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Indole-3-lactic acid suppresses colorectal cancer via metabolic reprogramming
Shizhen Zhou1,2, Kai Wang2,3, Jiandong Huang4
1Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Abstract:
Research indicates that abnormal gut microbiota metabolism is linked to colorectal cancer (CRC) progression, but the role of microbiota-related tryptophan metabolism disruption remains unclear. Using metagenomic sequencing and targeted Trp metabolomics, our research identified that CRC patients had abnormal indole-3-lactic acid (ILA) levels, which were related to tumor malignancy. Exogenous ILA administration suppressed CRC development in AOM/DSS induced and xenograft mice models. Furthermore, in vitro experiments demonstrated that ILA inhibits tumor cell proliferation, migration, and anti-apoptotic capabilities. Mechanistically, ILA appears to directly occupy the phosphorylation sites of STAT3, leading to a reduction in intracellular phosphorylated STAT3 (p-STAT3) levels and the inhibition of the HK2 pathway, thereby downregulating glucose metabolism in cancer cells. Notably, this inhibition is independent of the aryl hydrocarbon receptor (AHR). In conclusion, our research findings demonstrate that alterations in tryptophan metabolism among CRC patients can influence tumor progression and reveal a novel mechanism through which ILA exerts its inhibitory effects on CRC. These findings offer new insights into the role of gut microbiota in CRC and identify potential clinical therapeutic targets.
Insights
Altered gut microbiota tryptophan metabolism, specifically low indole-3-lactic acid (ILA), promotes colorectal cancer (CRC). Restoring ILA levels inhibits CRC progression by targeting cancer cell metabolism and survival.
Area of Science:
- Microbiology
- Oncology
- Metabolomics
Background:
- Gut microbiota dysbiosis is linked to colorectal cancer (CRC) progression.
- The specific role of tryptophan metabolism disruption in CRC remains largely unknown.
Purpose of the Study:
- To investigate the role of indole-3-lactic acid (ILA), a tryptophan metabolite, in colorectal cancer (CRC).
- To elucidate the underlying mechanisms by which ILA affects CRC progression.
Main Methods:
- Metagenomic sequencing and targeted metabolomics were used to analyze gut microbiota and tryptophan metabolites in CRC patients.
- In vivo studies utilized AOM/DSS induced and xenograft mouse models to assess the effects of ILA.
- In vitro experiments examined ILA's impact on cancer cell proliferation, migration, and apoptosis.
Main Results:
- CRC patients exhibited abnormal indole-3-lactic acid (ILA) levels correlated with tumor malignancy.
- Exogenous ILA administration suppressed CRC development in mouse models.
- ILA inhibited cancer cell proliferation and migration, and reduced anti-apoptotic capabilities in vitro.
- ILA was found to inhibit the HK2 pathway by reducing STAT3 phosphorylation, thereby downregulating cancer cell glucose metabolism, independent of AHR.
Conclusions:
- Alterations in gut microbiota tryptophan metabolism, particularly reduced ILA, contribute to CRC progression.
- Indole-3-lactic acid (ILA) demonstrates direct anti-cancer effects by inhibiting cancer cell metabolism and survival.
- ILA represents a potential therapeutic target for colorectal cancer treatment.
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