Microbial metabolite-receptor interactions in the gut microbiome.

The gut microbiome impacts many physiological processes that greatly influence host health and disease. Metabolites produced by the gut microbiota have emerged as central players in regulating these biological pathways, often through the engagement of specific host receptors. Despite the importance of these microbial metabolites and receptors in human biology, the vast majority of these interactions remain uncharted due to the complex nature of the gut microbiome and the multitude of metabolites that these microbes produce.

Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases.

The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the host's overall bile acid pool.

Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases.

The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the host's overall bile acid pool.

Bile Salt Hydrolase Activity-Based Probes for Monitoring Gut Microbial Bile Acid Metabolism.

Bile acids are bioactive metabolites that are biotransformed into secondary bile acids by the gut microbiota, a vast consortium of microbes that inhabit the intestines. The first step in intestinal secondary bile acid metabolism is carried out by a critical enzyme, bile salt hydrolase (BSH), that catalyzes the gateway reaction that precedes all subsequent microbial metabolism of these important metabolites. As gut microbial metabolic activity is difficult to probe due to the complex nature of the gut microbiome, approaches are needed to profile gut microbiota-associated enzymes such as BSH.

Dopamine receptor D2 confers colonization resistance via microbial metabolites.

The gut microbiome has major roles in modulating host physiology. One such function is colonization resistance, or the ability of the microbial collective to protect the host against enteric pathogens, including enterohaemorrhagic Escherichia coli (EHEC) serotype O157:H7, an attaching and effacing (AE) food-borne pathogen that causes severe gastroenteritis, enterocolitis, bloody diarrhea and acute renal failure (haemolytic uremic syndrome). Although gut microorganisms can provide colonization resistance by outcompeting some pathogens or modulating host defence provided by the gut barrier and intestinal immune cells, this phenomenon remains poorly understood.

Electrostatic Interactions Dictate Bile Salt Hydrolase Substrate Preference.

The human intestines are colonized by trillions of microbes, comprising the gut microbiota, which produce diverse small molecule metabolites and modify host metabolites, such as bile acids, that regulate host physiology. Biosynthesized in the liver, bile acids are conjugated with glycine or taurine and secreted into the intestines, where gut microbial bile salt hydrolases (BSHs) deconjugate the amino acid to produce unconjugated bile acids that serve as precursors for secondary bile acid metabolites. Among these include a recently discovered class of microbially conjugated bile acids (MCBAs), wherein alternative amino acids are conjugated onto bile acids.

Chemoproteomic Approaches for Unraveling Prokaryotic Biology.

Bacteria are ubiquitous lifeforms with important roles in the environment, biotechnology, and human health. Many of the functions that bacteria perform are mediated by proteins and enzymes, which catalyze metabolic transformations of small molecules and modifications of proteins. To better understand these biological processes, chemical proteomic approaches, including activity-based protein profiling, have been developed to interrogate protein function and enzymatic activity in physiologically relevant contexts.

Shedding Light on Bacterial Physiology with Click Chemistry.

Bacteria constitute a major lifeform on this planet and play numerous roles in ecology, physiology, and human disease. However, conventional methods to probe their activities are limited in their ability to visualize and identify their functions in these diverse settings. In the last two decades, the application of click chemistry to label these microbes has deepened our understanding of bacterial physiology.

Electrostatic Interactions Dictate Bile Salt Hydrolase Substrate Preference.

The human intestines are colonized by trillions of microbes, comprising the gut microbiota, which produce diverse small molecule metabolites and modify host metabolites, such as bile acids, that regulate host physiology. Biosynthesized in the liver, bile acids are conjugated with glycine or taurine and secreted into the intestines, where gut microbial bile salt hydrolases (BSHs) deconjugate the amino acid to produce unconjugated bile acids that serve as precursors for secondary bile acid metabolites. Among these include a recently discovered class of microbially-conjugated bile acids (MCBAs), wherein alternative amino acids are conjugated onto bile acids.

Activity-based protein profiling in microbes and the gut microbiome.

Activity-based protein profiling (ABPP) is a powerful chemical approach for probing protein function and enzymatic activity in complex biological systems. This strategy typically utilizes activity-based probes that are designed to bind a specific protein, amino acid residue, or protein family and form a covalent bond through a reactivity-based warhead. Subsequent analysis by mass spectrometry-based proteomic platforms that involve either click chemistry or affinity-based labeling to enrich for the tagged proteins enables identification of protein function and enzymatic activity.

Dopamine receptor D2 confers colonization resistance via gut microbial metabolites.

The gut microbiome plays major roles in modulating host physiology. One such function is colonization resistance, or the ability of the microbial collective to protect the host against enteric pathogens, including enterohemorrhagic (EHEC) serotype O157:H7, an attaching and effacing (AE) food-borne pathogen that causes severe gastroenteritis, enterocolitis, bloody diarrhea, and acute renal failure (hemolytic uremic syndrome). Although gut microbes can provide colonization resistance by outcompeting some pathogens or modulating host defense provided by the gut barrier and intestinal immune cells, this phenomenon remains poorly understood.

BSH-TRAP: Bile salt hydrolase tagging and retrieval with activity-based probes.

Bile acids are important molecules that participate in digestion and regulate many host physiological processes, including metabolism and inflammation. Primary bile acids are biosynthesized from cholesterol in the liver, where they are conjugated to glycine and taurine before secretion into the intestines. A small fraction of these molecules remain in the gut, where they are modified by a microbial enzyme, bile salt hydrolase (BSH), which deconjugates the glycine and taurine groups.

Integrating electronic health data records to develop and validate a predictive model of hospital-acquired acute kidney injury in non-critically ill patients.

Background: Models developed to predict hospital-acquired acute kidney injury (HA-AKI) in non-critically ill patients have a low sensitivity, do not include dynamic changes of risk factors and do not allow the establishment of a time relationship between exposure to risk factors and AKI. We developed and externally validated a predictive model of HA-AKI integrating electronic health databases and recording the exposure to risk factors prior to the detection of AKI.

Methods: The study set was 36 852 non-critically ill hospitalized patients admitted from January to December 2017.

External validation of the Madrid Acute Kidney Injury Prediction Score.

Background: The Madrid Acute Kidney Injury Prediction Score (MAKIPS) is a recently described tool capable of performing automatic calculations of the risk of hospital-acquired acute kidney injury (HA-AKI) using data from from electronic clinical records that could be easily implemented in clinical practice. However, to date, it has not been externally validated. The aim of our study was to perform an external validation of the MAKIPS in a hospital with different characteristics and variable case mix.

Engineered Th17 Cell Differentiation Using a Photoactivatable Immune Modulator.

T helper 17 (Th17) cells, an important subset of CD4 T cells, help to eliminate extracellular infectious pathogens that have invaded our tissues. Despite the critical roles of Th17 cells in immunity, how the immune system regulates the production and maintenance of this cell type remains poorly understood. In particular, the plasticity of these cells or their dynamic ability to trans-differentiate into other CD4 T cell subsets remains mostly uncharacterized.

Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor.

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are associated with dysbiosis of the gut microbiome. Emerging evidence suggests that small-molecule metabolites derived from bacterial breakdown of a variety of dietary nutrients confer a wide array of host benefits, including amelioration of inflammation in IBDs. Yet, in many cases, the molecular pathways targeted by these molecules remain unknown.

Chemical Mechanisms of Colonization Resistance by the Gut Microbial Metabolome.

The gut microbiome, the collection of 100 trillion microorganisms that resides in the intestinal lumen, plays major roles in modulating host physiology. One well-established function of the gut microbiota is that of colonization resistance or the ability of the microbial collective to protect the host against enteric pathogens. Although evidence suggests that these microbes may outcompete some pathogens, there remains a lack of mechanistic understanding that underlies this competitive exclusion.

Chemoproteomic Profiling of Gut Microbiota-Associated Bile Salt Hydrolase Activity.

The metagenome of the gut microbiome encodes tremendous potential for biosynthesizing and transforming small-molecule metabolites through the activities of enzymes expressed by intestinal bacteria. Accordingly, elucidating this metabolic network is critical for understanding how the gut microbiota contributes to health and disease. Bile acids, which are first biosynthesized in the liver, are modified in the gut by enzymes expressed by commensal bacteria into secondary bile acids, which regulate myriad host processes, including lipid metabolism, glucose metabolism, and immune homeostasis.

Deciphering the Chemical Lexicon of Host-Gut Microbiota Interactions.

The human intestine harbors an immense, diverse, and critical population of bacteria that has effects on numerous aspects of host physiology, immunity, and disease. Emerging evidence suggests that many of the interactions between the host and the gut microbiota are mediated via the microbial metabolome, or the collection of small-molecule metabolites produced by intestinal bacteria. This review summarizes findings from recent work by focusing on different classes of metabolites produced by the gut microbiota and their effects in modulating host health and disease.

Chemical optogenetic modulation of inflammation and immunity.

The immune system is an essential component of host defense against pathogens and is largely mediated by inflammatory molecules produced by immune cells, such as macrophages. These inflammatory mediators are regulated at the transcriptional level by chromatin-modifying enzymes including histone deacetylases (HDACs). Here we describe a strategy to regulate inflammation and immunity with photocontrolled HDAC inhibitors, which can be selectively delivered to target cells by UV irradiation to minimize off-target effects.

Cardiovascular calcifications in chronic kidney disease: Potential therapeutic implications.

Cardiovascular (CV) calcification is a highly prevalent condition at all stages of chronic kidney disease (CKD) and is directly associated with increased CV and global morbidity and mortality. In the first part of this review, we have shown that CV calcifications represent an important part of the CKD-MBD complex and are a superior predictor of clinical outcomes in our patients. However, it is also necessary to demonstrate that CV calcification is a modifiable risk factor including the possibility of decreasing (or at least not aggravating) its progression with iatrogenic manoeuvres.

Detection of cardiovascular calcifications: Is it a useful tool for nephrologists?

Chronic kidney disease (CKD) has been used as a model and source of knowledge concerning the mechanisms, clinical relevance and accelerated progression of cardiovascular (CV) calcification, as well as its consequences in clinical practice, despite we know that it is a late secondary ossification phenomenon and only circumstantial evidence is available. In this comprehensive review, we firstly describe the types of CV calcification which affect CKD patients, and we analyse how its presence is directly associated with CV events and increased mortality in these patients. We also justify the use of CV calcification assessment in regular nephrology clinical practice, because CV calcification is an important predictor of clinical outcome in these patients.

The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition.

Given the trillions of microbes that inhabit the mammalian intestines, the host immune system must constantly maintain a balance between tolerance to commensals and immunity against pathogens to avoid unnecessary immune responses against otherwise harmless bacteria. Misregulated responses can lead to inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. The mechanisms by which the immune system maintains this critical balance remain largely undefined.