The human gastrointestinal tract is home to an incredibly dense population of microbes. These microbes employ unique strategies to capture energy in this largely anaerobic environment. In the process ...of breaking down dietary- and host-derived substrates, the gut microbiota produce a broad range of metabolic products that accumulate to high levels in the gut. Increasingly, studies are revealing that these chemicals impact host biology, either by acting on cells within the gastrointestinal tract or entering circulation and exerting their effects at distal sites within the body. Given the high level of functional diversity in the gut microbiome and the varied diets that we consume, the repertoire of microbiota-derived molecules within our bodies varies dramatically across individuals. Thus, the microbes in our gut and the metabolic end products they produce represent a phenotypic lever that we can potentially control to develop new therapeutics for personalized medicine. Here, we review current understanding of how microbes in the gastrointestinal tract contribute to the molecules within our gut and those that circulate within our bodies. We also highlight examples of how these molecules affect host physiology and discuss potential strategies for controlling their production to promote human health and to treat disease.
Gut microorganisms modulate host phenotypes and are associated with numerous health effects in humans, ranging from host responses to cancer immunotherapy to metabolic disease and obesity. However, ...difficulty in accurate and high-throughput functional analysis of human gut microorganisms has hindered efforts to define mechanistic connections between individual microbial strains and host phenotypes. One key way in which the gut microbiome influences host physiology is through the production of small molecules
, yet progress in elucidating this chemical interplay has been hindered by limited tools calibrated to detect the products of anaerobic biochemistry in the gut. Here we construct a microbiome-focused, integrated mass-spectrometry pipeline to accelerate the identification of microbiota-dependent metabolites in diverse sample types. We report the metabolic profiles of 178 gut microorganism strains using our library of 833 metabolites. Using this metabolomics resource, we establish deviations in the relationships between phylogeny and metabolism, use machine learning to discover a previously undescribed type of metabolism in Bacteroides, and reveal candidate biochemical pathways using comparative genomics. Microbiota-dependent metabolites can be detected in diverse biological fluids from gnotobiotic and conventionally colonized mice and traced back to the corresponding metabolomic profiles of cultured bacteria. Collectively, our microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for characterizing microorganisms and interactions between microorganisms and their host.
The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate
. Regenerative ability is influenced by both ...injury-dependent and injury-independent mechanisms
. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration
. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF)
. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenes is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.
Renal disease is growing in prevalence and has striking co-morbidities with metabolic and cardiovascular disease. Indoxyl sulfate (IS) is a toxin that accumulates in plasma when kidney function ...declines and contributes to the progression of chronic kidney disease. IS derives exclusively from the gut microbiota. Bacterial tryptophanases convert tryptophan to indole, which is absorbed and modified by the host to produce IS. Here, we identify a widely distributed family of tryptophanases in the gut commensal Bacteroides and find that deleting this gene eliminates the production of indole in vitro. By altering the status or abundance of the Bacteroides tryptophanase, we can modulate IS levels in gnotobiotic mice and in the background of a conventional murine gut community. Our results demonstrate that it is possible to control host IS levels by targeting the microbiota and suggest a possible strategy for treating renal disease.
Display omitted
•Indole-producing tryptophanases (Tnases) in Bacteroides are identified computationally•Tnase activity and its control of indoxyl sulfate (IS) levels in vivo are established•Rational diet alteration in gnotobiotic mice with a synthetic community controls IS level•Colonization with Tnase-deficient Bacteroides lowers IS in conventional mice
Devlin et al. identify a widely distributed family of indole-producing tryptophanases in commensal gut bacteria. Using this information, they engineer bacteria to control in vivo production of the downstream product, the uremic toxin indoxyl sulfate. These results suggest a new strategy for treating chronic kidney disease by targeting the microbiome.
Against Fallibilism Dodd, Dylan
Australasian journal of philosophy,
12/2011, Letnik:
89, Številka:
4
Journal Article
Recenzirano
In this paper I argue for a doctrine I call 'infallibilism', which I stipulate to mean that If S knows that p, then the epistemic probability of p for S is 1. Some fallibilists will claim that this ...doctrine should be rejected because it leads to scepticism. Though it's not obvious that infallibilism does lead to scepticism, I argue that we should be willing to accept it even if it does. Infallibilism should be preferred because it has greater explanatory power than fallibilism. In particular, I argue that an infallibilist can easily explain why assertions of 'p, but possibly not-p' (where the 'possibly' is read as referring to epistemic possibility) is infelicitous in terms of the knowledge rule of assertion. But a fallibilist cannot. Furthermore, an infallibilist can explain the infelicity of utterances of 'p, but I don't know that p' and 'p might be true, but I'm not willing to say that for all I know, p is true', and why when a speaker thinks p is epistemically possible for her, she will agree (if asked) that for all she knows, p is true. The simplest explanation of these facts entails infallibilism. Fallibilists have tried and failed to explain the infelicity of 'p, but I don't know that p', but have not even attempted to explain the last two facts. I close by considering two facts that seem to pose a problem for infallibilism, and argue that they don't.
The human gastrointestinal tract is home to a dense population of microorganisms whose metabolism impacts human health and physiology. The gut microbiome encodes millions of genes, the products of ...which endow our bodies with unique biochemical activities. In the context of drug metabolism, microbial biochemistry in the gut influences humans in two major ways: (1) by producing small molecules that modulate expression and activity of human phase I and II pathways; and (2) by directly modifying drugs administered to humans to yield active, inactive, or toxic metabolites. Although the capacity of the microbiome to modulate drug metabolism has long been known, recent studies have explored these interactions on a much broader scale and have revealed an unprecedented scope of microbial drug metabolism. The implication of this work is that we might be able to predict the capacity of an individual's microbiome to metabolize drugs and use this information to avoid toxicity and inform proper dosing. Here, we provide a tutorial of how to study the microbiome in the context of drug metabolism, focusing on in vitro, rodent, and human studies. We then highlight some limitations and opportunities for the field.
The combustion of fossil‐derived fuels has a significant impact on atmospheric carbon dioxide (CO2) levels and correspondingly is an important contributor to anthropogenic global climate change. ...Plants have evolved photosynthetic mechanisms in which solar energy is used to fix CO2 into carbohydrates. Thus, combustion of biofuels, derived from plant biomass, can be considered a potentially carbon neutral process. One of the major limitations for efficient conversion of plant biomass to biofuels is the recalcitrant nature of the plant cell wall, which is composed mostly of lignocellulosic materials (lignin, cellulose, and hemicellulose). The heteropolymer xylan represents the most abundant hemicellulosic polysaccharide and is composed primarily of xylose, arabinose, and glucuronic acid. Microbes have evolved a plethora of enzymatic strategies for hydrolyzing xylan into its constituent sugars for subsequent fermentation to biofuels. Therefore, microorganisms are considered an important source of biocatalysts in the emerging biofuel industry. To produce an optimized enzymatic cocktail for xylan deconstruction, it will be valuable to gain insight at the molecular level of the chemical linkages and the mechanisms by which these enzymes recognize their substrates and catalyze their reactions. Recent advances in genomics, proteomics, and structural biology have revolutionized our understanding of the microbial xylanolytic enzymes. This review focuses on current understanding of the molecular basis for substrate specificity and catalysis by enzymes involved in xylan deconstruction.
Enzymes that degrade dietary and host-derived glycans represent the most abundant functional activities encoded by genes unique to the human gut microbiome. However, the biochemical activities of a ...vast majority of the glycan-degrading enzymes are poorly understood. Here, we use transcriptome sequencing to understand the diversity of genes expressed by the human gut bacteria Bacteroides intestinalis and Bacteroides ovatus grown in monoculture with the abundant dietary polysaccharide xylan. The most highly induced carbohydrate active genes encode a unique glycoside hydrolase (GH) family 10 endoxylanase (BiXyn10A or BACINT_04215 and BACOVA_04390) that is highly conserved in the Bacteroidetes xylan utilization system. The BiXyn10A modular architecture consists of a GH10 catalytic module disrupted by a 250 amino acid sequence of unknown function. Biochemical analysis of BiXyn10A demonstrated that such insertion sequences encode a new family of carbohydrate-binding modules (CBMs) that binds to xylose-configured oligosaccharide/polysaccharide ligands, the substrate of the BiXyn10A enzymatic activity. The crystal structures of CBM1 from BiXyn10A (1.8 Å), a cocomplex of BiXyn10A CBM1 with xylohexaose (1.14 Å), and the CBM from its homolog in the Prevotella bryantii B14 Xyn10C (1.68 Å) reveal an unanticipated mode for ligand binding. A minimal enzyme mix, composed of the gene products of four of the most highly up-regulated genes during growth on wheat arabinoxylan, depolymerizes the polysaccharide into its component sugars. The combined biochemical and biophysical studies presented here provide a framework for understanding fiber metabolism by an important group within the commensal bacterial population known to influence human health.
Microbial inhabitants of the bovine rumen fulfil the majority of the normal caloric requirements of the animal by fermenting lignocellulosic plant polysaccharides and releasing short chain fatty ...acids that are then metabolized by the host. This process also occurs within the human colon, although the fermentation products contribute less to the overall energy requirements of the host. Mounting evidence, however, indicates that the community structure of the distal gut microbiota is a critical factor that influences the inflammatory potential of the immune system thereby impacting the progression of inflammatory bowel diseases. Non-digestible dietary fibre derived from plant material is highly enriched in the lignocellulosic polysaccharides, cellulose and xylan. Members of the Bacteroidetes constitute a dominant phylum in both the human colonic microbiome and the rumen microbial ecosystem. In the current article, we review recent insights into the molecular mechanisms for xylan degradation by rumen and human commensal members of the Bacteroidetes phylum, and place this information in the context of the physiological and metabolic processes that occur within these complex microbial environments.
The human gut microbiota produces dozens of small molecules that circulate in blood, accumulate to comparable levels as pharmaceutical drugs, and influence host physiology. Despite the importance of ...these metabolites to human health and disease, the origin of most microbially-produced molecules and their fate in the host remains largely unknown. Here, we uncover a host-microbe co-metabolic pathway for generation of hippuric acid, one of the most abundant organic acids in mammalian urine. Combining stable isotope tracing with bacterial and host genetics, we demonstrate reduction of phenylalanine to phenylpropionic acid by gut bacteria; the host re-oxidizes phenylpropionic acid involving medium-chain acyl-CoA dehydrogenase (MCAD). Generation of germ-free male and female MCAD
mice enabled gnotobiotic colonization combined with untargeted metabolomics to identify additional microbial metabolites processed by MCAD in host circulation. Our findings uncover a host-microbe pathway for the abundant, non-toxic phenylalanine metabolite hippurate and identify β-oxidation via MCAD as a novel mechanism by which mammals metabolize microbiota-derived metabolites.
PDF
