The chemical interactome space between the human host and the genetically defined gut metabotypes

The bacteria that colonize the gastrointestinal tracts of mammals represent a highly selected microbiome that has a profound influence on human physiology by shaping the host's metabolic and immune system activity. Despite the recent advances on the biological principles that underlie microbial symbiosis in the gut of mammals, mechanistic understanding of the contributions of the gut microbiome and how variations in the metabotypes are linked to the host health are obscure. Here, we mapped the entire metabolic potential of the gut microbiome based solely on metagenomics sequencing data derived from fecal samples of 124 Europeans (healthy, obese and with inflammatory bowel disease). Interestingly, three distinct clusters of individuals with high, medium and low metabolic potential were observed. By illustrating these results in the context of bacterial population, we concluded that the abundance of the Prevotella genera is a key factor indicating a low metabolic potential. These metagenome-based metabolic signatures were used to study the interaction networks between bacteria-specific metabolites and human proteins. We found that thirty-three such metabolites interact with disease-relevant protein complexes several of which are highly expressed in cells and tissues involved in the signaling and shaping of the adaptive immune system and associated with squamous cell carcinoma and bladder cancer. From this set of metabolites, eighteen are present in DrugBank providing evidence that we carry a natural pharmacy in our guts. Furthermore, we established connections between the systemic effects of non-antibiotic drugs and the gut microbiome of relevance to drug side effects and health-care solutions.link_to_subscribed_fulltex

Simvastatin suppresses the differentiation of C2C12 myoblast cells via a Rac pathway.

Statins, which are known as cholesterol-lowering drugs, have several additional effects including the enhancement of bone formation and the stimulation of smooth muscle cell proliferation. In this study, we investigated the signal pathway of simvastatin operating in C2C12 myoblast cells. Myotube formation of C2C12 cells was efficiently blocked by 1 muM simvastatin, and mevalonic acid was able to cancel this effect. Geranylgeranyl pyrophosphate restored the myotube formation, whereas farnesyl pyrophosphate did not. These findings demonstrate that the Rho family, such as Rho, Rac and Cdc42, occurring downstream of geranylgeranyl pyrophosphate in the mevalonic acid pathway, was involved in the simvastatin-mediated blockage of myotube formation. An inhibitor of Rho kinase did not influence the myotube formation; whereas an inhibitor of Rac blocked this process. Taken together, we conclude that the differentiation of C2C12 cells into myotubes was blocked by simvastatin through the pathway mediated by Rac, not by Rho

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1α, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins