The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

Abstract

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. AbstractAs head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut‐brain axis

“…A number of studies have shown that TBI are associated with profound changes in gut dysfunction . Our previous studies have confirmed that Cb is effective in the treatment of brain disorders, by virtue of producing a large amount of butyrate .…”

“…Gastrointestinal dysfunction is one of several complications in patients with TBI . TBI can result in increased intestinal permeability and structural and functional damage of the gastrointestinal tract . There is evidence that intestinal bacteria are directly involved in the development of TBI .…”

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

“…Interestingly, the migratory influx of mature mucosal EGCs during adult gliogenesis in response to injury has been shown to rely on signals from the gut microbiota 68 . It has recently been postulated that a better understanding of the contributions and responses by the brain-gut-microbiota axis to chronic inflammation and brain injury would expand opportunities for therapeutics interventions for the long-term sequelae of TBI 69 . Acute and chronic changes in the gut microbiome following CNS injuries such as spinal cord injury and ischemic brain injury are associated with intestinal barrier dysfunction, immune dysregulation, and functional neurologic deficits 70,71 .…”

Innate immune responses to trauma

“…The well-established gut-brain axis is especially affected by TBI and contributes substantially to dysautonomia, gut-barrier dysfunction and alterations to the composition of local immune cells and the microbiome 146 . TBI induces, via unclear mechanisms, structural changes to the intestinal villi and epithelium, with the opening and loss of TJs and subsequent complications 146 .…”

“…TBI induces, via unclear mechanisms, structural changes to the intestinal villi and epithelium, with the opening and loss of TJs and subsequent complications 146 . TNF released by local macrophages after stimulation by brain-derived DAMPs impairs TJ function and increases gut permeability, even in a TBI model in flies 147 .…”