Dietary palmitoleic acid reprograms gut microbiota and improves biological therapy against colitis

ABSTRACT

Magnitude and diversity of gut microbiota and metabolic systems are critical in shaping human health and diseases, but it remains largely unclear how complex metabolites may selectively regulate gut microbiota and determine health and diseases. Here, we show that failures or compromised effects of anti-TNF-α therapy in inflammatory bowel diseases (IBD) patients were correlated with intestinal dysbacteriosis with more pro-inflammatory bacteria, extensive unresolved inflammation, failed mucosal repairment, and aberrant lipid metabolism, particularly lower levels of palmitoleic acid (POA). Dietary POA repaired gut mucosal barriers, reduced inflammatory cell infiltrations and expressions of TNF-α and IL-6, and improved efficacy of anti-TNF-α therapy in both acute and chronic IBD mouse models. Ex vivo treatment with POA in cultured inflamed colon tissues derived from Crohn’s disease (CD) patients reduced pro-inflammatory signaling/cytokines and conferred appreciable tissue repairment. Mechanistically, POA significantly upregulated the transcriptional signatures of cell division and biosynthetic process of Akkermansia muciniphila, selectively increased the growth and abundance of Akkermansia muciniphila in gut microbiota, and further reprogrammed the composition and structures of gut microbiota. Oral transfer of such POA-reprogrammed, but not control, gut microbiota induced better protection against colitis in anti-TNF-α mAb-treated recipient mice, and co-administration of POA with Akkermansia muciniphila showed significant synergistic protections against colitis in mice. Collectively, this work not only reveals the critical importance of POA as a polyfunctional molecular force to shape the magnitude and diversity of gut microbiota and therefore promote the intestinal homeostasis, but also implicates a new potential therapeutic strategy against intestinal or abenteric inflammatory diseases.

KEYWORDS:

• Gut microbiota
• Biological therapy
• Inflammatory bowel diseases
• Akkermansia muciniphila
• TNF-α

Acknowledgments

This work was partially supported by grants from the Natural Science Foundation of China (82072250 to G.C.Z.).

Author Contributions

Y.W.C., Q.D.M., Z.X.C., T.L. Y.J.C. L.J.Y., Y.S, L.X., and L.N.L. performed the experiments. Y.W.C., Q.D.M., Z.X.C., T.L., Y.J.C., S.M.T., Z.Y.W., T.M.C., B.Y.O., L.M.C., Z.Y.Z., Y.Y., L.J.Y., Y.S, S.E.Z, L.X., L.N.L., J.L., H.B.S., S.H.Z., L.C.Z., and G.C.Z. analyzed the data. Y.W.C., J.H., Y.W. and M.D.Z. contributed materials/analysis tools. Y.W.C., Q.D.M., L.J.Y., Y.S, L.X., L.N.L., G.C.Z., S.H.Z., and L.C.Z. drafted, discussed, and revised the manuscript. S.H.Z., L.C.Z., and G.C.Z. conceived this study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials. The datasets generated for this study can be found in the http://www.ncbi.nlm.nih.gov/bioproject/916399 (BioProject ID: PRJNA916399) and http://www.ncbi.nlm.nih.gov/bioproject/917464 (BioProject ID: PRJNA917464)

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2211501.

Additional information

Funding

The work was supported by the Natural Science Foundation of China [82072250].