February 24, 2024

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Probiotics Linked to Immune Suppression and Tumor Growth

Probiotics Linked to Immune Suppression and Tumor Growth



Probiotics Revealed to Have Detrimental Effects on Health – Linked to Immune Suppression and Tumor Growth

Lactic acid bacteria, once celebrated for their positive impact on gastrointestinal health, have taken an unexpected turn.

Renowned in the realm of yogurt, these seemingly benign bacteria have now been implicated as accomplices in the growth of pancreatic cancer.

A research paper titled “Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity,” published by the team led by Tracy L. McGaha from the University of Toronto in the journal Immunity, uncovers the mechanism through which lactic acid bacteria, by metabolizing tryptophan, activate tumor-associated macrophages, promoting the growth of pancreatic ductal adenocarcinoma.

Probiotics Linked to Immune Suppression and Tumor Growth

Tryptophan, an essential amino acid in the human body, produces metabolites with immune, metabolic, and neural regulatory functions. A 2019 review in Nature Reviews extensively detailed the role of tryptophan metabolites in central nervous system disorders, infectious diseases, autoimmune diseases, tumors, and more.

Tumor-associated macrophages, found in tumor tissues, play a dual role as both immune defenders and promoters of tumor growth, metastasis, and invasion.

The key role of AhR in suppressing tumor immunity and promoting pancreatic cancer

The researchers initially identified differentially expressed genes in TAMs in pancreatic ductal adenocarcinoma through RNA-seq. Compared to normal macrophages, TAMs exhibited significant upregulation of pro-cancer genes Arg1, Nos2, and Cd274. Among the upregulated genes, the researchers focused on Cyp1b1, which encodes the aryl hydrocarbon receptor (AhR), a receptor for tryptophan metabolites. Subsequent findings in AhR-deficient mice showed decreased CD45 expression and increased expression of MHCII, CD40, and PDL1, indicating AhR’s immunomodulatory role.

Furthermore, AhR-deficient mice exhibited increased T cell activation, significantly lower tumor weight, and a lower proportion of infiltrative adenocarcinoma compared to the control group. Survival curves also indicated improved survival in AhR-deficient mice.

The researchers further validated the impact of AhR inhibition using the AhR inhibitor CH223191. Co-administration with anti-PDL1 antibodies effectively improved mouse survival, demonstrating AhR’s ability to inhibit T cell maturation, disrupting immune suppression in pancreatic cancer cells.

AhR alters cell gene transcription

Utilizing mass cytometry (CyTOF) and single-cell sequencing, the researchers identified three macrophage clusters in tumor tissues. Gene set enrichment analysis (iGSEA) revealed AhR’s influence on interferon response pathways involving IFNg, IRF8, IFI16, IFNb, MYD88, interferon-induced transcription factors, signaling networks, and gene expression of inflammatory mediators.

Based on this data, the researchers analyzed an immune regulation network centered around STAT1, confirmed the immune effects on tumors using CD8 and INFγ antibodies.

Lactic acid bacteria activate AhR by metabolizing tryptophan

Lactic acid bacteria metabolize tryptophan to produce indoles. To pinpoint the source of AhR activation, researchers found that the broad-spectrum antibiotic Abx inhibited tumor growth in mice. Treating tumors with lactic acid bacteria-intolerant Amp effectively increased the expression of PDL1 and MHCII in cells, enhancing the immune response and suppressing tumor growth.

Among common lactic acid bacteria, L. reuteri and L. murinus produced two AhR-activating metabolites, IAA and ILA. Transplanting L. murinus into the sterile intestinal tracts of mice promoted tumor growth, immune suppression, and increased expression of pro-cancer genes such as Arg1, Ido1, and Il10.

Dietary regulation effects

Since tryptophan is obtained through food, dietary changes would inevitably impact pancreatic cancer growth. The research team implemented a tryptophan-deficient diet supplemented with IAA and ILA. Tumor weight in mice on a tryptophan-deficient diet was half that of the control group, while the addition of IAA and ILA significantly increased tumor weight. Consistently, the expression of immune factors and pro-cancer genes changed in response to dietary alterations.

Impact on the prognosis of pancreatic cancer patients

Analyzing single-cell sequencing results from tumor patients and TCGA data, researchers found that patients with high AhR expression had poorer survival, with AhR showing a negative correlation with genes associated with CD8+T cells. Human pancreatic cancer cell experiments validated AhR’s promotion of pancreatic cancer cell growth.


Conclusion

While most research has focused on the positive regulatory effects of microbiota on tumors, this study sheds light on the negative immune regulation of intestinal microbiota on tumors.

It challenges preconceived notions about the positive effects of probiotics in the gut, demonstrating that lactic acid bacteria, by metabolizing tryptophan, activate tumor-associated macrophages through AhR, ultimately promoting pancreatic cancer growth and disrupting immune checkpoint inhibition.

Pancreatic cancer, often dubbed the “king of cancers,” has posed challenges to researchers and medical professionals due to its poor treatment outcomes and low survival rates.

The team is collaborating with clinical practitioners to conduct relevant clinical experiments, believing that dietary adjustments or effective inhibitors could improve the survival outcomes of pancreatic cancer patients in the near future.

Probiotics Linked to Immune Suppression and Tumor Growth

Reference:

  1. https://doi.org/10.1016/j.immuni.2022.01.006

  2. DOI:10.1038/s41573-019-0016-5

(source:internet, reference only)


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