Streptococcus thermophilus inhibits colorectal tumorigenesis through secreting β-galactosidase.
- 2021-03
- Gastroenterology 160(4)
- Qing Li
- Wei Hu
- Weixin Liu
- Liuyang Zhao
- Dan Huang
- Xiao-Dong Liu
- H. Chan
- Yuchen Zhang
- Ju-deng Zeng
- O. Coker
- W. Kang
- S. Ng
- Lin Zhang
- S. Wong
- T. Gin
- M. Chan
- Jian-Lin Wu
- Jun Yu
- W. Wu
- PubMed: 32920015
- DOI: 10.1053/J.GASTRO.2020.09.003
Abstract
Background & aims: Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention.
Methods: The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by β-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing.
Results: Oral gavage of S thermophilus significantly reduced tumor formation in both Apcmin/+ and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. β-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and β-galactosidase activity assay. β-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional β-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via β-galactosidase. β-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus.
Conclusion: S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of β-galactosidase.
Keywords: S thermophilus; colorectal cancer; β-galactosidase.
Research Insights
| Supplement | Health Outcome | Effect Type | Effect Size |
|---|---|---|---|
| Streptococcus thermophilus | Increased Colorectal Cancer Cell Death | Beneficial | Moderate |
| Streptococcus thermophilus | Increased Gut Abundance of Probiotics | Beneficial | Moderate |
| Streptococcus thermophilus | Induced Cell Cycle Arrest | Beneficial | Moderate |
| Streptococcus thermophilus | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus | Retarded Growth of Colorectal Cancer Xenograft | Beneficial | Large |
| Streptococcus thermophilus MAK34S24T | Enhanced Gut Probiotic Levels | Beneficial | Moderate |
| Streptococcus thermophilus MAK34S24T | Enhanced Oxidative Phosphorylation | Beneficial | Moderate |
| Streptococcus thermophilus MAK34S24T | Induced Apoptosis in Colorectal Cancer Cells | Beneficial | Moderate |
| Streptococcus thermophilus MAK34S24T | Induced Cell Cycle Arrest | Beneficial | Moderate |
| Streptococcus thermophilus MAK34S24T | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus MAK34S24T | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus NBRC 13957 | Increased Probiotic Abundance | Beneficial | Moderate |
| Streptococcus thermophilus NBRC 13957 | Induced Cell Cycle Arrest | Beneficial | Moderate |
| Streptococcus thermophilus NBRC 13957 | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus NBRC 13957 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus PXN 66 | Increased Probiotic Levels | Beneficial | Moderate |
| Streptococcus thermophilus PXN 66 | Reduced Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus PXN 66 | Reduced Growth of CRC Xenograft | Beneficial | Moderate |
| Streptococcus thermophilus PXN 66 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus SD-5207 | Altered Energy Homeostasis in Colorectal Cancer Cells | Beneficial | Moderate |
| Streptococcus thermophilus SD-5207 | Increased Apoptosis in Colorectal Cancer Cells | Beneficial | Large |
| Streptococcus thermophilus SD-5207 | Increased Gut Abundance of Probiotics | Beneficial | Moderate |
| Streptococcus thermophilus SD-5207 | Induced Cell Cycle Arrest | Beneficial | Moderate |
| Streptococcus thermophilus SD-5207 | Reduced Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus SD-5207 | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus SD-5207 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus SEBiotic | Disrupted Energy Homeostasis | Beneficial | Moderate |
| Streptococcus thermophilus SEBiotic | Increased Gut Abundance of Probiotics | Beneficial | Moderate |
| Streptococcus thermophilus SEBiotic | Induced Apoptosis in Colorectal Cancer Cells | Beneficial | Moderate |
| Streptococcus thermophilus SEBiotic | Reduced Colony Formation of CRC Cells | Beneficial | Large |
| Streptococcus thermophilus SEBiotic | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus SEBiotic | Reduced Growth of CRC Xenograft | Beneficial | Moderate |
| Streptococcus thermophilus SEBiotic | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus SL-21 | Increased Probiotic Abundance in Gut | Beneficial | Moderate |
| Streptococcus thermophilus SL-21 | Reduced Colony Formation of CRC Cells | Beneficial | Large |
| Streptococcus thermophilus SL-21 | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus SL-21 | Reduced Growth of CRC Xenograft | Beneficial | Moderate |
| Streptococcus thermophilus SL-21 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus SP4 | Increased Probiotic Bacteria Abundance | Beneficial | Moderate |
| Streptococcus thermophilus SP4 | Reduced Cell Proliferation | Beneficial | Large |
| Streptococcus thermophilus SP4 | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus SP4 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus ST-21 | Increased Gut Abundance of Probiotics | Beneficial | Moderate |
| Streptococcus thermophilus ST-21 | Reduced Cell Proliferation | Beneficial | Large |
| Streptococcus thermophilus ST-21 | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus ST-21 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus ST1447 | Increased Probiotic Abundance in Gut | Beneficial | Moderate |
| Streptococcus thermophilus ST1447 | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus ST1447 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus TH-4 | Increased Gut Abundance of Probiotics | Beneficial | Moderate |
| Streptococcus thermophilus TH-4 | Reduced Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus TH-4 | Reduced Growth of CRC Xenograft | Beneficial | Moderate |
| Streptococcus thermophilus TH-4 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus UASt-09 | Downregulated Hippo Pathway Kinase Activity | Beneficial | Moderate |
| Streptococcus thermophilus UASt-09 | Enhanced Oxidative Phosphorylation | Beneficial | Moderate |
| Streptococcus thermophilus UASt-09 | Increased Gut Abundance of Probiotics | Beneficial | Moderate |
| Streptococcus thermophilus UASt-09 | Induced Apoptosis in Colorectal Cancer Cells | Beneficial | Moderate |
| Streptococcus thermophilus UASt-09 | Induced Cell Cycle Arrest | Beneficial | Moderate |
| Streptococcus thermophilus UASt-09 | Reduced Colon Cancer Cell Proliferation | Beneficial | Large |
| Streptococcus thermophilus UASt-09 | Reduced Colony Formation of CRC Cells | Beneficial | Large |
| Streptococcus thermophilus UASt-09 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus VPro 23 | Increased Gut Abundance of Probiotics | Beneficial | Moderate |
| Streptococcus thermophilus VPro 23 | Reduced Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus VPro 23 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus Y08 | Increased Gut Abundance of Probiotics | Beneficial | Moderate |
| Streptococcus thermophilus Y08 | Reduced Cell Proliferation | Beneficial | Large |
| Streptococcus thermophilus Y08 | Reduced Colorectal Cancer Cell Proliferation | Beneficial | Moderate |
| Streptococcus thermophilus Y08 | Reduced Tumor Formation | Beneficial | Large |
| Streptococcus thermophilus Y08 AF | Increased Gut Abundance of Probiotics | Beneficial | Moderate |
| Streptococcus thermophilus Y08 AF | Induced Apoptosis in Colorectal Cancer Cells | Beneficial | Moderate |
| Streptococcus thermophilus Y08 AF | Reduced Colon Cancer Cell Proliferation | Beneficial | Large |
| Streptococcus thermophilus Y08 AF | Reduced Colorectal Tumorigenesis | Beneficial | Large |