Functional changes in the gut microbiota are associated with the intestinal phenotype in A20 haploinsufficiency

A20 haploinsufficiency (HA20) is an autoinflammatory disease driven by pathogenic variants in TNFAIP3, which plays a crucial role in regulating immune responses. The clinical manifestations of HA20 resemble those of inflammatory bowel disease (IBD), with prominent gastrointestinal (GI) involvement. Given the well-established association between gut microbiota alterations and IBD, this study aimed to describe the GI involvement of HA20 patients and to investigate their fecal microbiota using shotgun sequencing and metabolomics.

This study included 16 HA20 patients and 22 healthy age and sex-matched controls. GI clinical phenotype, liver imaging, and liver and GI tissue histology were assessed. Shotgun metagenomic sequencing was performed on fecal DNA. Fecal metabolomic profiling of bile acids, short-chain fatty acids (SCFAs), and tryptophan metabolites was performed.

Liver imaging revealed chronic liver disease in 3/5 patients, showing as liver dysmorphia and portal hypertension. Histological analysis showed lymphoplasmocytic infiltrate of the GI tract and the liver. The fecal microbiota of HA20 patients was characterized by marked alterations, including a reduction in microbial diversity and an increase in the pro-inflammatory bacterium Ruminococcus gnavus. Microbial bile acid deconjugation and desulfation were impaired. Additionally, tryptophan metabolism was altered, with a shift towards the kynurenine pathway.

Our results show that HA20 is associated with gut microbiota alterations and significant disruptions in metabolic pathways, particularly involving bile acids. These alterations could contribute to the chronic inflammation observed in HA20. These findings highlight the role of the gut-liver axis and of mucosal barrier dysfunction in HA20.