Original ResearchFull Report: Basic and Translational—Alimentary TractStreptococcus thermophilus Inhibits Colorectal Tumorigenesis Through Secreting β-Galactosidase
Graphical abstract
Section snippets
Bacterial Strain and Culture Condition
Streptococcus salivarius (2593) and S thermophilus (19258) were purchased from the American Tissue Culture Collection (ATCC, Manassas, VA). Bacillus halodurans (DSM 18197) was obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig, Germany). They were cultured in Brain Heart Infusion (BHI) broth (CM1135B; Thermo Fisher Scientific, West Palm Beach, FL) for 24 hours at 37°C in aerobic conditions. A nonpathogenic human commensal intestinal bacterium, E coli strain
Streptococcus thermophilus Is Depleted in Stool Samples of Patients With Colorectal Cancer
Our previous shotgun metagenomic sequencing showed that there were 62 depleted bacteria species in CRC patients compared with normal individuals.6 We reanalyzed the top 20 depleted strains with the largest fold change and found that S salivarius and S thermophilus were 2 known probiotics (Supplementary Figure 1A). To determine the effect of the most significantly CRC-depleted S salivarius on intestinal tumorigenesis, we gavaged Apcmin/+ mice with S salivarius (1 × 108 CFU/d) for 8 weeks. Two
Discussion
In this study, we validated the depletion of S thermophilus using an orthogonal method. In 2 animal models of colon tumorigenesis, S thermophilus significantly lowered tumor number and tumor volume. Moreover, CRC but not normal colonic cell viability was suppressed by S thermophilus. Previous studies have already revealed the anti-inflammatory effect of S thermophilus18 and its production of lactate as a signal for modulating colonic epithelium.19 However, this is the first study to
Conclusion
In summary, we demonstrated that S thermophilus prevents colon tumorigenesis in animal models. The antitumor effect was mediated by the secretion of β-galactosidase for producing galactose and possibly its synergistic effect with other well-known probiotics. Galactose production then interferes with energy homeostasis and activates AMPK kinase, leading to the phosphorylation of YAP and activation of OXPHO, thus culminating in an anti-Warburg phenotype to inhibit tumorigenesis. Taken together, S
Acknowledgments
The authors thank Siu Hong Chu (Institute of Digestive Disease, CUHK) for his help with animal experiments.
CRediT Authorship Contributions
Qing Li, MD (Data curation: Lead; Project administration: Lead; Validation: Lead; Writing – original draft: Lead);
Wei Hu, PhD (Methodology: Equal);
Wei-Xin Liu, MPhil (Data curation: Equal; Formal analysis: Equal);
Liu-Yang Zhao, PhD (Methodology: Supporting; Visualization: Supporting);
Dan Huang, PhD (Data curation: Supporting; Formal analysis: Supporting);
Xiao-Dong Liu, PhD (Methodology:
References (25)
- et al.
Aspirin reduces colorectal tumor development in mice and gut microbes reduce its bioavailability and chemopreventive effects
Gastroenterology
(2020) - et al.
Probiotics, prebiotics and colorectal cancer prevention
Best Pract Res Clin Gastroenterol
(2016) - et al.
Comprehensive molecular characterization of the Hippo signaling pathway in cancer
Cell Rep
(2018) - et al.
The SLC2 (GLUT) family of membrane transporters
Mol Aspects Med
(2013) - et al.
Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg effect” and a pivotal target for effective therapy
Semin Cancer Biol
(2009) - et al.
Impact of the metabolic activity of Streptococcus thermophilus on the colon epithelium of gnotobiotic rats
J Biol Chem
(2011) - et al.
Diet and colorectal cancer: an investigation of the lectin/galactose hypothesis
Gastroenterology
(2002) - et al.
Cancer statistics, 2019
CA Cancer J Clin
(2019) - et al.
Personalized medicine for prevention: can risk stratified screening decrease colorectal cancer mortality at an acceptable cost?
Cancer Causes Control
(2017) - et al.
Gut microbiota in colorectal cancer: mechanisms of action and clinical applications
Nat Rev Gastroenterol Hepatol
(2019)
Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers
Microbiome
A randomized formula controlled trial of Bifidobacterium lactis and Streptococcus thermophilus for prevention of antibiotic-associated diarrhea in infants
J Clin Gastroenterol
Cited by (114)
The role of human microbiota in the development of colorectal cancer: A literature review
2024, Medicine in MicroecologyAnt may well destroy a whole dam: glycans of colonic mucus barrier disintegrated by gut bacteria
2024, Microbiological ResearchOral probiotics microgel plus Galunisertib reduced TGF-β blockade resistance and enhanced anti-tumor immune responses in colorectal cancer
2024, International Journal of Pharmaceuticsβ-Galactosidase activity monitoring and bioimaging by a novel ICT mechanism-based NIR fluorescent probe with large Stokes shift
2024, Sensors and Actuators B: Chemical
Conflicts of interest The authors declare that they have no conflicts of interest.
Funding This project was supported by Science and Technology Program Grant Shenzhen (JCYJ20170413161534162), National Key R&D Program of China (2017YFE0190700), Health and Medical Research Fund (HMRF) Hong Kong (17160862), and Lim Peng Suan Charitable Trust. The study sponsor did not play any role in the study design or in the collection, analysis, and interpretation of data.
Author names in bold designate shared co-first authorship.
- ∗
Authors are co-corresponding authors.