Network Analysis of Gut Microbiome and Metabolome to Discover Microbiota-Linked Biomarkers in Patients Affected by Non-Small Cell Lung Cancer

Abstract

Several studies in recent times have linked gut microbiome (GM) diversity to the pathogenesis of cancer and its role in disease progression through immune response, inflammation and metabolism modulation. This study focused on the use of network analysis and weighted gene co-expression network analysis (WGCNA) to identify the biological interaction between the gut ecosystem and its metabolites that could impact the immunotherapy response in non-small cell lung cancer (NSCLC) patients undergoing second-line treatment with anti-PD1. Metabolomic data were merged with operational taxonomic units (OTUs) from 16S RNA-targeted metagenomics and classified by chemometric models. The traits considered for the analyses were: (i) condition: disease or control (CTRLs), and (ii) treatment: responder (R) or non-responder (NR). Network analysis indicated that indole and its derivatives, aldehydes and alcohols could play a signaling role in GM functionality. WGCNA generated, instead, strong correlations between short-chain fatty acids (SCFAs) and a healthy GM. Furthermore, commensal bacteria such as Akkermansia muciniphila, Rikenellaceae, Bacteroides, Peptostreptococcaceae, Mogibacteriaceae and Clostridiaceae were found to be more abundant in CTRLs than in NSCLC patients. Our preliminary study demonstrates that the discovery of microbiota-linked biomarkers could provide an indication on the road towards personalized management of NSCLC patients.

The Role of Gut Microbiota in Lung Cancer: From Carcinogenesis to Immunotherapy

“…Although few studies have been conducted on the characteristics of the intestinal flora of patients with lung cancer, similar acknowledgments have been achieved. The intestinal flora of patients with lung cancer is mainly characterized by significant changes in its composition and function, primarily manifested by a reduction in intestinal microbial diversity and a reduction in metabolic-related biological activities compared with healthy subjects ( 1 , 16 , 24 , 52 , 53 ). Many specific changes in intestinal bacterial composition ( Table 1 ) and metabolism ( Table 2 ) are closely related to lung cancer.…”

The Comprehensive “Omics” Approach from Metabolomics to Advanced Omics for Development of Immune Checkpoint Inhibitors: Potential Strategies for Next Generation of Cancer Immunotherapy

“…Some studies applied GC-MS/SPME-based metabolomics for the detection of volatile organic compounds (VOCs) and NMR-based metabolomics for non-VOCs to investigate the gut metabolome involved in nivolumab treatment for NSCLC. These studies introduced metabolomic approaches and their network analysis as promising strategies for the management of cancer patients and prediction of good responders using microbiota-linked indicators [99,100]. In addition, another study proposed integrated parameters, including gut metabolites and immunological molecules from serum and stool for identification of nivolumab responders before treatment [101].…”

“…For example, the specific gut microbiome of nivolumab and pembrolizumab responders was identified, while the synergistic effect of anti-PD-1 and B. bifidum strains reportedly reduced cancer growth by modulating the production of IFN-γ by intensifying biosynthesis of immune-stimulating metabolites [102,113]. The development of techniques and information regarding how the microbiome interacts with ICIs have promoted the discovery of microbiota-linked biomarkers for response prediction of ICIs (e.g., indole, aldehydes, and short-chain fatty acids), which could be a promising target for precision medicine [99].…”

A Perspective on the Role of Microbiome for Colorectal Cancer Treatment

“…Probiotics are defined by the World Health Organisation as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” [ 94 ]. As a novel approach to augment cancer therapy, they are thought to improve the diversity profile of the intestinal microbiota and reduce the extent of chronic inflammation and production of carcinogenic material in dysbiosis [ 2 , 95 , 96 ].…”