Targeting the gut microbiome in the management of sepsis-associated encephalopathy

Abstract

Brain injury resulting from sepsis, or sepsis-associated encephalopathy (SAE), occurs due to impaired end-organ perfusion, dysregulated inflammation affecting the central nervous system (CNS), blood-brain barrier (BBB) disruption, mitochondrial dysfunction, oxidative stress, accumulation of toxic neuropeptides and impaired toxin clearance secondary to sepsis-induced hepatic and renal dysfunction. The gut microbiome becomes pathologically altered in sepsis, which likely contributes to the pathogenesis of SAE. Herein, we review the literature detailing dysregulation of microbiota-gut-brain axis (MGBA) in SAE and highlight potential therapeutic strategies to modulate the gut microbiome to mitigate sepsis-induced brain injury.

Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection

“…In the case of acute and subacute inflammation, as seen in systemic infection, the mechanisms through which immune dysregulation exerts deleterious neurological effects are now becoming clearer. Furthermore, the dysregulation of typical neuroendocrine immune networks, and even, potentially, the gut–microbiome–brain axis, leads to a vicious cycle of further systemic immune dysregulation, gut dysbiosis, exacerbation of neuroinflammation, and ischemic injury, which represent characteristic features of SAE [ 96 , 97 ].…”

“…Direct autonomic stimulation by sepsis-induced peripheral infectious stimuli (e.g., bacterial, fungal, viral, and LPS) can also lead to cytokine signal transmission to the brain and may form a direct link between the peripheral immune system and the CNS [ 96 , 105 ]. This link, and that of the microbiome–gut–brain axis (MGBA), while typically essential for homeostatic brain function, cognition and memory under normal conditions, can lead to a feedback loop that promotes dysregulation of all three systems in a septic state [ 96 , 97 , 113 , 114 ].…”

“…Autonomic and HPA dysfunction in sepsis have effects not only on peripheral immunity, but also the MGBA, with multiple proposed pathways of communication that have only recently come under investigation [ 97 ]. Under normal conditions, autonomic and neuroendocrine signaling (via the HPA axis) result in enteric nervous system stimulation and modulation of gastrointestinal motility and acidity, optimizing the landscape for resident immune and enteric cells, and by extension maintaining a healthy gut microbiome (reviewed in [ 97 ]). A gut microbiome in homeostasis secretes anti-inflammatory metabolites, such as short-chain fatty acids (SCFAs), critical for maintenance of the MGBA as well as the BBB [ 116 , 117 ].…”

“…Microbes themselves are capable of local neurotransmitter synthesis (such as dopamine, noradrenaline, and GABA) and neuroactive metabolite production, which can directly influence the CNS [ 118 ]. In sepsis, gut dysbiosis results from disruption of normal homeostatic systems and exogenous alteration of the microbiome via antibiotic administration, and increased gut permeability can lead to increased systemic release of endotoxin and worsen systemic inflammatory responses [ 97 ]. Moreover, excess production of GABA by a pathologic microbiome could potentially contribute to the progression of altered mental status.…”

Exploring Neuroprotective Agents for Sepsis-Associated Encephalopathy: A Comprehensive Review

“…The dysregulation of the brain–gut axis and dysbiosis are observed in many conditions, especially in neurological and behavioral diseases [ 30 ]. The medication commonly used in sepsis treatment affects the homeostasis of the gut microbiome; the gut–blood barrier can be disrupted, allowing the substances that are produced by bacteria to easily cross the barrier, which contributes to sepsis severity [ 31 ].…”