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Correlation between microbes and colorectal cancer: tumor apoptosis is induced by sitosterols through promoting gut microbiota to produce short-chain fatty acids

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Abstract

The diversity of the bacterial community in the gut is closely related to human health. Gut microbes accomplish multiple physiological and biochemical functions. Sitosterols are a series of phytochemicals that have multiple pharmacological activities and are used as cholesterol-lowering drugs in clinical practice. In this study, we investigated the roles of bacteria and short-chain fatty acids (SCFAs) to the anti-colorectal cancer (anti-CRC) effects of sitosterols in BALB/c nude mice. Sitosterols were administered orally and gut microbiota composition and intestinal SCFAs changes were analyzed. The correlation between gut microbiota, SCFAs, and tumor apoptosis was assessed by a series of in vivo and in vitro experiments. Tumor growth in the mice was inhibited by sitosterol-treatment. Mechanistic studies revealed that sitosterol-treatment reduced the expression of PI3K/Akt, promoted the activation of Bad, decreased Bcl-xl, and enhanced cyto-c release, leading to caspase-9 and caspase-3 activation, PARP cleavage, and apoptosis. 16S rDNA analysis revealed that the diversity of microbiota, particularly phyla Bacteroidetes and Firmicutes, reduced dramatically in the gut of tumor-bearing mice, whilst treatment with sitosterols reversed these changes. The levels of SCFAs in the fecal samples of sitosterol-treated mice increased, leading to cancer cell apoptosis in vitro. Moreover, tumor apoptosis was induced after mice received a daily dose of 2 × 108 CFU/0.2 mL Lactobacillus pentosus or 20 mM/0.2 mL SCFAs. Taken together, these results demonstrate that sitosterols maintain a diverse microbial environment and enrich the content of L. pentosus in the gut, leading to the production of beneficial metabolites including SCFAs that promote tumor apoptosis.

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Abbreviations

CRC:

Colorectal cancer

SCFAs:

Short-chain fatty acids

NC:

Normal control

TC:

Tumor control

ST:

β-Sitosterol

STG:

β-Sitosterol-glucoside

STGL:

β-Sitosterol-glucoside-linoleate

LAC:

Lactobacillus pentosus

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Acknowledgements

This work was financially supported by the Special Program for Scientific and Technical Innovation of Chongqing Social Livelihood (cstc2015shmszx80012, cstc2017shms-kjfp80004), Fundamental Research Funds for the Central Universities (XDJK2017D151, XDJK2017D160), Chongqing Postgraduate Research and Research Innovation Project (CYS17068), Achievement Transfer Program of Institutions of Higher Education in Chongqing (KJZH17105), and County-University Cooperation Innovation Funds of Southwest University (Zx201601).

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Authors and Affiliations

  1. Chongqing Productivity Promotion Center for the Modernization of Chinese Traditional Medicine, School of Pharmaceutical Sciences, Southwest University, Chongqing, 400716, China

    Hang Ma, Yang Yu, Meimei Wang, Zhaoxing Li, Cheng Tian & Xuegang Li

  2. Chongqing Engineering Research Center for Sweet Potato, School of Life Sciences, Southwest University, Chongqing, 400715, China

    Heshan Xu, Jian Zhang & Xiaoli Ye

  3. McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA

    Zhaoxing Li

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  1. Hang Ma
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Correspondence to Xuegang Li.

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Ma, H., Yu, Y., Wang, M. et al. Correlation between microbes and colorectal cancer: tumor apoptosis is induced by sitosterols through promoting gut microbiota to produce short-chain fatty acids. Apoptosis 24, 168–183 (2019). https://doi.org/10.1007/s10495-018-1500-9

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