burhani MD, Rasenick MM. Fish oil and depression: The skinny on fats. J Integr Neurosci. 2017. 16: S115-24

16. Burokas A, Arboleya S, Moloney RD, Peterson VL, Murphy K, Clarke G. Targeting the microbiota-gut-brain axis: Prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice. Biol Psychiatry. 2017. 82: 472-87

17. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015. 28: 203-9

18. Chen Y, Rosazza JP. A bacterial nitric oxide synthase from a Nocardia species. Biochem Biophys Res Commun. 1994. 203: 1251-8

19. Chu F, Shi M, Lang Y, Shen D, Jin T, Zhu J. Gut microbiota in multiple sclerosis and experimental autoimmune encephalomyelitis: Current applications and future perspectives. Mediators Inflamm. 2018. 2018: 8168717

20. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012. 488: 178-84

21. Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. 2018. 15: 490-503

22. Corpas FJ, Barroso JB. Nitro-oxidative stress vs oxidative or nitrosative stress in higher plants. New Phytol. 2013. 199: 633-5

23. Cristiano C, Volpicelli F, Lippiello P, Buono B, Raucci F, Piccolo M. Neutralization of IL-17 rescues amyloid-β-induced neuroinflammation and memory impairment. Br J Pharmacol. 2019. 176: 3544-57

24. Cryan JF, O’Riordan KJ, Cowan CS, Sandhu KV, Bastiaanssen TF, Boehme M. The microbiota-gut-brain axis. Physiol Rev. 2019. 99: 1877-2013

25. D’Argenio V, Salvatore F. The role of the gut microbiome in the healthy adult status. Clin Chim Acta. 2015. 451: 97-102

26. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014. 505: 559-63

27. Dinan TG, Stilling RM, Stanton C, Cryan JF. Collective unconscious: How gut microbes shape human behavior. J Psychiatr Res. 2015. 63: 1-9

28. Donia MS, Cimermancic P, Schulze CJ, Wieland Brown LC, Martin J, Mitreva M. A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell. 2014. 158: 1402-14

29. Dumitrescu L, Popescu-Olaru I, Cozma L, Tulbă D, Hinescu ME, Ceafalan LC. Oxidative stress and the microbiota-gut-brain axis. Oxid Med Cell Longev. 2018. 2018: 2406594

30. Dziewulska D, Rafałowska J. Role of endoglin and transforming growth factor-beta in progressive white matter damage after an ischemic stroke. Neuropathology. 2006. 26: 298-306

31. Ellamushi H, Moran NF, Kitchen ND, Stevens JM, Kendall BE, Lemieux L. Generalised cerebral atrophy following temporal lobectomy for intractable epilepsy associated with mesial temporal sclerosis. Magn Reson Imaging. 2000. 18: 269-74

32. Erickson MA, Banks WA. Blood-brain barrier dysfunction as a cause and consequence of Alzheimer’s disease. J Cereb Blood Flow Metab. 2013. 33: 1500-13

33. Falcão de Arruda IS, de Aguilar-Nascimento JE. Benefits of early enteral nutrition with glutamine and probiotics in brain injury patients. Clin Sci (Lond). 2004. 106: 287-92

34. Ferreiro A, Crook N, Gasparrini AJ, Dantas G. Multiscale evolutionary dynamics of host-associated microbiomes. Cell. 2018. 172: 1216-27

35. Forsythe P, Bienenstock J, Kunze WA. Vagal pathways for microbiome-brain-gut axis communication. Adv Exp Med Biol. 2014. 817: 115-33

36. Fu Y, Ito M, Fujita Y, Ito M, Ichihara M, Masuda A. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson’s disease. Neurosci Lett. 2009. 453: 81-5

37. Giannoni P, Claeysen S, Noe F, Marchi N. Peripheral routes to neurodegeneration: Passing through the blood-brain barrier. Front Aging Neurosci. 2020. 12: 3

38. Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS. Metagenomic analysis of the human distal gut microbiome. Science. 2006. 312: 1355-9

39. Grau-Olivares M, Arboix A, Junqué C, Arenaza-Urquijo EM, Rovira M, Bartrés-Faz D. Progressive gray matter atrophy in lacunar patients with vascular mild cognitive impairment. Cerebrovasc Dis. 2010. 30: 157-66

40. Grube B, Chong PW, Lau KZ, Orzechowski HD. A natural fiber complex reduces body weight in the overweight and obese: A double-blind, randomized, placebo-controlled study. Obesity (Silver Spring). 2013. 21: 58-64

41. Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 2010. 3: 148-58

42. Hoban AE, Stilling RM, Ryan FJ, Shanahan F, Dinan TG, Claesson MJ. Regulation of prefrontal cortex myelination by the microbiota. Transl Psychiatry. 2016. 6: e774

43. Houlden A, Goldrick M, Brough D, Vizi ES, Lénárt N, Martinecz B. Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production. Brain Behav Immun. 2016. 57: 10-20

44. Isolauri E, Kirjavainen PV, Salminen S. Probiotics: A role in the treatment of intestinal infection and inflammation?. Gut. 2002. 50: III54-9

45. Jadhav V, Zhang JH. Surgical brain injury: Prevention is better than cure. Front Biosci. 2008. 13: 3793-7

46. Jašarević E, Howerton CL, Howard CD, Bale TL. Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain. Endocrinology. 2015. 156: 3265-76

47. Kanoski SE, Zhang Y, Zheng W, Davidson TL. The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat. J Alzheimers Dis. 2010. 21: 207-19

48. Kelly JR, Allen AP, Temko A, Hutch W, Kennedy PJ, Farid N. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain Behav Immun. 2017. 61: 50-9

49. Kigerl KA, Hall JC, Wang L, Mo X, Yu Z, Popovich PG. Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med. 2016. 213: 2603-20

50. Kim GH, Kim JE, Rhie SJ, Yoon S. The role of oxidative stress in neurodegenerative diseases. Exp Neurobiol. 2015. 24: 325-40

51. Kramer MS, Kakuma R. Optimal duration of exclusive breastfeeding. Cochrane Database Syst Rev. 2012. 8: CD003517

52. Kunze WA, Mao YK, Wang B, Huizinga JD, Ma X, Forsythe P. Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium-dependent potassium channel opening. J Cell Mol Med. 2009. 13: 2261-70

53. Marlow G, Ellett S, Ferguson IR, Zhu S, Karunasinghe N, Jesuthasan AC. Transcriptomics to study the effect of a Mediterranean-inspired diet on inflammation in Crohn’s disease patients. Hum Genomics. 2013. 7: 24

54. Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: Paradigm shift in neuroscience. J Neurosci. 2014. 34: 15490-6

55. McCusker RH, Kelley KW. Immune-neural connections: How the immune system’s response to infectious agents influences behavior. J Exp Biol. 2013. 216: 84-98

56. McVey Neufeld KA, Mao YK, Bienenstock J, Foster JA, Kunze WA. The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse. Neurogastroenterol Motil. 2013. 25: 183-e88

57. Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011. 23: 255-64

58. Nicholson JK, Holmes E, Wilson ID. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol. 2005. 3: 431-8

59. Noble EE, Hsu TM, Kanoski SE. Gut to brain dysbiosis: Mechanisms linking western diet consumption, the microbiome, and cognitive impairment. Front Behav Neurosci. 2017. 11: 9

60. O’Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K. Lactobacillus and Bifidobacterium in irritable bowel syndrome: Symptom responses and relationship to cytokine profiles. Gastroenterology. 2005. 128: 541-51

61. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med. 2013. 19: 1584-96

62. Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O’Leary OF. Adult hippocampal neurogenesis is regulated by the microbiome. Biol Psychiatry. 2015. 78: e7-9

63. Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: Initiation, development and potential of hydrogen medicine. Pharmacol Ther. 2014. 144: 1-1

64. Oleskin AV, Shenderov BA. Neuromodulatory effects and targets of the SCFAs and gasotransmitters produced by the human symbiotic microbiota. Microb Ecol Health Dis. 2016. 27: 30971

65. Osadchiy V, Martin CR, Mayer EA. The gut-brain axis and the microbiome: Mechanisms and clinical implications. Clin Gastroenterol Hepatol. 2019. 17: 322-32

66. Ostojic SM. Inadequate production of H2 by gut microbiota and Parkinson disease. Trends Endocrinol Metab. 2018. 29: 286-8

67. Pacheco AR, Barile D, Underwood MA, Mills DA. The impact of the milk glycobiome on the neonate gut microbiota. Annu Rev Anim Biosci. 2015. 3: 419-45

68. Pavelescu D, Mirea L, Grintescu I. Could selected probiotics have beneficial effects on clinical outcome of severe traumatic brain injury patients?. Crit Care. 2014. 18: 472

69. Pereira C, Ferreira NR, Rocha BS, Barbosa RM, Laranjinha J. The redox interplay between nitrite and nitric oxide: From the gut to the brain. Redox Biol. 2013. 1: 276-84

70. Przyklenk K, Kloner RA. Ischemic preconditioning: Exploring the paradox. Prog Cardiovasc Dis. 1998. 40: 517-47

71. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010. 464: 59-65

72. Salim S. Oxidative stress and the central nervous system. J Pharmacol Exp Ther. 2017. 360: 201-5

73. Sandhu KV, Sherwin E, Schellekens H, Stanton C, Dinan TG, Cryan JF. Feeding the microbiota-gut-brain axis: Diet, microbiome, and neuropsychiatry. Transl Res. 2017. 179: 223-44

74. Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF, Burnet PWJ. Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends Neurosci. 2016. 39: 763-81

75. Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord. 2015. 30: 350-8

76. Schmidt K, Cowen PJ, Harmer CJ, Tzortzis G, Errington S, Burnet PW. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology (Berl). 2015. 232: 1793-801

77. Sczesnak A, Segata N, Qin X, Gevers D, Petrosino JF, Huttenhower C. The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe. 2011. 10: 260-72

78. Shedlack KJ, Lee EK, Radtke RA, Friedman AH, Crain BJ, Boyko O. Ipsilateral subcortical atrophy associated with temporal lobectomy. Psychiatry Res. 1994. 54: 295-304

79. Sherchan P, Huang L, Akyol O, Reis C, Tang J, Zhang JH. Recombinant Slit2 reduces surgical brain injury induced blood brain barrier disruption via Robo4 dependent Rac1 activation in a rodent model. Sci Rep. 2017. 7: 746

80. Smith PA. The tantalizing links between gut microbes and the brain. Nature. 2015. 526: 312-4

81. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: An updated systematic review and meta-analysis. Am J Clin Nutr. 2010. 92: 1189-96

82. Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL. Diet-induced extinctions in the gut microbiota compound over generations. Nature. 2016. 529: 212-5

83. Stamp DH. Three hypotheses linking bile to carcinogenesis in the gastrointestinal tract: Certain bile salts have properties that may be used to complement chemotherapy. Med Hypotheses. 2002. 59: 398-405

84. Stebbins GT, Nyenhuis DL, Wang C, Cox JL, Freels S, Bangen K. Gray matter atrophy in patients with ischemic stroke with cognitive impairment. Stroke. 2008. 39: 785-93

85. Steinert JR, Chernova T, Forsythe ID. Nitric oxide signaling in brain function, dysfunction, and dementia. Neuroscientist. 2010. 16: 435-52

86. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 2004. 558: 263-75

87. Sukhanova I. Long-term consequences in model of mild perinatal hypoxic brain damage in albino rat pups. Eur Neuropsychopharmacol. 2016. 26: S712-3

88. Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD, Yang Q. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav Immun. 2018. 70: 48-60

89. Takada M, Nishida K, Kataoka-Kato A, Gondo Y, Ishikawa H, Suda K. Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models. Neurogastroenterol Motil. 2016. 28: 1027-36

90. Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013. 144: 1394-401

91. Tse JK. Gut microbiota, nitric oxide, and microglia as prerequisites for neurodegenerative disorders. ACS Chem Neurosci. 2017. 8: 1438-47

92. Vergnolle N, Cirillo C. Neurons and glia in the enteric nervous system and epithelial barrier function. Physiology (Bethesda). 2018. 33: 269-80

93. Vulevic J, Juric A, Walton GE, Claus SP, Tzortzis G, Toward RE. Influence of galacto-oligosaccharide mixture (B-GOS) on gut microbiota, immune parameters and metabonomics in elderly persons. Br J Nutr. 2015. 114: 586-95

94. Wang Y, Sherchan P, Huang L, Akyol O, McBride DW, Zhang JH. Multiple mechanisms underlying neuroprotection by secretory phospholipase A2 preconditioning in a surgically induced brain injury rat model. Exp Neurol. 2018. 300: 30-40

95. Watanabe H, Muramatsu Y, Kurosaki R, Michimata M, Matsubara M, Imai Y. Protective effects of neuronal nitric oxide synthase inhibitor in mouse brain against MPTP neurotoxicity: An immunohistological study. Eur Neuropsychopharmacol. 2004. 14: 93-104

96. Winek K, Engel O, Koduah P, Heimesaat MM, Fischer A, Bereswill S. Depletion of cultivatable gut microbiota by broad-spectrum antibiotic pretreatment worsens outcome after murine stroke. Stroke. 2016. 47: 1354-63

97. Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes. 2012. 3: 4-14

98. Xiao Y, Li G, Chen Y, Zuo Y, Rashid K, He T. Milk fat globule-epidermal growth factor-8 pretreatment attenuates apoptosis and inflammation via the integrin-β3 pathway after surgical brain injury in rats. Front Neurol. 2018. 9: 96

99. Yang XD, Wang LK, Wu HY, Jiao L. Effects of prebiotic galactooligosaccharide on postoperative cognitive dysfunction and neuroinflammation through targeting of the gut-brain axis. BMC Anesthesiol. 2018. 18: 177

100. Yokoyama H, Kuroiwa H, Yano R, Araki T. Targeting reactive oxygen species, reactive nitrogen species and inflammation in MPTP neurotoxicity and Parkinson’s disease. Neurol Sci. 2008. 29: 293-301

101. Zakhary G, Sherchan P, Li Q, Tang J, Zhang JH. Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model. J Neurosci Res. 2020. 98: 155-67

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