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Understanding How Microbiome Proteins Are Involved in Disease

Written by Vered Smith, Science Writer 

Researchers have developed an interaction network that can identify how commensals (such as many bacteria) are involved in disease-relevant pathways. 

In a study published in Genome Biology, researchers investigated proteins from the gut microbiome with a high genetic sequence identity to known human-protein interactors. They analysed nine metagenomic cohorts, and functionally annotated hundreds of microbiome proteins by describing their potential disease-causing mechanisms.  

Microbiome Importance in Health and Disease 

Previous metagenomic case-control studies have indicated that interactions between the microbiome and their human host are implicated in many diseases. However, there was little known about the mechanisms through which they cause these diseases, and the links between bacterial genes and human health. 

Host-microbiome protein-protein interactions (PPI) may underlie microbiome-driven disorders.  There are a few known specific examples, but the scientists wanted to research this on a much broader scale. They therefore built a putative bacteria-human protein-protein interaction (PPI) network using publicly available PPI data, and investigated the links between microbial proteins and inflammatory bowel disease (IBD), colorectal cancer (CRC), obesity, and type 2 diabetes (T2D).  

Identifying Potential Disease-Causing Mechanisms 

Human proteins that interacted with the microbiome had roles in pathways involved in the pathogenesis of IBD, CRC, obesity and T2D, including the immune system, apoptosis, oncogenesis, and endocrine signalling pathways. 

Some specific examples correlated with known molecular mechanisms involved in disease, which implicated that the microbiome may also be involved. One example is actin-related protein 2/3 complex subunit 2 (ARPc2), a protein that regulates the epithelial adherens junction remodelling. This pathway is commonly disrupted in IBD, and was associated in this study with IBD and CRC cohorts’ microbiome. DNA methyltransferase 3a (DNMT3A), a protein involved in chromatin remodelling, intestinal tumorigenesis, and mediating insulin resistance, was associated with the CRC, IBD, T2D, and obesity cohorts.  

The data suggested that there are several pathways that could allow microbe proteins to reach and interact with human proteins. The researchers proposed that these include secreted human proteins, secreted bacterial proteins, membrane vesicles and cell lysis.  

Interestingly, most microbial proteins that were functionally annotated also had a secondary ‘interspecies moonlighting’ function, usually in central metabolism or translation.  

The researchers found several examples of microbiome proteins interacting with drug target proteins. Complement C1R, the target of the anticoagulant nafamostat mesylate, was found to interact with the transcriptional regulator spo0A from Lactobacilli, Streptococci, and F. prausnitzii differentially in healthy patients. Additionally, several Src family tyrosine kinases, such as LCK and BLK, are targeted by the drug imatinib mesylate (brand name Gleevec). Bacterial proteins interacting with these kinases were enriched in IBD and CRC cohort healthy controls. 

Future Research 

Functional experiments would confirm host-microbiome PPIs and provide more details, such as whether the bacterial proteins activate or inhibit the human proteins they are interacting with. Continuing to build on this research will enable the discovery of new diagnostic and therapeutic strategies for microbiome-mediated diseases. 

Image Credit: Canva

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Gut / Microbiome / Protein