Reduced calorie diet combined with NNMT inhibition establishes a distinct microbiome in DIO mice.
This animal study investigated whether treatment with a nicotinamide N-methyltransferase inhibitor (NNMTi; 5-amino-1-methylquinolinium) combined with a low-fat diet (LD) switch produced distinct gut microbiome changes in diet-induced obese (DIO) mice, compared to mice maintained on a high-fat Western diet, switched to LD alone, or kept as lean controls. Researchers analyzed cecal microbiome profiles using amplicon sequence variant (ASV) sequencing across these groups. The study found that diet switch (regardless of NNMTi treatment) drove several microbiome differences at the genus and phylum levels relative to controls, while differences between lean and obese controls were minimal, suggesting adiposity alone had limited microbiome impact in this model. Alpha diversity did not significantly differ between groups, but beta diversity analyses indicated within-group similarity. K-means clustering revealed that NNMTi-treated LD-switched mice had a distinct microbiome pattern, characterized by decreased Erysipelatoclostridium and increased Lactobacillus—genera associated with metabolic regulation and body weight. Parasutterella abundance, elevated in both LD-switched groups, significantly correlated with several adipose tissue metabolites. The authors acknowledge this is a foundational, exploratory study in mice, limiting direct translation to human metabolic disease.
Why this grade: All experimental subjects were diet-induced obese mice; no human participants were included, so findings cannot be directly extrapolated to human health outcomes.
Treatment with a nicotinamide N-methyltransferase inhibitor (NNMTi; 5-amino-1-methylquinolinium) combined with low-fat diet (LD) promoted dramatic whole-body adiposity and weight loss in diet-induced obese (DIO) mice, rapidly normalizing these measures to age-matched lean animals, while LD switch alone was unable to restore these measures to age-matched controls in the same time frame. Since mouse microbiome profiles often highly correlate with body weight and fat composition, this study was designed to test whether the cecal microbiomes of DIO mice treated with NNMTi and LD were comparable to the microbiomes of age-matched lean counterparts and distinct from microbiomes of DIO mice maintained on a high-fat Western diet (WD) or subjected to LD switch alone. There were minimal microbiome differences between lean and obese controls, suggesting that diet composition and adiposity had limited effects. However, DIO mice switched from an obesity-promoting WD to an LD (regardless of treatment status) displayed several genera and phyla differences compared to obese and lean controls. While alpha diversity measures did not significantly differ between groups, beta diversity principal coordinates analyses suggested that mice from the same treatment group were the most similar. K-means clustering analysis of amplicon sequence variants by animal demonstrated that NNMTi-treated DIO mice switched to LD had a distinct microbiome pattern that was highlighted by decreased Erysipelatoclostridium and increased Lactobacillus relative abundances compared to vehicle counterparts; these genera are tied to body weight and metabolic regulation. Additionally, Parasutterella relative abundance, which was increased in both the vehicle- and NNMTi-treated LD-switched groups relative to the controls, significantly correlated with several adipose tissue metabolites' abundances. Collectively, these results provide a novel foundation for future investigations.
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