Prediabetes is a critical stage characterized by insulin resistance. Morus nigra L., an edible plant, is widely used in food and nutritive supplements and exhibits various pharmacological activities; however, its therapeutic effects and mechanisms on prediabetes have rarely been reported. In this research, the major components of total flavonoids of M. nigra L. (TFM) were identified, and TFM treatment was found to reduce prediabetes progressing to type 2 diabetes mellitus (T2DM) from 93.75 to 18.75%. The microbiota and next-generation sequencing combined with western blotting in vivo and in vitro demonstrated that TFM and its components ameliorated insulin resistance mediated by the suppressor of cytokine signaling and protein tyrosine phosphatase 1B, which benefited by maintaining intestinal homeostasis and restraining plasma levels of inflammatory factors. This study confirmed the T2DM prevention effect of TFM and revealed the underlying mechanism, setting the stage for the design of functional foods for diabetes prevention.

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Interspecific interaction mediated crosstalk was regarded as an important feature among the microorganisms under natural conditions and also the key mechanism for the biosynthesis of newly induced compounds in the co-culture. However, there is still a lack of direct experimental evidence for this mechanism. In this study, the interaction between A. sydowii and B. subtilis in the co-culture was firstly verified by the morphological observation. Subsequently, through the strategy combining substrate feeding, stable isotope labeling and gene expression analysis, the crosstalk in the co-culture for the production of five benzoic acid derivatives (N1-N4 and N7) were demonstrated: the secondary metabolites 10-deoxygerfelin of A. sydowii acted as an inducer to induce B. subtilis to produce benzoic acid, which was further converted into 3-OH-benzoic acid by A. sydowii. Subsequently, A. sydowii used 3-OH-benzoic acid as the substrate to synthesize the new compound N2, and then N1, N3, N4 and N7 were biosynthesized upon the up-regulation of hydrolase, hydroxylase, and acyltransferase during co-culture. The plate zone analysis suggested that the biosynthesis of the newly induced compounds N1-N4 was mainly attributed to A. sydowii, and both A. sydowii and B. subtilis were indispensable for the biosynthesis of N7. The current study provides an important basis for a better understanding of the metabolites transfer and the biosynthetic pathways of the newly induced compounds in the co-culture, providing a new insight into the interaction-mediated crosstalk among microorganisms.