# Adipokine Metabolic Drivers, Gut Dysbiosis, and the Prostate Microbiome: Novel Pathway Enrichment Analysis of the Adiposity-Based Chronic Disease—Prostate Cancer Network

## TL;DR

This paper explores how excess body fat and gut bacteria contribute to prostate cancer through chronic inflammation and identifies new molecular pathways linking these factors.

## Contribution

A novel pathway enrichment analysis reveals how gut dysbiosis and adiposity-based inflammation may drive prostate cancer development.

## Key findings

- Excess adiposity and gut dysbiosis are linked to prostate cancer via chronic inflammation and specific molecular pathways.
- Key inflammatory molecules like MCP-1, IL-1β, and CXCL-1 are central to the ABCD-prostate cancer network.
- Pathway enrichment analysis identified extracellular and intracellular signaling pathways connecting gut bacteria and prostate inflammation.

## Abstract

Excess Adiposity and Adiposity-Based Chronic Disease (ABCD) is a worldwide epidemic that has been linked to several cancers, including prostate cancer. One of the principal drivers is thought to be the development of chronic inflammation from visceral white adipose tissue, but a recent paper from our group that focused on prostate cancer and used network topology and gene set enrichment analysis of relevant metabolic drivers highlighted an additional source of inflammation relating to dietary exposure to lipopolysaccharides and bacterial exposure from gut and prostatic bacteria. This narrative review investigates the interplay between inflammatory signaling and exposure to gut and prostate bacteria and performs a novel pathway enrichment analysis on prominent inflammatory pathways to further unravel how excess adiposity can increase prostate cancer risk over a man’s life. Our findings support a novel molecular pathway for the development of prostate cancer linking excess adiposity, gut dysbiosis, and both systemic and local inflammation.

Adiposity-Based Chronic Disease (ABCD) is known to increase the risk of aggressive prostate cancer (PCa), recurrent disease after treatment for localized PCa, and PCa mortality. A key mechanistic link contributing to this enhanced risk is chronic inflammation originating from excess white visceral adipose tissue (WAT; VAT) and periprostatic adipose tissue (ppWAT). Contributing to systemic inflammation is gut dysbiosis, which itself may be caused by ABCD as well as background local inflammation (prostatitis), which is common in aging men and may be exacerbated by the urinary microbiome. Investigating the molecular biology driving inflammation and its association with increased PCa risk, a recent paper applied a network and gene set enrichment to adipokine drivers in the ABCD-PCa network. It found prominent roles for MCP-1, IL-1β, and CXCL-1 in addition to confirming the importance of exposure to lipopolysaccharides and bacterial components, corroborating the role of gut dysbiosis. To further unravel the mechanistic links between ABCD and PCa risk, this critical review will discuss the current literature on prominent inflammatory signaling pathways activated in ABCD; the influence of gut dysbiosis, the urinary microbiome, and chronic prostatitis; and current hypotheses on how these domains may result in the development of aggressive PCa over a man’s life. Moreover, we performed a novel pathway enrichment analysis to further evaluate the associations between ABCD, PCa risk, gut dysbiosis, and the prostate microbiome, the results of which were partitioned into extracellular and intracellular signaling pathways. In the extracellular space, novel mechanistic links between gut dysbiosis and MCP-1, IL-1β, CXCL1, and leptin via bacterial pathogen signaling and the intestinal immune network (for IgA production), crucial for gut immune homeostasis, were found. Within the intracellular space, there were downstream signals activating chemokine and type 2 interferon pathways, focal adhesion PI3K/Akt/mTOR pathways, as well as the JAK/STAT, NF-κB, and PI3K/Akt pathways. Overall, these findings point to an emerging molecular pathway for PCa oncogenesis influenced by ABCD, gut dysbiosis, and inflammation, and further research, possibly with lifestyle program-based clinical trials, may discover novel biomarker panels and molecular targeted therapies for the prevention and treatment of PCa.