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Highlights d Mutations in PfAcAS confer resistance to antiplasmodials MMV019721 and MMV084978 d MMV019721 and MMV084978 specifically inhibit PfAcAS by competing with substrates d cKD and IFA show PfAcAS is an essential nuclear enzyme in blood-stage parasites d PfAcAS inhibitors deplete parasite acetyl-CoA and result in histone hypoacetylation

INTRODUCTIONThe ketogenic diet (KD) is an intriguing therapeutic candidate for Alzheimer's disease (AD) given its protective effects against metabolic dysregulation and seizures. Gut microbiota are essential for KD‐mediated neuroprotection against seizures as well as modulation of bile acids, which play a major role in cholesterol metabolism. These relationships motivated our analysis of gut microbiota and metabolites related to cognitive status following a controlled KD intervention compared with a low‐fat‐diet intervention.METHODSPrediabetic adults, either with mild cognitive impairment (MCI) or cognitively normal (CN), were placed on either a low‐fat American Heart Association diet or high‐fat modified Mediterranean KD (MMKD) for 6 weeks; then, after a 6‐week washout period, they crossed over to the alternate diet. We collected stool samples for shotgun metagenomics and untargeted metabolomics at five time points to investigate individuals’ microbiome and metabolome throughout the dietary interventions.RESULTSParticipants with MCI on the MMKD had lower levels of GABA‐producing microbes Alistipes sp. CAG:514 and GABA, and higher levels of GABA‐regulating microbes Akkermansia muciniphila. MCI individuals with curcumin in their diet had lower levels of bile salt hydrolase‐containing microbes and an altered bile acid pool, suggesting reduced gut motility.DISCUSSIONOur results suggest that the MMKD may benefit adults with MCI through modulation of GABA levels and gut‐transit time.

GI disturbances in ASD such as severe constipation can be medically significant and often require medication. This is especially true for individuals with PTHS, suggesting that the gut microbiome may be involved in PTHS’s pathology.

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