Investigating the detrimental role of Bacteroides fragilis on the development of depression in irritable bowel syndrome via sphingolipid generation

Irritable bowel syndrome (IBS) affects 10% to 20% of the population worldwide and has been related to altered gut microbiota. Among them, 30-40 % IBS patients would develop depression, which mostly worsens their psychiatric status and social-economic burden. The microbiome-gut-brain axis is believed to be associated with neurological symptoms, but how gut dysbiosis impacts mental health in individuals with IBS remains unclear.
In our diarrhea-predominant IBS cohort (IBS-D, n=147), we identify Bacteroides fragilis to be strongly associated with depression in IBS. The abundance of B. fragilis is further positively associated with Hamilton Depression Rating Scale (HAM-D), a standard clinical depression grading in IBS patients. In pseudo germ-free mice, we showed B. fragilis (ATCC 25285) administration induced a series of depressive behavioral changes including anhedonia in novel food, female urine stimulation, behaviour despair in tail suspension, and IBS-D-like diarrhea symptoms as well. Therefore, B. fragilis is considered to be a driver factor for depression in IBS patients.
Mechanistically, metagenomics, metabolome, and experimental analyses revealed that B. fragilis may exert its detrimental role in depression through the production of ceramide 1-phosphate (C1P) by bacterial ceramide biosynthesis pathway. C1P, as a key sphingolipid metabolite, is reported to inhibit the activity of sphingomyelin phosphodiesterase (SMase) in brain. Accordingly, our host transcriptome and lipidomic results identified a key SMase, named sphingomyelin phosphodiesterase 4 (SMPD4), which was notably downregulated in B. fragilis-treated mouse brain and consistent with
increased brain C1P level. The reduction of SMPD4 was also reported in public dataset from mouse depression model, which can cause neurodevelopmental abnormality.
Based on these observations, we hypothesize that B. fragilis may lead to depression via the production of C1P, which can across the blood-brain axis, thereby dysregulating SMPD4 in animal model. This proposal aims to investigate the regulatory role of B. fragilis-derived C1P on host SMPD4 and associated pathology in depression. To address this hypothesis, we will (1) validate the regulatory role of B. fragilis in depressive behavior in germ-free mice; (2) explore the in vivo action of C1P production on the development of depression-like behavior in mice; (3) investigate the underlying
mechanism by which C1P derived from B. fragilis regulates SMPD4 expression and hence the development of depression. This study will not only provide molecular insights into the regulation of host metabolism by gut-brain axis but also lay a foundation for novel druggable targets for the treatment of depression comorbidity in IBS.