Defining the Intestinal eCBome and Oxylipin Signaling Systems in a TDP‐43 Mouse Model of Frontotemporal Dementia

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ABSTRACTFrontotemporal dementia (FTD) is a group of early onset and progressive disorders, characterized by degeneration in the frontal and temporal lobes, and subsequent deterioration in cognition, personality, social behavior, and language, with aggregates of the RNA‐binding protein TDP‐43 being present in ~45% of the cases. We reported alterations of the endocannabinoidome (eCBome) in the brain of a TDP‐43 mouse model of FTD. Here we investigated the small intestinal eCBome, oxylipins, and, preliminarily, the gut microbiome. The duodenum, jejunum, and ileum of TDP‐43 overexpressing versus wildtype mice were investigated. Lipid mediators were measured by HPLC‐MS/MS, and mRNA expression of genes involved in eCBome mediator action and metabolism, or intestinal permeability and inflammation, was analyzed by qPCR. Intestinal content microbiota composition and fecal short‐chain fatty acids were studied by 16S DNA sequencing and GC‐FID, respectively. Alterations were observed in TDP‐43 mice for polyunsaturated fatty acids, N‐acyl‐ethanolamines, and oxylipins in the duodenum and the jejunum, and for oxylipins and 2‐monoacylglycerols in the ileum. Regarding the receptors, mRNA expression of Cnr1 and Gpr119 was increased in the ileum, and that of Pparg in the duodenum, where Gpr55 was instead down‐regulated. Regarding the enzymes, Faah and Napepld expression was increased in the ileum. Preliminary gut microbiota data suggest increases of Paraprevotella and Monoglobus in the feces, of DNF00809 in the ileum, and of Butyricicoccus, Candidatus_Arthromitus, and Oscillospira in the cecum, where Paraprevotella, Mucispirillum, and Akkermansia were instead decreased. Fecal acetic, butyric, and isobutyric acid were reduced. We suggest the existence of lipid signal‐mediated gut‐brain interactions in FTD.