Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal ...barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2−/−) mice showed a distinctly “leaky” gut physiology coupled with upregulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2−/−Tlr4−/− mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway that involves luminal sensing and signaling by TLR4.
•Pregnane X receptor (PXR) is a physiologic regulator of intestinal permeability•Microbial-derived indoles can regulate intestinal barrier function through PXR•PXR regulates intestinal barrier function through TLR4•Specific indole-producing bacteria can reduce intestinal inflammation
How commensal microbial metabolites affect mucosal integrity and barrier function is unclear. Mani and colleagues show that indole 3 propionic acid regulates intestinal barrier permeability through the PXR-TLR4 pathway.
The symbiotic gut microbiota modulate health and disease of the host through a series of transgenomic metabolic and immune regulatory axes. We explore connections between microbiome composition and ...function related to individual metabolic phenotypes and consider these interactions as possible targets for developing new personalized therapies and clinical management strategies.
Abstract The gut microbiota have both direct and indirect effects on drug and xenobiotic metabolism and this can have consequences for both efficacy and toxicity. Indeed microbiome-driven drug ...metabolism is essential for the activation of certain prodrugs such as e.g., azo drugs such as prontosil and neoprontosil resulting in the release of sulphanilamide. In addition to providing a major source of reductive metabolizing capability the gut microbiota provide a suite of additional reactions including acetylation/deacylation decarboxylation, dehydroxylation, demethylation, dehalogenation and importantly, in the context of certain types of drug-related toxicity, conjugate hydrolysis reactions. In addition to direct effects the gut microbiota can affect drug metabolism and toxicity indirectly via e.g., the modulation of host drug metabolism and disposition and competition of bacterial-derived metabolites for xenobiotic metabolism pathways. And, of course, the therapeutic drugs themselves can have effects, both intended and unwanted, which can impact on the health and composition of the gut microbiota with unforeseen consequences.
The human gut microbiome is known to be associated with various human disorders, but a major challenge is to go beyond association studies and elucidate causalities. Mathematical modeling of the ...human gut microbiome at a genome scale is a useful tool to decipher microbe-microbe, diet-microbe and microbe-host interactions. Here, we describe the CASINO (Community And Systems-level INteractive Optimization) toolbox, a comprehensive computational platform for analysis of microbial communities through metabolic modeling. We first validated the toolbox by simulating and testing the performance of single bacteria and whole communities in vitro. Focusing on metabolic interactions between the diet, gut microbiota, and host metabolism, we demonstrated the predictive power of the toolbox in a diet-intervention study of 45 obese and overweight individuals and validated our predictions by fecal and blood metabolomics data. Thus, modeling could quantitatively describe altered fecal and serum amino acid levels in response to diet intervention.
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•Community And Systems-level INteractive Optimization toolbox•Modeling the effect of diet and gene richness on the gut microbiota•Revealing altered amino acid and SCFA levels after diet interventions
Shoaie et al. describe a computational platform designed to elucidate the complex metabolic interactions between gut microbes, host, and diet. The model predictions are validated in humans and reveal how microbial gene richness and diet affect gut microbiota composition, as well as amino acid and SCFA levels.
Host-Gut Microbiota Metabolic Interactions Nicholson, Jeremy K.; Holmes, Elaine; Kinross, James ...
Science (American Association for the Advancement of Science),
06/2012, Letnik:
336, Številka:
6086
Journal Article
Recenzirano
Odprti dostop
The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut ...microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.
Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of ...anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.
While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by ...tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene
knockout (KO) mutant
unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR
) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of
,
, and
genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
The human gut harbors more than 100 trillion microbial cells, which have an essential role in human metabolic regulation via their symbiotic interactions with the host. Altered gut microbial ...ecosystems have been associated with increased metabolic and immune disorders in animals and humans. Molecular interactions linking the gut microbiota with host energy metabolism, lipid accumulation, and immunity have also been identified. However, the exact mechanisms that link specific variations in the composition of the gut microbiota with the development of obesity and metabolic diseases in humans remain obscure owing to the complex etiology of these pathologies. In this review, we discuss current knowledge about the mechanistic interactions between the gut microbiota, host energy metabolism, and the host immune system in the context of obesity and metabolic disease, with a focus on the importance of the axis that links gut microbes and host metabolic inflammation. Finally, we discuss therapeutic approaches aimed at reshaping the gut microbial ecosystem to regulate obesity and related pathologies, as well as the challenges that remain in this area.
Analyzing metabolites (small molecules <1 kDa) in body fluids such as urine and plasma using various spectroscopic methods provides information on the metabotype (metabolic phenotype) of individuals ...or populations, information that can be applied to personalized medicine or public healthcare.
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