Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation.

Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1ß and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions.

Smoking-induced microbial dysbiosis in health and disease.

Smoking is associated with an increased risk of cancer, pulmonary and cardiovascular diseases, but the precise mechanisms by which such risk is mediated remain poorly understood. Additionally, smoking can impact the oral, nasal, oropharyngeal, lung and gut microbiome composition, function, and secreted molecule repertoire. Microbiome changes induced by smoking can bear direct consequences on smoking-related illnesses. Moreover, smoking-associated dysbiosis may modulate weight gain development following smoking cessation. Here, we review the implications of cigarette smoking on microbiome community structure and function. In addition, we highlight the potential impacts of microbial dysbiosis on smoking-related diseases. We discuss challenges in studying host-microbiome interactions in the context of smoking, such as the correlations with smoking-related disease severity versus causation and mechanism. In all, understanding the microbiome's role in the pathophysiology of smoking-related diseases may promote the development of rational therapies for smoking- and smoking cessation-related disorders, as well as assist in smoking abstinence.

Time-limited diets and the gut microbiota in cardiometabolic disease.

In recent years, intermittent fasting (IF), including periodic fasting and time-restricted feeding (TRF), has been increasingly suggested to constitute a promising treatment for cardiometabolic diseases (CMD). A deliberate daily pause in food consumption influences the gut microbiome and the host circadian clock, resulting in improved cardiometabolic health. Understanding the molecular mechanisms by which circadian host-microbiome interactions affect host metabolism and immunity may add a potentially important dimension to effective implementation of IF diets. In this review, we discuss emerging evidence potentially linking compositional and functional alterations of the gut microbiome with IF impacts on mammalian metabolism and risk of development of hypertension, type 2 diabetes (T2D), obesity, and their long-term micro- and macrovascular complications. We highlight the challenges and unknowns in causally linking diurnal bacterial signals with dietary cues and downstream metabolic consequences and means of harnessing these signals toward future microbiome integration into precision medicine.

Utilization of Host and Microbiome Features in Determination of Biological Aging.

The term 'old age' generally refers to a period characterized by profound changes in human physiological functions and susceptibility to disease that accompanies the final years of a person's life. Despite the conventional definition of old age as exceeding the age of 65 years old, quantifying aging as a function of life years does not necessarily reflect how the human body ages. In contrast, characterizing biological (or physiological) aging based on functional parameters may better reflect a person's temporal physiological status and associated disease susceptibility state. As such, differentiating 'chronological aging' from 'biological aging' holds the key to identifying individuals featuring accelerated aging processes despite having a young chronological age and stratifying them to tailored surveillance, diagnosis, prevention, and treatment. Emerging evidence suggests that the gut microbiome changes along with physiological aging and may play a pivotal role in a variety of age-related diseases, in a manner that does not necessarily correlate with chronological age. Harnessing of individualized gut microbiome data and integration of host and microbiome parameters using artificial intelligence and machine learning pipelines may enable us to more accurately define aging clocks. Such holobiont-based estimates of a person's physiological age may facilitate prediction of age-related physiological status and risk of development of age-associated diseases.

Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry.

Targeted covalent inhibitors are an important class of drugs and chemical probes. However, relatively few electrophiles meet the criteria for successful covalent inhibitor design. Here we describe α-substituted methacrylamides as a new class of electrophiles suitable for targeted covalent inhibitors. While typically α-substitutions inactivate acrylamides, we show that hetero α-substituted methacrylamides have higher thiol reactivity and undergo a conjugated addition-elimination reaction ultimately releasing the substituent. Their reactivity toward thiols is tunable and correlates with the pKa/pKb of the leaving group. In the context of the BTK inhibitor ibrutinib, these electrophiles showed lower intrinsic thiol reactivity than the unsubstituted ibrutinib acrylamide. This translated to comparable potency in protein labeling, in vitro kinase assays, and functional cellular assays, with improved selectivity. The conjugate addition-elimination reaction upon covalent binding to their target cysteine allows functionalizing α-substituted methacrylamides as turn-on probes. To demonstrate this, we prepared covalent ligand directed release (CoLDR) turn-on fluorescent probes for BTK, EGFR, and K-RasG12C. We further demonstrate a BTK CoLDR chemiluminescent probe that enabled a high-throughput screen for BTK inhibitors. Altogether we show that α-substituted methacrylamides represent a new and versatile addition to the toolbox of targeted covalent inhibitor design.