# UMI‐77 Ameliorates Lipopolysaccharide‐Induced Sepsis‐Associated Encephalopathy by Modulating the Brain‐Gut Axis

## TL;DR

UMI-77 improves sepsis-related brain damage by altering metabolism in the brain and gut, potentially through key amino acid pathways.

## Contribution

This study reveals UMI-77's novel role in treating sepsis-associated encephalopathy via brain-gut axis modulation and identifies key metabolic biomarkers.

## Key findings

- UMI-77 disrupts gut microbiota and improves neurological function in septic mice.
- Key metabolites like L-phenylalanine, L-tyrosine, and 5-hydroxy-tryptophan are central to UMI-77's mechanism.
- Metabolomic analysis shows UMI-77 affects amino acid and biotin metabolism in the brain and gut.

## Abstract

Sepsis‐associated encephalopathy (SAE) is a common neurological complication of sepsis. UMI‐77 has shown unique benefits in modulating inflammation to improve sepsis. However, the exact role of UMI‐77 in the treatment of SAE and its mechanism are unknown.

This article analyzes UMI‐77 based on metabolomics and explores its mechanism of action in treating SAE based on the brain‐gut axis.

In this study, hematoxylin and eosin (H&E) and immunofluorescence staining were used to evaluate the therapeutic effect of UMI‐77 on SAE mice. Applying untargeted metabolomics analysis, the metabolic changes in the brain and intestines of septic mice treated with UMI‐77 were examined. Furthermore, Receiver Operating Characteristic (ROC) analysis was used to select predictive biomarkers for exploring the mechanism of UMI‐77 in treating SAE.

Sixty‐six significant biomarkers in the brain were found and selected with the aid of untargeted the metabolomic method. Metabolic pathway analysis indicates that these differential metabolites are mainly involved in the metabolism of linoleic acid, biosynthesis of phenylalanine, tyrosine, and tryptophan, and phenylalanine metabolism. Seventy‐eight important biomarkers were identified and selected in the intestine; metabolic pathway analysis revealed that these differential metabolites were mainly involved in phenylalanine, tyrosine, and tryptophan biosynthesis, and biotin metabolism. L‐phenylalanine, L‐tyrosine, and 5‐hydroxy‐tryptophan are the most important metabolites.

UMI‐77 plays a positive regulatory role in disrupting the gut microbiota of mice through pathways such as the biosynthesis of phenylalanine, tyrosine, and tryptophan, and can significantly improve neurological function and reduce apoptosis of brain tissue cells.

Metabolomics‐based analysis of SAE mice by brain‐gut axis found that metabolic pathway analysis indicates that these differential metabolites are mainly involved in the metabolism of linoleic acid, biosynthesis of phenylalanine, tyrosine, and tryptophan, and phenylalanine metabolism in the brain. Metabolic pathway analysis revealed that these differential metabolites were mainly involved in phenylalanine, tyrosine, and tryptophan biosynthesis and biotin metabolism in the intestine. Through an integrated analysis of brain and intestinal metabolomics, L‐phenylalanine, L‐tyrosine, and 5‐hydroxy‐tryptophan are the most important metabolites.