# Decorin Is a Newly Discovered Target of Akkermansia muciniphila in the Treatment of Sepsis‐Associated Encephalopathy

## TL;DR

A gut bacterium, Akkermansia muciniphila, helps treat sepsis-related brain damage by reducing inflammation and protecting neurons through a protein called Decorin.

## Contribution

This study identifies Decorin as a novel target of Akkermansia muciniphila in mitigating sepsis-associated encephalopathy.

## Key findings

- Akkermansia muciniphila reduces hippocampal inflammation via a Decorin-independent pathway.
- Akkermansia muciniphila promotes neuronal survival by upregulating Decorin, which modulates autophagy and suppresses apoptosis.
- Oral administration of Akkermansia muciniphila ameliorates cognitive deficits in a murine model of sepsis.

## Abstract

Sepsis‐associated encephalopathy (SAE) is a major contributor to mortality in septic patients, with its mechanisms being incompletely understood and effective therapies lacking. While the gut bacterium
Akkermansia muciniphila
(AKK) has shown beneficial effects in systemic infections, its specific role and mechanisms in SAE remain undefined.

We investigated the role of AKK in a murine model of sepsis induced by cecal ligation and puncture (CLP). Oral administration of AKK was confirmed via 16S rRNA sequencing. Mice underwent behavioral assessments to evaluate cognitive function. Hippocampal levels of pro‐inflammatory cytokines were measured, and transcriptomic profiling was performed to identify key mediators. Functional analyses were conducted to delineate the role of the identified protein, Decorin (DCN), in neuronal survival, apoptosis, and autophagy. Simultaneously, we intervened in the expression of mouse DCN using AAV virus and further validated.

Oral AKK pretreatment was successfully enriched in the gut and significantly ameliorated CLP‐induced cognitive deficits. It concurrently reduced hippocampal pro‐inflammatory cytokine levels through a robust, DCN‐independent anti‐inflammatory pathway. Transcriptomics revealed that AKK treatment notably upregulated hippocampal DCN expression. Functional studies demonstrated that DCN contributed to AKK's neuroprotective effects by promoting autophagy and suppressing neuronal apoptosis, representing a distinct mechanism of action.

Our findings reveal a dual mechanism through which AKK mitigates SAE: (1) suppression of hippocampal inflammation via a DCN‐independent pathway, and (2) DCN‐dependent modulation of neuronal apoptosis and autophagy. This study establishes AKK as a promising microbial intervention for SAE and identifies DCN as a context‐specific mediator of its neuroprotective effects.

Akkermansia muciniphila
protects against sepsis‐associated encephalopathy by reducing hippocampal inflammation and modulating neuronal survival through decorin‐dependent and ‐independent pathways, highlighting its potential as a microbial therapy.