Mineral crude drug mirabilite (Mangxiao) inhibits the occurrence of colorectal cancer by regulating the Lactobacillus–bile acid–intestinal farnesoid X receptor axis based on multiomics integration analysis

Abstract

Mineral crude drug has revolutionized the treatment landscape in precision oncology niche that leads to the improvement in therapeutic efficiency on various tumor subtypes. Mangxiao (MX), a mineral crude drug in traditional Chinese medicine, has been used for treating gastrointestinal diseases for thousands of years. However, the action mechanisms are still ambiguous. Here, we attempt to explore inhibitory roles and associated pharmacological mechanisms of MX upon colorectal cancer (CRC) in APC^Min/+ male mice by integrating metabolomics, 16S rDNA sequencing analyses, and metagenomic-based microbiota analysis. We found that MX can significantly inhibit the occurrence of CRC through the regulation of the dysregulated gut microbe metabolism. Furthermore, the correlation analysis of metabolomes and 16S rDNA revealed that MX could restore the disorders of gut microbes by specifically enriching the abundance of Lactobacilli to improve bile acid metabolism, which further activated the farnesoid X receptor (FXR) in CRC mice, then the improvement of gut dysbiosis could inhibit the development of CRC. Collectively, our effort confirmed MX has the capacity to intervene the development of CRC and further discovered that it targets Lactobacillus–bile acid–intestinal FXR axis, which can be regarded as a candidate medicine for future drug discovery and development against CRC.

Keywords

colorectal cancer / Mangxiao / multiomics / traditional Chinese medicine

References

1	H de Thé. Differentiation therapy revisited. Nat Rev Cancer. 2018;18(2):117-127.
2	L Wang, GB Zhou, P Liu, et al. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia. Proc Natl Acad Sci USA. 2008;105(12):4826-4831.
3	D Liu, C Gao, JS Li, et al. Experimental studies on hemostatic effect and hemostatic mechanism of ochre. Trad Chin Drug Res Clin Pharmacol. 2009;20(2):131-133.
4	H Sun, HL Zhang, AH Zhang, et al. Network pharmacology combined with functional metabolomics discover bile acid metabolism as a promising target for mirabilite against colorectal cancer. RSC Adv. 2018;8(53):30061-30070.
5	GQ Chen, XG Shi, W Tang, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): i. As2O3 exerts dose-dependent dual effects on APL cells. Blood. 1997;89(9):3345-3353.
6	L Chen, HM Zhu, Y Li, et al. Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial). Proc Natl Acad Sci USA. 2021;118(6):e2020382118.
7	JE Henney. From the food and drug administration: drug product problem reports. JAMA. 2000;284(17):2178.
8	J Liu, Y Lu, Q Wu, et al. Mineral arsenicals in traditional medicines: orpiment, realgar, and arsenolite. J Pharmacol Exp Ther. 2008;326(2):363-368.
9	N Wang, LW Wang, BD Gou, et al. Preparation of realgar nanoparticle suspension and its inhibition effect on the proliferation of human myelocytic leukaemia HL-60 cells. J Dispers Sci Technol. 2009;30(2):237-240.
10	FR Yang, YF Zhao, XW Hu, et al. Nano-realgar suppresses lung cancer stem cell growth by repressing metabolic reprogramming. Gene. 2021;788:145666.
11	H Sun, HL Zhang, AH Zhang, et al. Network pharmacology combined with functional metabolomics discover bile acid metabolism as a promising target for mirabilite against colorectal cancer. RSC Adv. 2018;8(62):35600-35610.
12	HL Zhang, AH Zhang, XH Zhou, et al. High-throughput lipidomics reveal mirabilite regulating lipid metabolism as anticancer therapeutics. RSC Adv. 2018;8(62):35600-35610.
13	H Sun, AH Zhang, HL Zhang, et al. Ultra-performance liquid chromatography/mass spectrometry technology and high-throughput metabolomics for deciphering the preventive mechanism of mangxiao on colorectal cancer via the modulation of complex metabolic networks. RSC Adv. 2019;9:35356.
14	A Shaukat, TR Levin, et al. Current and future colorectal cancer screening strategies. Nat Rev Gastroenterol Hepatol. 2022;19(8):521-531.
15	H Sung, J Ferlay, RL Siegel, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71: 209-249.
16	RL Siegel, KD Miller, NS Wagle, et al. 2023a. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.
17	RL Siegel, NS Wagle, A Cercek, et al. 2023b. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233-254.
18	M Housini, B Dariya, N Ahmed, et al. Colorectal cancer: genetic alterations, novel biomarkers, current therapeutic strategies and clinical trials. Gene. 2024;892:147857.
19	A Janney, F Powrie, EH Mann. Host–microbiota maladaptation in colorectal cancer. Nature. 2020;585(7826):509-517.
20	D Rothschild, O Weissbrod, E Barkan, et al. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018;555: 210-215.
21	C Kong, L Liang, G Liu, et al. Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer. Gut. 2023;72(6):1129-1142.
22	JC Sedlak, ?H Yilmaz, J Roper. Metabolism and colorectal cancer. Annu Rev Pathol. 2023;18: 467-492.
23	M Christine, F Payam, M John, et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science. 2018;359: 592-597.
24	L Yufeng, C Harry, L Yali, et al. Altered mycobiota signatures and enriched pathogenic Aspergillus rambellii are associated with colorectal cancer based on multicohort fecal metagenomic analyses. Gastroenterology. 2022;163(4):P908-P921.
25	CA Brennan, WS Garrett. Fusobacterium nucleatum—symbiont, opportunist and oncobacterium. Nat Rev Microbiol. 2019;17(3):156-166.
26	HN Bell, RJ Rebernick, J Goyert, et al. Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance. Cancer Cell. 2022;40(2):185-200. e6.
27	J Cai, L Sun, FJ Gonzalez. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe. 2022;30(3):289-300.
28	AR Moser, C Luongo, KA Gould, et al. ApcMin: a mouse model for intestinal and mammary tumorigenesis. Eur J Cancer. 1995;31A(7-8):1061-1064.
29	E Read, MA Curtis, JF Neves. The role of oral bacteria in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18(10):731-742.
30	M Silva, V Brunner, M Tschurtschenthaler. Microbiota and colorectal cancer: from gut to bedside. Front Pharmacol. 2021;12:760280.
31	SL Clay, D Fonseca-Pereira, WS Garrett. Colorectal cancer: the facts in the case of the microbiota. J Clin Invest. 2022;132(4):e155101.
32	AM Thomas, P Manghi, F Asnicar, et al. Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nat Med. 2019;25(4):667-678.
33	SH Sun. Research the method of cure cancer of Sun Bing-yan. Chin Arch Tradit Chin Med. 2010;28(9):1816-1818.
34	N Sugimura, Q Li, ESH Chu, et al. Lactobacillus gallinarum modulates the gut microbiota and produces anti-cancer metabolites to protect against colorectal tumourigenesis. Gut. 2021;71(10):2011-2021.
35	Y Chung, Y Ryu, BC An, et al. A synthetic probiotic engineered for colorectal cancer therapy modulates gut microbiota. Microbiome. 2021;9(1):122.
36	W Jia, G Xie, W Jia, et al. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol. 2018;15(2):111-128.
37	M Funabashi, TL Grove, M Wang, et al. A metabolic pathway for bile acid dehydroxylation by the gut microbiome. Nature. 2020;582(7813):566-570.
38	S Wang, W Dong, L Liu, et al. Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis. Mol Carcinog. 2019;58(7):1155-1167.
39	CL Bowlus, PJ Pockros, AE Kremer, et al. Long-term obeticholic acid therapy improves histological endpoints in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol. 2020;18(5):1170-1178.
40	P Pathak, C Xie, RG Nichols, et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology. 2018;68(4):1574-1588.
41	T Fu, S Coulter, E Yoshihara, et al. FXR regulates intestinal cancer stem cell proliferation. Cell. 2019;176(5):1098-1112. e18.
42	MD Thompson, A Moghe, P Cornuet, et al. β-catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis. Hepatology. 2017;67(3):955-971.