Gut microbiota and sepsis-associated encephalopathy: pathogenesis and precision therapies

Abstract

Sepsis is defined as a condition of immune dysregulation in response to an infection, and sepsis-associated encephalopathy (SAE) is often the initial symptom that manifests in patients with sepsis. This condition is characterized by its high mortality rates and the potential to cause significant disability among survivors. Despite its severity, the underlying pathophysiologic mechanisms that contribute to the development of SAE are not yet fully understood. Additionally, there are no established strict diagnostic criteria or potent treatment options available for this condition. However, an increasing body of evidence suggests that an imbalance in the gut microbiota is associated with SAE, potentially through the gut-brain axis (GBA). The GBA axis refers to the bidirectional communication between the gut microbiota and the central nervous system. In this review, we discuss the changes in the gut microbiota in SAE and the mechanisms of the GBA axis, involving neural, immune, endocrine, and neurotransmitter pathways. Finally, we conclude by evaluating the preclinical and clinical evidence for fecal microbiota transplantation and probiotics in SAE. Targeting the GBA axis will be an actionable target to ameliorate the development and progression of SAE.

Keywords: fecal microbiota transplantation; gut microbiota; probiotics; sepsis; sepsis-associated encephalopathy.

FIGURE 1

The healthy gut microbiota is dominated by the phyla Bacteroidetes and Firmicutes. During sepsis, gut microbiota composition is perturbed, characterized by increased relative abundance of Proteobacteria and decreased relative abundance of Firmicutes and Bacteroidetes. Concurrently, intestinal epithelial barrier integrity is compromised, with reduced expression of tight junction proteins ZO-1 and occludin (critical components of the epithelial barrier). These result in increased intestinal permeability (“leaky gut”), which exacerbates systemic inflammation, thereby leading to the occurrence of SAE. (Created in https://BioRender.com.)

FIGURE 2

Involvement of gut microbiota in the pathogenesis of SAE. Gut microbiota dysbiosis drives SAE pathogenesis through four interconnected pathways: I. Barrier dysfunction: sepsis alters gut microbiota/metabolites, increasing intestinal and BBB permeability via reduced tight junctions (ZO-1 and occludin), allowing pathogen translocation into systemic and CNS circulation. II. Neuroendocrine axis dysregulation: gut microbiota produce hormones (e.g., serotonin) that modulate intestinal metabolism and brain function via the vagus nerve and the cholinergic anti-inflammatory pathway. III. Immune dysregulation: dysbiosis triggers systemic inflammation (TNF-α and IL-6), which crosses the BBB to activate CNS microglia/astrocytes, amplifying neuroinflammation via reactive ROS. IV. Metabolic/neurotransmitter disorders: altered microbial metabolites (e.g., SCFAs) exacerbate barrier dysfunction and disrupt neurotransmitter balance (e.g., serotonin and dopamine). Collectively, these mechanisms position the gut microbiota as a key therapeutic target for SAE, emphasizing the need for precision microbiome interventions. ROS, reactive oxygen species; BECs, cerebrovascular endothelial cells; TJs, tight junctions; HPA, hypothalamic-pituitary-adrenal; VN, vagus nerve; CAP, cholinergic anti-inflammatory pathway; IECs, intestinal epithelial cells; EECs, enteroendocrine cells; TLRs, Toll-like receptors; PRPs, pattern recognition receptors; PSA, polysaccharide A; PAMPs, pathogen-associated molecular patterns; DAMPs, danger-associated molecular patterns. (Created in https://BioRender.com.)