**6. Conclusions**

Due to the strong antioxidant and anti-inflammatory properties, anthocyanins present in natural products offer grea<sup>t</sup> hope as an alternative therapy for chronic disorders, such as cardiovascular disease, fatty liver disease, inflammatory bowel disease, and glucose-lipid metabolism disorders. Maintaining the gu<sup>t</sup> integrity plays an important role in the health-promoting functions of anthocyanins, as the intestinal tract is not only the main place for digestion and absorption of food but also the first defense barrier against external pathogens and stimulus. It is commonly believed that the degradation of anthocyanins in the gastrointestinal tract decreases their bioavailability; however, recent studies based on the microbiome and metabonomics have suggested that the interaction between natural bioactive compounds and gu<sup>t</sup> microbiota may potentially increase health benefits. On the one hand, anthocyanins can modulate the gu<sup>t</sup> microbiota composition through either bacteriostasis

effect or as nutrients to promote the growth of specific microbes. On the other hand, gu<sup>t</sup> microbiota may break down anthocyanins to form multiple metabolites, which are absorbed into the systemic circulation to exert positive or negative effects. Thus, understanding the interactions between anthocyanins and microorganisms, as well as the effects of anthocyanin-derived metabolites on cellular signaling pathways, is necessary for the rational use of anthocyanins. The breakdown of C3G in the gastrointestinal tract generates a series of secondary phenolic metabolites, which take up the main part of C3G-derived bioactive phenolics in circulation. Those metabolites, such as PCA, PGA, VA, and FA, not only regulate the gu<sup>t</sup> microbiota potentially by their lethal effects on microorganisms but also affect the Nrf2-mediated antioxidant system and inflammatory pathways, such as the TAK1-mediated MAPK pathway and SphK/S1P mediated NF-κB pathway. Based on this, C3G and its metabolites improve the microenvironment and attenuate the oxidative stress and inflammation to reduce the cell death of enterocytes, which ultimately maintain intestinal integrity and function. However, species-specific microbial communities and their products affected by C3G and its bioactive metabolites, and how those products regulate signaling pathways and physiological responses are still not clear. Future studies based on multi-omics analysis will provide an insight into both the health benefits and negative effects of C3G and contribute to the rational use of this common natural anthocyanin.

**Author Contributions:** Writing—original draft preparation, J.T. and Y.L.; Writing—review and editing, S.W. and D.-X.H.; supervision, S.W.

**Funding:** The authors gratefully acknowledge the support from the National Natural Science Foundation of China (31772819), Hunan Provincial Natural Science Foundation for Distinguished Young Scholars (2019JJ30012), and Double-First-Class Construction Project of Hunan Province (kxk201801004).

**Conflicts of Interest:** The authors declare no conflicts of interest.
