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Review
. 2024 May 10;21(1):124.
doi: 10.1186/s12974-024-03118-3.

Dysregulated brain-gut axis in the setting of traumatic brain injury: review of mechanisms and anti-inflammatory pharmacotherapies

Mahmoud G El Baassiri  1 , Zachariah Raouf  1 , Sarah Badin  1 , Alejandro Escobosa  1 , Chhinder P Sodhi  1 , Isam W Nasr  2
Affiliations
Review

Dysregulated brain-gut axis in the setting of traumatic brain injury: review of mechanisms and anti-inflammatory pharmacotherapies

Mahmoud G El Baassiri et al. J Neuroinflammation. .

Abstract

Traumatic brain injury (TBI) is a chronic and debilitating disease, associated with a high risk of psychiatric and neurodegenerative diseases. Despite significant advancements in improving outcomes, the lack of effective treatments underscore the urgent need for innovative therapeutic strategies. The brain-gut axis has emerged as a crucial bidirectional pathway connecting the brain and the gastrointestinal (GI) system through an intricate network of neuronal, hormonal, and immunological pathways. Four main pathways are primarily implicated in this crosstalk, including the systemic immune system, autonomic and enteric nervous systems, neuroendocrine system, and microbiome. TBI induces profound changes in the gut, initiating an unrestrained vicious cycle that exacerbates brain injury through the brain-gut axis. Alterations in the gut include mucosal damage associated with the malabsorption of nutrients/electrolytes, disintegration of the intestinal barrier, increased infiltration of systemic immune cells, dysmotility, dysbiosis, enteroendocrine cell (EEC) dysfunction and disruption in the enteric nervous system (ENS) and autonomic nervous system (ANS). Collectively, these changes further contribute to brain neuroinflammation and neurodegeneration via the gut-brain axis. In this review article, we elucidate the roles of various anti-inflammatory pharmacotherapies capable of attenuating the dysregulated inflammatory response along the brain-gut axis in TBI. These agents include hormones such as serotonin, ghrelin, and progesterone, ANS regulators such as beta-blockers, lipid-lowering drugs like statins, and intestinal flora modulators such as probiotics and antibiotics. They attenuate neuroinflammation by targeting distinct inflammatory pathways in both the brain and the gut post-TBI. These therapeutic agents exhibit promising potential in mitigating inflammation along the brain-gut axis and enhancing neurocognitive outcomes for TBI patients.

Keywords: Brain-gut axis; Enteroendocrine cell; Intestinal inflammation; Microbiome; TBI.

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Conflict of interest statement

The authors declare they have no competing interests.

Figures

Fig. 1
Fig. 1
Bidirectional cross-talk between the brain and gut in TBI. TBI induces tissue and cellular disruption, leading to the release of various inflammatory cytokines, chemokines, complement factors and damage-associated patterns (DAMPs), which promote diverse cellular responses: a Microglia, the resident immune cells of the brain, become activated and migrate towards the injury site to phagocytose debris and release proinflammatory cytokines. b Astrocytes contribute to the inflammatory response and undergo reactive gliosis, leading to the formation of a protective glial scar to limit injury spread. c Increased production of reactive oxygen species (ROS), excessive release of excitatory glutamate, and reduced blood flow to the brain promotes neuronal apoptosis and neurodegeneration. d Blood–brain barrier breakdown leads to the infiltration of various immune cells, such as neutrophils, monocytes and T-cells, into the brain parenchyma to aid in debris clearance. However, excessive infiltration can exacerbate tissue damage and worsen neurologic outcomes. I TBI affects the gut through several pathways, including the activation of the hypothalamic–pituitary–adrenal (HPA) axis, which releases cortisol, and sympathetic arm of the autonomic nervous system (ANS), which releases catecholamines, leading to gut intestinal barrier disintegration. e This allows the translocation of pathogenic bacteria from the gut lumen into the intestinal parenchyma, exacerbating microbial dysbiosis. f The enteric nervous system (ENS) becomes dysfunctional, with reactive gliosis in enteric glial cells, leading to dysmotility. g These changes also result in decreased expression of enteroendocrine cells (EECs), reducing their secretion of anti-inflammatory hormones such as serotonin. h Inflammatory immune cells, including T-cells and monocytes, infiltrate the intestinal epithelium and further increase gut inflammation. The gut sends signal back to the brain through various pathways: (II) Decreased release of microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids, as well as reduced anti-inflammatory hormone secretion from EECs, worsen this detrimental cycle. Furthermore, the impairment of afferent and efferent vagus nerve pathways disrupts brain-gut homeostasis and exacerbate the neuroinflammatory response in the injured brain. These overlapping and interrelated pathways offer potential therapeutic targets for mitigating TBI-induced neuroinflammation and improving neurologic outcomes. Created with www.Biorender
Fig. 2
Fig. 2
TBI induces enteroendocrine cell loss and decreases EEC differentiation. male C57BL/6 mice were used at the age of 4–6 weeks to induce moderate-severe TBI as previously described [66]. Mice were sacrificed three days later, and the ileum was harvested to investigate the expression of EECs. Intestinal tissues were fixed overnight with 4% paraformaldehyde and processed for paraffin embedding. Subsequently, 5-μm tissue sections were cut from paraffin blocks using a CUT 6062 microtome (SLEE Medical GmbH, D-55129 Mainz, Germany) and stained for DAPI (blue) and chromogranin A (ChgA) (green). ChgA+ cells were counted using ImageJ2 software. Scale bars, 50-μm. A–C Representative confocal images showing decreased intestinal ChgA expression in TBI mice when compared to sham on post-injury day (PID) 3. D An illustration of EEC differentiation pathway in the intestine. TBI reduces the expression of key transcription factors implicated in the differentiation of Lgr5+ intestinal stem cells into ChgA+ mature EECs, including E Notch1, F Atoh1, and G Nuerog3, as measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The mRNA levels are expressed as relative to housekeeping gene Rplp0 expression. Statistical significance was determined by student’s t-test using GraphPad Prism 10 software. Each dot on the graph represents a different mouse. Error bars indicate the mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 3
Fig. 3
TBI induces gut dysfunction via the brain-gut axis. This illustration depicts the intricate pathways through which TBI disrupts gut function via the brain-gut axis. Four main pathways contribute to the cross-talk between the brain and gut, including the systemic immune system, autonomic and enteric nervous systems, neuroendocrine system, and microbiota axis. In a healthy gut (left), (i) a balanced microbial flora transforms dietary components into various metabolites, including short-chain fatty acids (SCFAs), tryptophan metabolites, and bile acids. SCFAs, particularly acetate, propionate and butyrate exert various beneficial effects on brain function by acting as energy substrates for neurons and microglia. They have the ability to directly influence the brain by entering the systemic circulation and crossing the blood–brain-barrier or indirectly by binding to receptors on vagus nerve endings; (ii) Additionally, enteroendocrine cells (EECs), the largest endocrine system in the body, regulate digestive processes by secreting various hormones, such as like serotonin, ghrelin and glucagon-like peptide 1 (GLP-1), in response to luminal stimuli. These cells communicate bidirectionally with the CNS by sending hormonal signals to the brain via the blood stream or and neural signals through vagal afferent pathways; (iii) An intact vagus nerve also releases acetylcholine (Ach), which binds to the α7-subtype of the nicotinic acetylcholine receptor (α7nAChR) located on intestinal macrophages and decreases the production of inflammatory cytokines. Ach also binds to muscarinic receptors located on smooth muscle cells in the GI tract facilitating peristalsis and Ach also stimulate excitatory motor neurons in the ENS which further enhances gut motility; (iv) In normal homeostasis, immune cell activation is balanced, cortisol secretion follows diurnal rhythms and catecholamine levels remain within physiologic ranges, collectively maintaining a stable circulation and tissue perfusion. However, TBI-induced intestinal dysfunction triggers a cascade of changes (right). (I) The microbiome shifts towards a pathogenic state, with bacteria translocating into the intestinal parenchyma through the compromised intestinal barrier; (II) EECs become dysfunctional, reducing their expression, differentiation and secretion of anti-inflammatory hormones; (III) Concurrently, vagus nerve dysfunction occurs, resulting in decreased Ach, which can polarize macrophages into a proinflammatory state and heighten inflammation; and (IV) The activation of hypothalamic–pituitary–adrenal (HPA) axis during TBI increased circulating catecholamines and cortisol, leading to a leaky gut and mucosal damage. Furthermore, systemic monocytes and T-cells infiltrate the gut and exacerbate inflammation by upregulating proinflammatory cytokines. In addition, reactive gliosis in enteric glial cells (EGCs) results in intestinal dysmotility. Finally, Paneth cells reduce their secretion of antimicrobial peptides, further exacerbating microbiome dysbiosis. These intricate changes collectively aggravate brain inflammation and neurodegeneration through the gut-brain axis. Created with www.Biorender
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