Abstract 3046: A common gut commensal utilizes tryptophan to promote cancer via the aryl hydrocarbon receptor
Bibliographic record
Abstract
Abstract Background: We have previously showed that gut microbiota-depleting oral antibiotics decrease tumor growth in C57BL/6J mice via the immune system (Sethi et al, Gastroenterology, 2018). The gut microbiota, however, includes thousands of species producing numerous metabolites. The search for individual bacterial species and metabolites that can promote cancer continues. Methods: We studied the effects of common microbiota modulation techniques in C57BL/6 mice procured from various commercial vendors and injected subcutaneously with cancer cells. 16S rRNA gene sequencing and metabolomics analyses were used to identify the putative cancer-promoting species and metabolites. Results: Mice procured from The Jackson Laboratory (JAX mice) form larger tumors at baseline compared to mice procured from the Charles River Laboratories (CR mice). JAX mice have tumor promoting microbiota that can be targeted by oral antibiotics unlike CR mice. This tumor-promoting microbiota gets transferred from JAX to CR mice via cohousing or fecal microbiota transplant. In a preclinical trial, oral vancomycin slowed the growth of cancer in avatar mice gavaged with stools of some pancreatic cancer patients but not of others. Statistical analyses reveal that the gut of JAX mice hosts a common human gram-positive gut commensal Ruminococcus gnavus that is associated with increased cancer growth in those mice. Monocolonization of germ-free mice with R gnavus directly increases tumor growth. Similarly, feeding R gnavus, but not a control bacterial species, brings the baseline tumor kinetics of CR mice up to that of JAX mice. Our experiments reveal that R gnavus needs sufficient dietary tryptophan (Trp) to promote tumor growth and in turn, catabolizes Trp into various metabolites including the Aryl Hydrocarbon Receptor (AHR) ligand Tryptamine, which we find, is also tumor-promoting per se. The tumor-modulating effects of oral vancomycin, tryptophan catabolites and R gnavus are abolished when murine AHR is stimulated by an exogenous ligand or when it is knocked out. Finally, we find that Ly6G+ cells are essential in effecting these bacteria-cancer interactions. Conclusions: We present initial evidence on how a common gut commensal hijacks an essential dietary amino acid to promote cancer via the AHR. We also demonstrate the essential but underappreciated role that the source of animal procurement plays in studies involving cancer models. Citation Format: Vrishketan Sethi, Junyi Tao, Saba Kurtom, Utpreksha Vaish, Farrukh Afaq, Shuan Zao, Xian Luo, Tejeshwar Jain, Prateek Sharma, Ejas Bava, Sundaram Ramakrishnan, Liang Li, Ashok Saluja, Vikas Dudeja. A common gut commensal utilizes tryptophan to promote cancer via the aryl hydrocarbon receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3046.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".