Abstract
The incidence and prevalence of inflammatory disorders have increased globally, and is projected to double in the next decade. Gut microbiome-based therapeutics have shown promise in ameliorating chronic inflammation. However, they are largely experimental, context- or strain-dependent and lack a clear mechanistic basis. This hinders precision probiotics and poses significant risk, especially to individuals with pre-existing conditions. Molecules secreted by gut microbiota act as ligands to several health-relevant receptors expressed in human gut, such as the G-protein coupled receptors (GPCRs), Toll-like receptor 4 (TLR4), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AhR). Among these, the human AhR expressed in different tissues exhibits anti-inflammatory effects and shows activity against a wide range of ligands produced by gut bacteria. However, different AhR ligands induce varying host responses and signaling in a tissue/organ-specific manner, which remain mostly unknown. The emerging systems biology paradigm, with its powerful in silico tool repertoire, provides opportunities for comprehensive and high-throughput strain characterization. In particular, combining metabolic models with machine learning tools can be useful to delineate tissue and ligand-specific signaling and thus their causal mechanisms in disease and health. The knowledge of such a mechanistic basis is indispensable to account for strain heterogeneity and actualize precision probiotics.
Highlights
The human gut microbiome has attracted attention in the past decade for its role in inflammatory disorders (Kamada et al, 2013)
This approach has been successful in recommending candidate strains to promote gut health, the absence of a mechanistic basis limits their application to “generic” probiotic supplements
Inflammatory disorders such as inflammatory bowel disease (IBD) and colorectal cancer, being complex manifestations of unhealthy gut and microbiota dysbiosis extensively depend on host-genetic, age, diet and other environmental factors, require precision probiotic targeting
Summary
The human gut microbiome has attracted attention in the past decade for its role in inflammatory disorders (Kamada et al, 2013). Small molecules produced by the microbiota in gut environment interact with the host cell lining in intestine and enter the blood circulation and access receptors expressed in most human organs. Such interactions play a wide array of roles in health and disease, ranging from intestinal homeostasis, dysbiosis, inflammation and cancer. The human receptors such as GPCRs, PXR, and TLRs have been shown to play an important role in gut-microbiome mediated immunomodulation including their anti-inflammatory roles (Valentini et al, 2014; Venkatesh et al, 2014; Chen et al, 2019; Melhem et al, 2019). Tools to simulate genome-scale metabolism of microbiome and hosts and their interactions https://github.com/SysBioChalmers/RAVEN http://opencobra.github.io/
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