Multi-omics investigation of spontaneous T2DM macaque reveals gut microbiota promote T2DM by up-regulating the absorption of excess palmitic acid

Reviewer #1 (Public review):

Summary:

The authors tried to identify the relationships among the gut microbiota, lipid metabolites, and the host in type 2 diabetes (T2DM) by using macaques that spontaneously develop T2DM, considered one of the best models of the human disease.

Strengths:

The authors comprehensively compared the gut microbiota and plasma fatty acids between macaques with spontaneous T2DM and control macaques and verified the results with macaques on a high-fat diet-fed mice model.

Weaknesses:

The observed multi-omics of the macaques can be done on humans, which weakens the impact of the conclusion of the manuscript.

In addition, the age and sex of the control macaque group did not necessarily match those of the T2DM group, leaving the possibility for compromising the analysis.

Regarding the metabolomic analysis, the authors did not include fecal samples which are important, considering the authors' claim about the importance of gut microbiota in the pathogenesis of T2DM.

In the mouse experiments, the control group should be given a FMT from control macaques rather than just untreated SPF mice since the fecal microbiota composition is likely very different between macaques and mice. Additionally, the palmitic acid-containing diets fed to mice to induce a diabetes-like condition do not mimic spontaneous T2DM in macaques.

Reviewer #2 (Public review):

This study analyzes the interaction among the gut microbiota, lipid metabolism, and the host in type 2 diabetes (T2DM) using rhesus macaques. The authors first identified 8 macaques with T2DM from 1698 individuals. Then, they observed in T2DM macaques: dysbiosis by 16S rRNA gene amplicon analysis and shotgun sequencing, imbalanced tryptophan metabolism and fatty acid beta oxidization in the feces by metabolome analysis, increased plasma concentration of palmitic acid by MS analysis, and sn inflammatory gene signature of blood cells by transcriptomic analysis. Finally, they transplanted feces of T2DM macaques into mice and fed them with palmitic acid and showed that those mice became diabetic through increased absorption of palmitic acid in the ileum.

This study clearly shows the interaction among gut microbiota, lipid metabolism, and the host in T2DM. The experiments were well designed and performed, and the data are convincing. One point I would suggest is that in the experiments of mice with FMT, control mice should be those colonized with feces of healthy macaques, but not with no FMT.