Depression aggravates immune-mediated hepatitis through disruption of intestinal barrier integrity and overactivation of hepatic NLRP3 inflammasome, with gut-derived Lactococcus formosensis translocating to the liver as a key mechanistic driver.
Key Findings
Results
Depression was common among AIH patients and was associated with cirrhosis.
106 out of 260 AIH patients (40.8%) had depression, compared to 173 healthy controls assessed.
Patients received 2-year standardized treatment before depression assessment.
Depression in AIH patients was specifically associated with cirrhosis.
The study assessed depression prevalence as part of a clinical cohort design.
Results
Depressed AIH patients showed exacerbated intestinal barrier dysfunction and hepatic NLRP3 inflammasome overactivation compared to nondepressed AIH patients.
Comparison was made between depressed (n=106) and nondepressed AIH patients within the 260-patient cohort.
Intestinal barrier dysfunction was measurably worse in the depressed group.
Hepatic NLR family pyrin domain containing 3 (NLRP3) inflammasome activation was overactivated in depressed versus nondepressed AIH patients.
These findings were observed in patients already receiving standardized treatment for 2 years.
Results
Chronic unpredictable mild stress (CUMS) exposure aggravated intestinal barrier dysfunction and hepatic NLRP3 inflammasome overactivation in the ConA-induced hepatitis mouse model.
Depressive-like behaviors were induced in mice using the CUMS protocol.
Immune-mediated hepatitis was induced by intravenous injection of concanavalin A (ConA).
CUMS exposure worsened both intestinal barrier abnormalities and hepatic NLRP3 inflammasome overactivation compared to non-CUMS hepatitis mice.
These CUMS-induced abnormalities were attenuated by mirtazapine treatment.
Results
Mirtazapine attenuated CUMS-aggravated intestinal barrier dysfunction and hepatic NLRP3 inflammasome overactivation in the ConA-induced hepatitis model.
Mirtazapine was used as a pharmacological intervention in the CUMS plus ConA mouse model.
Treatment reduced the exacerbated intestinal barrier disruption caused by CUMS.
Treatment reduced the hepatic NLRP3 inflammasome overactivation caused by CUMS.
This finding suggests an antidepressant-mediated protective mechanism against depression-aggravated liver injury.
Results
Mice colonized with MDD patient-derived microbiota exhibited greater intestinal barrier disruption and hepatic NLRP3 inflammasome overactivation than those colonized with control microbiota.
Fecal microbiota transplantation (FMT) was performed using fecal samples from patients with major depressive disorder (MDD) and healthy controls.
MDD microbiota-colonized mice showed significantly greater intestinal barrier disruption compared to control microbiota-colonized mice.
Hepatic NLRP3 inflammasome overactivation was greater in MDD microbiota-colonized mice.
This experiment established a causal link between depression-associated gut microbiota and hepatic pathology.
Results
Lactococcus formosensis, a gut-derived bacterium, was isolated from the livers of MDD microbiota-colonized mice and was found to translocate to the liver and induce hepatic NLRP3 inflammasome overactivation.
L. formosensis was isolated specifically from the livers of mice colonized with MDD-derived microbiota.
The bacterium originated from the gut and translocated to the liver.
Hepatic NLRP3 inflammasome overactivation was induced by L. formosensis translocation.
This identifies L. formosensis as a specific mechanistic mediator of depression-aggravated liver injury.
Results
Vaccination against L. formosensis prevented its translocation to the liver and alleviated liver injury in monocolonized mice.
A vaccination approach targeting L. formosensis was tested in a monocolonization mouse model.
Vaccination prevented translocation of L. formosensis from the gut to the liver.
Liver injury was alleviated in vaccinated monocolonized mice.
This finding provides proof-of-concept that targeting L. formosensis can be a therapeutic strategy.
Conclusions
The study concludes that screening for depression in AIH patients is necessary given depression's role in aggravating immune-mediated hepatitis.
Depression prevalence of 40.8% was observed among 260 AIH patients.
The mechanistic pathway identified involves intestinal barrier disruption and NLRP3 inflammasome overactivation.
Both clinical and experimental evidence supported the clinical relevance of depression in AIH outcomes.
Authors state the study 'provides the necessity of screening for depression in patients with AIH.'
Zhou S, Guo L, Chen N, Liu H, Liu X, Li J, et al.. (2026). Depression Aggravates Immune-Mediated Hepatitis Through NLRP3 Overactivation Induced by Intestinal Microbiota.. CNS neuroscience & therapeutics. https://doi.org/10.1002/cns.70743