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Pancreatic cancer: bacteria to the rescue of chemotherapy

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A study reports that the production of certain molecules by intestinal bacteria improves the effectiveness of chemotherapy against pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC), better known as pancreatic cancer, is a tumor associated with a very poor prognosis due to its resistance to treatment.

Combination chemotherapy, for example with FOLFIRINOX (5-FU, irinotecan, oxyplatin and folinic acid), is considered the standard treatment for patients with metastatic PDAC.

However, less than half of all patients respond at least partially to treatment, while non-responders are doomed to significant suffering and death within weeks. A better understanding of the mechanisms that explain these inter-individual differences in responses is therefore of great importance in order to improve the treatment of this terrible cancer.

Reinforcing bacteria

In recent years, it has been observed that intestinal microorganisms (the microbiome) play important roles in tumor development, resistance to treatment as well as in the immune response to cancer.

For example, establishment of a more diverse gut microbiome, for example as a result of increased dietary fiber intake, has been shown to be associated with improved tumor response to immunotherapy.1.

A recent study attempted to determine whether an analogous mechanism, involving the activity of the microbiome, could contribute to the effectiveness of chemotherapy against pancreatic cancer.2.

In this study, the researchers first showed that the composition of the microbiome of patients who responded to treatment was very different from the microbiome found in non-responding patients. This difference appears to play a crucial role in the effectiveness of chemotherapy, as they observed that transferring the microbiome from responders to mice with pancreatic tumors caused a much greater decrease in the size of these tumors in response to treatment.

Tryptophan metabolite

Further metabolomics analysis, which analyzes all blood molecules produced during treatment, revealed that improved response to chemotherapy was correlated with increased blood levels of indole-3-acetic acid (3-IAA), a molecule produced by microbial metabolism of the amino acid tryptophan.

This molecule plays a very important role, because it is present in much higher quantities in responders to chemotherapy.

According to the results obtained by the researchers, the 3-IAA produced by the intestinal bacteria is captured by the immune cells (neutrophils) where it is transformed into toxic molecules which will weaken the cancer cells and make them more sensitive to the lethal effects of chemotherapy.

Does this mean that a diet enriched with tryptophan could promote the growth of certain bacterial strains and improve the effectiveness of pancreatic cancer treatment? It is still too early to tell, but preliminary results suggest that this possibility is worth exploring.

The researchers observed that mice with pancreatic cancer who were fed a diet containing a higher proportion of tryptophan responded much better to chemotherapy than those fed a standard diet.

It is therefore possible that in the near future, the treatment of certain cancers will involve in parallel dietary modifications intended to promote the growth of certain types of intestinal bacteria in order to positively influence the effectiveness of the treatments.

♦ 1. Spencer CN et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science 2021; 374: 1632-1640.

♦ 2. Tintelnot J et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature 2023; 615: 168-174.



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