# Widely targeted metabolomics and machine learning identify succinate as a key metabolite in sepsis-associated encephalopathy

## TL;DR

The study finds that succinate, a metabolite, increases in sepsis patients and is linked to brain dysfunction, suggesting it could help diagnose and treat sepsis-associated encephalopathy.

## Contribution

The novel integration of metabolomics and machine learning identifies succinate as a key driver of sepsis-associated encephalopathy.

## Key findings

- Succinate levels increase progressively from health to sepsis to sepsis-associated encephalopathy.
- Succinate supplementation worsens cognitive deficits and neuroinflammation in a mouse model of sepsis.
- Dysregulated glycerophospholipid metabolism and fatty acid oxidation contribute to SAE progression.

## Abstract

Sepsis-associated encephalopathy (SAE) is a common and serious complication of sepsis that leads to acute brain dysfunction and long-term cognitive impairment. We used widely targeted LC-MS/MS plasma metabolomics in 29 healthy controls, 32 sepsis patients, and 27 SAE patients, combined with machine learning, to define metabolic patterns across these groups. This approach identified 12 discriminatory metabolites, with succinate showing a stepwise increase from health to sepsis to SAE and associations with clinical severity scores. To test its functional relevance, we used a cecal ligation and puncture (CLP) mouse model and found that exogenous succinate supplementation aggravated cognitive deficits, neuronal injury, and microglial activation. Together, these findings link systemic metabolic remodeling to brain inflammation and dysfunction in sepsis and suggest that succinate and related pathways may help stratify SAE risk and provide mechanistic entry points for future therapeutic exploration.

•Succinate increases from health to sepsis and SAE, serving as a key metabolic driver•Machine learning-integrated metabolomics identifies robust biomarkers for SAE diagnosis•Succinate supplementation aggravates cognitive deficits and neuroinflammation in CLP mice•Dysregulated glycerophospholipid metabolism and fatty acid oxidation drive SAE progression

Succinate increases from health to sepsis and SAE, serving as a key metabolic driver

Machine learning-integrated metabolomics identifies robust biomarkers for SAE diagnosis

Succinate supplementation aggravates cognitive deficits and neuroinflammation in CLP mice

Dysregulated glycerophospholipid metabolism and fatty acid oxidation drive SAE progression

Health sciences