# Depression Aggravates Immune‐Mediated Hepatitis Through NLRP3 Overactivation Induced by Intestinal Microbiota

## TL;DR

Depression worsens liver inflammation in autoimmune hepatitis by disrupting gut barriers and overactivating liver immune responses, with a specific gut bacteria playing a key role.

## Contribution

This study identifies a novel mechanism linking depression to immune-mediated liver injury through gut microbiota and NLRP3 inflammasome activation.

## Key findings

- Depression in AIH patients is linked to worsened liver outcomes and increased cirrhosis risk.
- Gut microbiota from depressed individuals induces liver inflammation via NLRP3 overactivation in mice.
- Lactococcus formosensis from the gut can translocate to the liver and cause liver injury.

## Abstract

Depression is associated with adverse effects in patients with autoimmune hepatitis (AIH). However, the underlying mechanism remains unclear. This study explores the impact of depression and related intestinal microbiota on immune‐mediated hepatitis.

We assessed depression in 260 AIH patients receiving 2‐year standardized treatment and 173 healthy controls. In mice, depressive‐like behaviors were induced by chronic unpredictable mild stress (CUMS), and immune‐mediated hepatitis was induced by intravenous injection of concanavalin A (ConA). Fecal microbiota transplantation (FMT) was performed using samples from patients with major depressive disorder (MDD) and controls.

Depression was common in patients with AIH (106/260, 40.8%) and was associated with cirrhosis. Compared with nondepressed AIH patients, those with depression showed exacerbated intestinal barrier dysfunction and hepatic NLR family pyrin domain containing 3 (NLRP3) inflammasome overactivation. In the ConA‐induced hepatitis model, CUMS exposure aggravated these abnormalities, which were then attenuated by mirtazapine. Furthermore, mice colonized with MDD microbiota exhibited greater intestinal barrier disruption and hepatic NLRP3 inflammasome overactivation than those colonized with control microbiota. Notably, gut‐derived Lactococcus formosensis, isolated from the livers of MDD microbiota‐colonized mice, could translocate to the liver and induce hepatic NLRP3 inflammasome overactivation. In addition, vaccination against
L. formosensis
prevented translocation and alleviated liver injury in monocolonized mice.

Depression aggravates immune‐mediated hepatitis through disruption of intestinal barrier integrity and overactivation of hepatic NLRP3 inflammasome. Gut‐derived
L. formosensis
could translocate to the liver and induce liver injury in mice. This study provides the necessity of screening for depression in patients with AIH.

Depression is common in AIH patients and is associated with an elevated cirrhosis risk. AIH patients with depression, mice colonized with MDD microbiota, and ConA‐treated mice subjected to CUMS exhibit intestinal barrier dysfunction and hepatic NLRP3 inflammasome overactivation. Gut‐derived Lactococcus formosensis, isolated from the livers of mice harboring MDD microbiota, play pivotal roles in the disruption of intestinal epithelial integrity and overactivation of hepatic NLRP3 inflammasome.