Tying the microbiome + virome to metabolic diseases like diabetes and obesity comes down to mechanism. The genes of our microbial inhabitants greatly outnumber the ~20,500 in the human genome. It follows that the majority of protein/metabolites in the human body are produced or modified by the microbiome. A growing body of research now demonstrates how many of these foreign proteins/metabolites can dysregulate human metabolic signaling pathways. Here are several of my favorite 2018 studies on the topic:

The extracellular domain of Staphylococcus aureus LtaS binds insulin and induces insulin resistance during infection

Lead author: Guang Yang, Beijing Institute of Basic Medical Sciences

Here, eLtaS, a protein created by S. aureus, prevented insulin from correctly binding its target receptor. This inhibited signaling and led mice to develop impaired glucose tolerance. The team then developed a human monoclonal antibody against eLtaS that blocked the interaction between eLtaS and insulin. This restored glucose tolerance in certain strains of S.aureus-challenged mice.

Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions.

Lead author: Ronald Kahn, Harvard Medical School

The team found that viruses carry sequences with significant homology to human insulin-like growth factors (the sequences are called viral insulin-like peptides or VILPs). In the lab, these VILPs were shown to bind human and murine insulin receptors, resulting in autophosphorylation and downstream signaling.

Paper highlight: “Furthermore, since only 2% of viruses have been sequenced, this study raises the potential for discovery of other viral hormones which, along with known virally encoded growth factors, may modify human health and disease.”

PS: This study found that a microbial metabolite can also dysregulate insulin pathway signaling.

A selective gut bacterial bile salt hydrolase alters host metabolism.

Lead author: A. Sloan Devlin, Harvard Medical School

The study found that deletion of a single Bacteriodes bacteria gene—and the bile salt hydrolase it expresses—altered (mouse) host metabolism in a manner that impacted weight gain, respiratory exchange ratios, and transcriptional changes in metabolic, circadian rhythm, and immune pathways in the gut and liver.

Study highlight: “Our results demonstrate that metabolites generated by a single microbial gene and enzymatic activity can profoundly alter host metabolism and gene expression at local and organism-level scales.”