PAGln in Gut Microbiome Represents Potential Link to Lethal Prostate Cancer

Men with diet-associated molecules in the gut may be at a higher risk for lethal prostate cancer, according to results from a prospective analysis of a PLCO (prostate, lung, colorectal, and ovarian) prostate cancer screening cohort of the PLCO cancer screening trial (NCT00002540).¹

Men with elevated levels of phenylacetylglutamine (PAGln) were 2 to 3 times more likely to receive a diagnosis of lethal prostate cancer, said Nima Sharifi, MD, PLCO corresponding author. He added PAGln is linked to animal-based food products, such as meat.

“The gut microbiome may make a real contribution to the development of lethal prostate cancer. The interaction with dietary intake and other factors is going to be quite complex,” Sharifi said. “Although the data are quite exciting, there is much more to be worked out in terms of how these correlative data link up with exactly how they work in individual [patients].”

In an interview with OncLive^®, Sharifi, director at the Center for GU Malignancies Research, Lerner Research Institute at the Cleveland Clinic, discussed the results of the prostate cancer cohort in the PLCO trial and how PAGln could be linked to patients eventually diagnosed with lethal prostate cancer.

OncLive^®: Can you describe the rationale for this study investigating the link between gut microbiome and aggressive prostate cancer?

We don’t understand the causes of prostate cancer [or] lethal prostate cancer. It's a mixture of genetic or inherited, [plus] environmental, factors. We have to parse that out, and all of the contributing factors are not well known.

The other factor, in terms of the rationale, is that we know that not all prostate cancers are bad actors. Prostate cancer is a common disease, and we know that a fraction of prostate cancers ends up becoming lethal. There’s another fraction that doesn’t have to be treated, and it’s more indolent. How do we distinguish between these 2 and what are the etiologies of these 2?

What did investigators use methodologies in this trial?

The intent for the study was to figure out what are the metabolites in circulation that either come from diet or are a function of diet and the gut microbiome that are linked to the eventual development of lethal prostate cancer.

We took advantage of a PLCO prostate cancer–screening cohort. The advantage here was that it was a prospective study. We also had biospecimens from before men were diagnosed with prostate cancer. Effectively, we took a cohort of men who were eventually diagnosed with prostate cancer that became lethal, and compared them to men who were not diagnosed with lethal prostate cancer. We looked at circulating metabolites that were present before any of this. There was a range of samples, but they were about 20 years old.

What were the results of the study?

To set the stage, what we knew prior to the study was that there is population-level evidence that suggests there is a link between animal product intake, meat intake, and prostate cancer. But the exact mechanisms and the role of the gut microbiome in processing nutritional intake were not well worked out.

What was surprising was that we found a strong signal between a particular metabolite that results from ingestion of a specific amino acid, phenylalanine, [that] is converted to a gut microbiome–dependent metabolite. You ingest meat or animal product, and that’s converted by the gut microbiome to a specific metabolite called phenylacetylglutamine [PAGln].

There was a strong link between that metabolite and the risk of developing lethal prostate cancer. I should add that it's not just a metabolite itself. In the prior year, another investigator at Cleveland Clinic, Stanley L. Hazen, MD, PhD, who was a collaborator on this study, identified the activity of this metabolite and its link to cardiovascular disease.²

Specifically, it ends up stimulating the adrenergic system. You can think of this as the stress system that has clear links to cardiovascular disease. This link to prostate cancer and lethal prostate cancer is surprising, not only for the fact that that metabolite is there in men who develop lethal prostate cancer, but we know something about how it works and it seems to work through the adrenergic nervous system.

Are there any next steps to take with this research?

There are a variety of things that can be done with this, from doing other prospective studies of nutritional intake manipulation of the gut microbiome to understanding the mechanisms for how this works and how this may link up to the adrenergic system. There are pharmacologic modalities of blocking the action of PAGln [by utilizing] adrenergic blockade. These are drugs that are used commonly, [though] not for prostate cancer, but it makes sense to think about how we test this more mechanistically at the patient level.

What kind of impact can this data have for the patient population? What should patients and care providers know about this topic?

This builds upon the data confirming a link between certain dietary intake, [specifically] meat and animal products, and risk of developing not just prostate cancer, but also lethal prostate cancer. At the next level, it tells us this is more complex than just what you eat. It is also reliant, or seems to be, on how your gut microbiome metabolically converts what you eat into other products, some of which may be beneficial and others that are potentially harmful.

What would be a take home message from these results?

The gut microbiome may make a real contribution to the development of lethal prostate cancer. The interaction with dietary intake and other factors is going to be quite complex. Although the data are quite exciting, there is much more to be worked out in terms of how these correlative data link up with exactly how they work in individual [patients].

Reference

1. Reichard CA, Naelitz BD, Wang Z, et al. Gut microbiome-dependent metabolic pathways and risk of lethal prostate cancer: prospective analysis of a PLCO cancer screening trial cohort. Cancer Epidemiol Biomarkers Prev. 2022;31(1):192-199. doi: 10.1158/1055-9965.EPI-21-0766
2. Nemet I, Sahad PP, Gupta N, et al. A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. Cell. March 5, 2020. https://doi.org/10.1016/j.cell.2020.02.016