The dietary ligands, omega-3 fatty acid endocannabinoids and short-chain fatty acids prevent cytokine-induced reduction of human hippocampal neurogenesis and alter the expression of genes involved in neuroinflammation and neuroplasticity

The dietary ligands, omega-3 fatty acid endocannabinoids (eCBs) eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA), and short-chain fatty acids (SCFAs) acetate, propionate and butyrate, have anti-inflammatory and antidepressant properties. However, the molecular mechanisms underlying their action in the human brain remain elusive. Here, we treated human hippocampal neurons (HPC0A07/03 C) with eCBs (EPEA (300 pM) or DHEA (700 pM)), or SCFAs (acetate (200 uM), propionate (30 uM), butyrate (20 uM)), followed by interleukin (IL)1β (10,000 pg/ml) or IL6 (50 pg/ml). We found that treatment with either eCBs or SCFAs prevented IL1β- and IL6-induced reduction in neurogenesis and increase in apoptosis. These effects were mediated by IL1β-induced production of IL6, interferon-gamma (IFNγ) and tumour necrosis factor-alpha (TNFα), and by IL6-induced IL1β, IL8 and IL13, all of which were prevented by treatment with eCBs. In contrast, IL1β-induced production of IL6, IL12 and fractalkine (CX3CL1), and IL6-induced production of CX3CL1, were prevented by SCFAs. Treatment with IL1β and IL6 also increased the production of candidate kynurenine pathway metabolites, such as kynurenine (KYN) and nicotinic acid (NICA), which again were prevented by eCBs and SCFAs. We then conducted mRNA sequencing analysis to investigate cellular genes and signalling pathways relevant for the neuro-inflammatory changes previously observed, and putatively prevented by eCB and SCFA treatment. We found that IL1β decreased the expression of the neuroplasticity gene, FRY microtubule binding gene (FRY), and increased the expression of the neuroinflammation gene, U3 small nucleolar ribonucleoprotein homolog C subunit processome component (UTP14C), and both these effects were prevented by either acetate or propionate. Similarly, the expression of the proinflammatory gene, ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1), was increased by IL6, an effect that was prevented by either EPEA or acetate. Altogether, we identify novel anti-inflammatory and neurogenic mechanisms mediating the effect of eCBs and SCFAs on human hippocampal neurogenesis, which can be significant as potential future treatment candidates in the context of neuropsychiatric disorders.