Thursday, December 3, 2015
The microbiome and its pharmacological targets: therapeutic avenues in cardiometabolic diseases
Cardiometabolic diseases (CMD) present a complex array of interrelated risk factors affecting more than one billion people with a dramatic impact on mortality, morbidity and quality of life. These factors (including impaired glucose tolerance, dyslipidemia, arterial hypertension, insulin resistance and central obesity) are epidemiologically clustered — the presence of at least three of five of these symptoms corresponding to the ‘metabolic syndrome’ clinical diagnosis. Although many pharmacological mechanisms have been suggested, the underlying causes of CMD and its potential therapeutic avenues remain to be fully explored. With the advent of high-throughput methodologies (metagenomics, metabolomics), the gut microbiome emerged as one of the key drivers for CMD. The gut ecosystem, as well as its individual members, was shown to contribute to the host metabolism. A lower bacterial gene count (LGC) is associated to increased adiposity, insulin resistance and dyslipidemia and dietary intervention can improve both bacterial gene richness and clinical metabolic outcomes. Patients with type 2 diabetes (T2D) also show specific compositional and functional changes in their metagenomes.
With the increasing number of clinical studies reporting associations between the composition of the gut microbiota and CMD outcomes, one question arises — how are these changes in microbial ecology translated into pharmacological messages to the mammalian host? Consisting of trillions of non-pathogenic bacteria living in a symbiotic relationship with their host, gut microbiota produces several signalling molecules (e.g., LPS, peptidoglycans, but also metabolites) that bind host proteins and impact signalling networks, therefore playing a central role as chemical messengers in the microbial–mammalian crosstalk. The identification of the pharmacological targets and signalling pathways of these metabolites is key to a better understanding the molecular crosstalk supporting the microbial–mammalian metabolic axis — and provides a suitable framework for the discovery of the mechanistic basis of these associations. In this context, fine mapping of the microbial signalling metabolome and its host molecular targets opens up novel pharmacological avenues for microbiome interventions.
Modulation of GLP-1 signalling is one of the possible routes through which prebiotics participate in the control of obesity and associated disorders. Treatment with the prebiotic oligofructose increases the total number of GLP-1 expressing cells in the colon of male Wistar rats. Interestingly, butyrate stimulates the production of GLP-1 in intestinal cells, highlighting that gut microbial modulation with prebiotics promotes the growth of butyrate-producing bacteria, thus increasing GLP-1 production. In general the beneficial effects of prebiotic and probiotics have been attributed to the increased SCFA production.
Faecal microbiota transplantation (FMT) was suggested as a strategy to transfer an ecologically stable bacterial community with beneficial properties. Studies on animal models demonstrated that murine microbiomes could be transplanted to impact body weight and that the architecture of the microbiome in obese mice matches the observations in obese patients. However, the effect of microbiome transplantations can be mitigated by environmental influences such as co-housing for animal models.
Vrieze et al. showed that transplanting patients with metabolic syndrome with intestinal content from lean donors resulted in an improvement of both insulin sensitivity and levels of butyrate-producing intestinal microbiota (Roseburia intestinalis and Eubacterium hallii). Hence, it can be speculated that this untargeted approach might be considered as a potential therapeutic strategy for glucose impairment disorders in humans.
Metabolomic approaches allowed the identification and monitoring of microbial metabolites as potential risk markers for CMD. However, the gut microbiota is a dynamic ecological community deeply affected by external stimuli and the causality of these correlations must be interpreted cautiously. A more complete understanding of the targets and pathways of these metabolites is therefore crucial, placing the study of the pharmacology of the microbial–mammalian interaction as one of the most relevant areas of future research in CMD. The microbial metabolites addressed exemplify the broad scope of the interaction between the gut microbiota and its mammalian host, and their potential to influence key mechanisms of CMD (e.g., glucose homeostasis, lipid homeostasis, inflammation, gut barrier integrity). Revisiting the pharmacology of these four classes of metabolites reveals the tip of the iceberg of the mammalian–microbial pharmacological interaction — and suggests how potentially powerful could be the plethora of metabolites that have been identified, but whose targets and signalling pathways remain to be fully understood. The modification of the gut microbiota, its metabolites and pharmacological targets arises therefore as a promising therapeutic avenue. As novel and powerful analytical methods provide a clearer understanding complexity of this interaction, specific interventions might be designed for personalized healthcare approaches.