Indole-3 Propionic Acid Deficiency and Gut Microbiota Imbalance in Follicular Lymphoma: Implications for Disease Progression and Therapeutic Potential

Introduction

Follicular lymphoma (FL), known as the most prevalent indolent B-cell lymphoma, can achieve remission with CD20-targeting treatments, such as the monoclonal antibody rituximab. Nonetheless, a complete cure is not possible, and about 20% of patients relapse within the first 24 months (POD24), leading to a significantly increased risk of reduced survival. The mechanisms behind these are still not fully understood. Indole-3 propionic acid (IPA), a metabolite of tryptophan synthesized by certain Clostridium species in the gut, has been reported to potentially supress the progression of breast cancer and hepatocellular carcinoma by activating various cellular receptors. Futhermore IPA regulates epithelial cell junction complexes to promote intestinal mucosal barrier integrity. In this study, fecal and serum samples from 42 patients with follicular lymphoma, as well as IPA-deficient mice, were examined.

Results

In the group of 42 patients, the median age was 52, ranging from 30 to 71 years, with 25 (58%) being female. The majority, 28 patients, were diagnosed with grade 1/2 follicular lymphoma, while 14 had grade 3A/3B, from who 5 patients showed partial transformation to diffuse large B-cell lymphoma (DLBCL).

Fecal samples were analyzed using 16S rDNA sequencing and LC-MS to assess gut microbiome diversity and metabolites. A negative correlation was found between follicular lymphoma progression and gut microbial diversity. Notably, the gut microbiota of FL patients exhibited a significant increase in certain probiotics, such as Bacteroides, which may be associated with the relatively indolent progression of the disease. Interestingly, we observed in the analysis of differential abundance of gut metabolites an enrichment of metabolites in multiple amino acid pathways, such as those for tyrosine, phenylalanine, and tryptophan. In FL patients, the tryptophan metabolism pathway primarily showed an enrichment of the niacin precursor formylanthranilate, while indole metabolites, such as indole-3 propionic acid that can only be produced through the metabolism of Clostridia bacteria, were significantly reduced. This finding was consisted with the result of gut microbiome diversity, which showed that the relative abundance of Clostrida, were decreased in the gut of FL patients.

Furthermore, serum samples from patients were analyzed using LC-MS. Surprisingly, the levels of IPA in the serum of patients with grade 1/2 FL were 1.6 times higher than those in the control group, whereas IPA levels in the serum of patients with grade 3a/3b FL were 2.3 times lower than in the control group. The concentration of IPA in the serum is strongly correlated with the malignancy of FL.

To investigate the potential molecular role of IPA in the progression of FL, quantitative qRT-PCR was performed to measure the mRNA expression levels of cytokines in the gut of mice. The analysis revealed that IPA-deficient mice exhibited an upregulation of pro-inflammatory cytokine TNF-α mRNA expression and a downregulation of anti-inflammatory cytokine IL-10 mRNA expression.

Conclusion

The study reveals that IPA levels in the serum are inversely correlated with the progression of FL. As a potential therapeutic agent, IPA possesses significant immunomodulatory and anti-cancer properties, and it may help restore microbiota balance in FL patients, making it a promising candidate for further research and therapy. However, the unexpected findings regarding serum IPA levels suggest that systemic factors influencing metabolite concentrations may differ from local gut microbiome activities. Additional research is required to clarify the mechanisms underlying these observations and to fully understand the role of IPA in FL.

No relevant conflicts of interest to declare.