Multi-omics profiling reveals microbiota-gut-brain axis dysregulation in an LPS-induced model of sepsis-associated encephalopathy
In LPS-exposed zebrafish, disruption of the microbiota-gut-brain axis is associated with SAE-like neurobehavioral abnormalities, but evidence is preclinical and not directly transferable to humans.
| Population | Adult zebrafish exposed to LPS (experimental endotoxemia/SAE model) |
|---|---|
| Intervention | Systemic lipopolysaccharide (LPS) exposure to induce endotoxemia |
| Comparator | Control zebrafish without LPS exposure |
| Outcome | Gut microbiome composition; Blood-brain barrier integrity; Anxiety-like behavior; Cognitive function; Intestinal and brain metabolomics; Brain transcriptomics (PI3K-Akt, cell adhesion, autophagy pathways); Intestinal inflammation and barrier integrity |
Summary of findings
| Outcome | Effect | 95% CI | Certainty | Clinical relevance | Notes |
|---|---|---|---|---|---|
| Gut microbiome composition | compositional dysbiosis reported; in the quantitative effect size or 95% CI available | — | Very low | — | 1 studies |
| Blood-brain barrier integrity | neurovascular dysfunction reported; in the quantitative effect size or 95% CI available | — | Very low | — | 1 studies |
| Anxiety-like behavior | anxiety-like behavior reported in LPS group; in the quantitative effect size or 95% CI available | — | Very low | — | 1 studies |
| Cognitive function | cognitive impairment reported in LPS group; in the quantitative effect size or 95% CI available | — | Very low | — | 1 studies |
| Intestinal and brain metabolomics | widespread metabolic disturbances reported; in the quantitative effect size or 95% CI available | — | Very low | — | 1 studies |
| Brain transcriptomics (PI3K-Akt, cell adhesion, autophagy pathways) | differentially expressed genes associated with PI3K-Akt, cell adhesion, autophagy reported; in the quantitative effect size or 95% CI available | — | Very low | — | 1 studies |
| Intestinal inflammation and barrier integrity | intestinal inflammation and barrier disruption reported in LPS group; in the quantitative effect size or 95% CI available | — | Very low | — | 1 studies |
Context
Sepsis-associated encephalopathy (SAE) affects 50–70% of septic patients and lacks specific biomarkers and targeted treatments. The microbiota-gut-brain axis is mechanistically plausible but not established as causal in SAE. Multi-omics animal models can generate mechanistic hypotheses for subsequent studies.
What the study showed
LPS induced intestinal inflammation, barrier disruption, neurovascular dysfunction, anxiety-like behavior, and cognitive impairment in zebrafish. Microbiome profiling revealed marked compositional dysbiosis. Metabolomics detected widespread metabolic disturbances in intestinal and brain tissues. Brain transcriptomics identified differentially expressed genes associated with PI3K-Akt signaling, cell adhesion, and autophagy pathways. Cross-omics association analyses suggested links among dysbiosis, metabolic disturbances, and brain molecular responses; absolute numbers, effect sizes with 95% CIs, and detailed p-values were not reported in the available text.
How it was done
Preclinical experimental study in zebrafish using an LPS-induced endotoxemia model. Multi-omics profiling (microbiome, metabolomics, transcriptomics), histopathology, behavioral assessment, and blood-brain barrier integrity assays were applied. Exact sample size, exposure duration, and full protocol details are not available in the provided text.
Effect magnitude
Quantitative effect sizes with 95% CIs were not reported in the available summary; the magnitude of behavioral, metabolic, and transcriptomic alterations cannot be quantified from the provided text.
Risk of bias
Animal model (zebrafish/LPS) with limited translational validity for human SAE — physiological, immunological, and microbiome differences are substantial. Causality between dysbiosis and neurological alterations is not established; multi-omics correlations are associative. Sample size, randomization, blinding, and risk of bias assessment tools (e.g., ARRIVE guidelines for in vivo studies) are not detailed in the available text.
What this study does NOT prove
This study does not prove causality between gut dysbiosis and SAE, nor that microbiome modulation prevents or treats SAE in humans. Findings are not generalizable to adult septic patients.
In clinical practice
This study generates no direct clinical recommendation. Clinicians should recognize the microbiota-gut-brain axis as a mechanistically relevant hypothesis for SAE without modifying practice based on these preclinical data. The biological plausibility of PI3K-Akt and autophagy pathways may guide future translational study design.
Limitations
Animal model (zebrafish/LPS) with limited translational validity for human SAE — physiological, immunological, and microbiome differences are substantial. Causality between dysbiosis and neurological alterations is not established; multi-omics correlations are associative. Sample size, randomization, blinding, and risk of bias assessment tools (e.g., ARRIVE guidelines for in vivo studies) are not detailed in the available text.
What is still missing
Mammalian and subsequently human studies are needed to validate the identified multi-omics associations. RCTs investigating microbiome modulation in SAE are absent and represent the next critical step.
Technical appendix
Version history
- 1.0 · 2026-10-30 — Auto-generated under Evidence Standard v1.0