Fucose promotes intestinal stem cell-mediated intestinal epithelial development through promoting Akkermansia-related propanoate metabolism

ABSTRACT

Intestinal stem cells (ISCs) are critical for the development and rapid turnover of intestinal epithelium. The regulatory effects of gut microbiota and their metabolites on ISCs stemness remain elusive. Fucose has been demonstrated to mediate host–microbe interactions in the intestine. However, the association between fucose, gut bacteria, and ISCs stemness remains unclear. To investigate the effects of fucose on ISCs-mediated intestinal epithelial cells (IECs) development, we administered fucose to 4-week-old mice for 4 weeks. ISCs stemness, IECs proliferation, and differentiation were examined. Variations in gut microbes and metabolism were detected using 16S rDNA sequencing and metabolomic analysis. Fucose was added to the bacterial culture medium to further study its effects on metabolism. Crypts were isolated from the mouse ileum for organoids culture in vitro to evaluate the effects of metabolites and the underlying mechanism. The results showed that fucose accelerated ISCs proliferation and secretory lineage differentiation in mice, whereas antibiotics eliminated these effects. The composition and functions of gut bacteria were altered by fucose treatment, while significant increases in Akkermansia and propanoate metabolism were noted. Propionic acid and propionate have been shown to promote organoid development. Fucose fermentation increases the production of propionic acid in Akkermansia muciniphila and enhances its ability to increase the stemness of ISCs. Moreover, ileal contents from fucose-treated mice promoted organoid development in a Gpr41/Gpr43-dependent manner. Fucose administration activates the Wnt signaling pathway in ISCs, and Wnt inhibitors suppress the effects of fucose. We conclude that fucose accelerates ISC-mediated intestinal epithelial development by promoting Akkermansia-related propanoate metabolism. These findings provide new insights into the promotion of gut homeostasis and the application potential of fucose as a prebiotic.

KEYWORDS:

• Fucose
• intestinal stem cell
• gut microbe
• Akkermansia muciniphila
• propionic acid

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets used and analyzed during the current study are available in Science Data Bank (ScienceDB, https://www.scidb.cn/, DOI: 0.57760/sciencedb.07487) upon reasonable request.

Author contribution

Caihan Duan and Junhao Wu contributed equally to this study. Caihan Duan performed the experiments, analyzed the data, and drafted the manuscript; Junhao Wu performed some of the experiments and analyzed the data. Zhe Wang and Chen Tan helped perform part of the experiments. Lingzhi Hou and Wei Qian supported the data evaluation; Chaoqun Han and Xiaohua Hou designed the study, revised the manuscript, provided funding, and obtained grants.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2233149

Additional information

Funding

This study was financially supported by the National Natural Science Foundation of China [Grant Nos. 82170570, 81974062, and 92268108].