Circadian-clock-controlled endocrine and cytokine signals regulate multipotential innate lymphoid cell progenitors in the bone marrow.

Innate lymphoid cells (ILCs), strategically positioned throughout the body, undergo population declines over time. A solution to counteract this problem is timely mobilization of multipotential progenitors from the bone marrow. It remains unknown what triggers the mobilization of bone marrow ILC progenitors (ILCPs). We report that ILCPs are regulated by the circadian clock to emigrate and generate mature ILCs in the periphery. We found that circadian-clock-defective ILCPs fail to normally emigrate and generate ILCs. We identified circadian-clock-controlled endocrine and cytokine cues that, respectively, regulate the retention and emigration of ILCPs at distinct times of each day. Activation of the stress-hormone-sensing glucocorticoid receptor upregulates CXCR4 on ILCPs for their retention in the bone marrow, while the interleukin-18 (IL-18) and RORα signals upregulate S1PR1 on ILCPs for their mobilization to the periphery. Our findings establish important roles of circadian signals for the homeostatic efflux of bone marrow (BM) ILCPs.

Digital Health in Diabetes and Cardiovascular Disease.

BACKGROUND: Digital health technologies are rapidly evolving and transforming the care of diabetes and cardiovascular disease (CVD). PURPOSE OF THE REVIEW: In this review, we discuss emerging approaches incorporating digital health technologies to improve patient outcomes through a more continuous, accessible, proactive, and patient-centered approach. We discuss various mechanisms of potential benefit ranging from early detection to enhanced physiologic monitoring over time to helping shape important management decisions and engaging patients in their care. Furthermore, we discuss the potential for better individualization of management, which is particularly important in diseases with heterogeneous and complex manifestations, such as diabetes and cardiovascular disease. This narrative review explores ways to leverage digital health technology to better extend the reach of clinicians beyond the physical hospital and clinic spaces to address disparities in the diagnosis, treatment, and prevention of diabetes and cardiovascular disease. CONCLUSION: We are at the early stages of the shift to digital medicine, which holds substantial promise not only to improve patient outcomes but also to lower the costs of care. The review concludes by recognizing the challenges and limitations that need to be addressed for optimal implementation and impact. We present recommendations on how to navigate these challenges as well as goals and opportunities in utilizing digital health technology in the management of diabetes and prevention of adverse cardiovascular outcomes.

The discovery of gut microbial metabolites as modulators of host susceptibility to acetaminophen-induced hepatotoxicity.

The mammalian gut microbiota plays diverse and essential roles in modulating host physiology. Key mediators determining the outcome of the microbiota-host interactions are the small molecule metabolites produced by the gut microbiota. The liver is the organ massively exposed to gut microbial metabolites, and it serves as the nexus, maintaining healthy interactions between the gut microbiota and host. At the same time, the liver is the primary target of harmful gut microbial metabolites. This review provides an up-to-date list of gut microbial metabolites identified to increase or decrease host susceptibility to APAP-induced liver injury. Signaling pathways and molecular factors involved in the progression of APAP-induced hepatotoxicity are well-established, and we propose that the mouse model of APAP-induced hepatotoxicity serves as an excellent system for uncovering gut microbial metabolites of previously unknown function. Moreover, we envision that gut microbial metabolites identified to alter APAP-induced hepatotoxicity likely have broader implications in other liver diseases. Significance Statement This review provides an overview of recent discoveries from investigating whether and how the gut microbiota modulates the host susceptibility to APAP-induced liver injury. It focuses on the roles of gut bacterial small molecule metabolites as mediators of the interaction between the gut microbiota and the liver. It also illustrates the utility of APAP-induced liver injury as a model to identify gut microbial metabolites with biological function.

Rationale and Design of the mTECH-Rehab Randomized Controlled Trial: Impact of a Mobile Technology Enabled Corrie Cardiac Rehabilitation Program on Functional Status and Cardiovascular Health.

BACKGROUND: Cardiac rehabilitation (CR) is an evidence-based, guideline-recommended intervention for patients recovering from a cardiac event, surgery or procedure that improves morbidity, mortality, and functional status. CR is traditionally provided in-center, which limits access and engagement, most notably among underrepresented racial and ethnic groups due to barriers including cost, scheduling, and transportation access. This study is designed to evaluate the Corrie Hybrid CR, a technology-based, multicomponent health equity-focused intervention as an alternative to traditional in-center CR among patients recovering from a cardiac event, surgery, or procedure compared with usual care alone. METHODS: The mTECH-Rehab (Impact of a Mobile Technology Enabled Corrie CR Program) trial will randomize 200 patients who either have diagnosis of myocardial infarction or who undergo coronary artery bypass grafting surgery, percutaneous coronary intervention, heart valve repair, or replacement presenting to 4 hospitals in a large academic health system in Maryland, United States, to the Corrie Hybrid CR program combined with usual care CR (intervention group) or usual care CR alone (control group) in a parallel arm, randomized controlled trial. The Corrie Hybrid CR program leverages 5 components: (1) a patient-facing mobile application that encourages behavior change, patient empowerment, and engagement with guideline-directed therapy; (2) Food and Drug Administration-approved smart devices that collect health metrics; (3) 2 upfront in-center CR sessions to facilitate personalization, self-efficacy, and evaluation for the safety of home exercise, followed by a combination of in-center and home-based sessions per participant preference; (4) a clinician dashboard to track health data; and (5) weekly virtual coaching sessions delivered over 12 weeks for education, encouragement, and risk factor modification. The primary outcome is the mean difference between the intervention versus control groups in distance walked on the 6-minute walk test (ie, functional capacity) at 12 weeks post randomization. Key secondary and exploratory outcomes include improvement in a composite cardiovascular health metric, CR engagement, quality of life, health factors (including low-density lipoprotein-cholesterol, hemoglobin A1c, weight, diet, smoking cessation, blood pressure), and psychosocial factors. Approval for the study was granted by the local institutional review board. Results of the trial will be published once data collection and analysis have been completed. CONCLUSIONS: The Corrie Hybrid CR program has the potential to improve functional status, cardiovascular health, and CR engagement and advance equity in access to cardiac rehabilitation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05238103.

Retinoic Acid Signaling Is Required for Dendritic Cell Maturation and the Induction of T Cell Immunity.

Vitamin A and its biologically active metabolites, all-trans and 9-cis retinoic acid (RA), are thought to be important in generating and modulating immune function. However, RA modulates the function of many types of immune cells, and its specific role in dendritic cell (DC) activation, Ag presentation, and T cell effector function has not been fully characterized. Because RA works primarily through RA receptor (RAR)α, we examined mice with a myeloid cell-specific defect in RA signaling. These transgenic mice have a CD11c-cre-driven expression of a truncated form of RARα that specifically blocks the signaling of all forms of RARs in myeloid cells. This defect results in abnormal DC function, with impaired DC maturation and activation, and reduced Ag uptake and processing. These DC abnormalities were associated with a reduced ability to mount Ag-specific T cell responses to immunization despite having normally functioning T cells. In contrast, the loss of DC-specific RA signaling did not significantly alter levels of Ag-specific Abs postimmunization and resulted in an increase in bronchial IgA. Our findings indicate that RA signaling in DCs is crucial for immune activation, and its absence impairs the development of Ag-specific effector functions of T cell immunity.

Complex regulatory effects of gut microbial short-chain fatty acids on immune tolerance and autoimmunity.

Immune tolerance deletes or suppresses autoreactive lymphocytes and is established at multiple levels during the development, activation and effector phases of T and B cells. These mechanisms are cell-intrinsically programmed and critical in preventing autoimmune diseases. We have witnessed the existence of another type of immune tolerance mechanism that is shaped by lifestyle choices, such as diet, microbiome and microbial metabolites. Short-chain fatty acids (SCFAs) are the most abundant microbial metabolites in the colonic lumen and are mainly produced by the microbial fermentation of prebiotics, such as dietary fiber. This review focuses on the preventive and immunomodulatory effects of SCFAs on autoimmunity. The tissue- and disease-specific effects of dietary fiber, SCFAs and SCFA-producing microbes on major types of autoimmune diseases, including type I diabetes, multiple sclerosis, rheumatoid arthritis and lupus, are discussed. Additionally, their key regulatory mechanisms for lymphocyte development, tissue barrier function, host metabolism, immunity, autoantibody production, and inflammatory effector and regulatory lymphocytes are discussed. The shared and differential effects of SCFAs on different types and stages of autoimmune diseases are discussed.

Microbial Metabolite Dysbiosis and Colorectal Cancer.

The global burden of colorectal cancer (CRC) is expected to continuously increase. Through research performed in the past decades, the effects of various environmental factors on CRC development have been well identified. Diet, the gut microbiota and their metabolites are key environmental factors that profoundly affect CRC development. Major microbial metabolites with a relevance for CRC prevention and pathogenesis include dietary fiber-derived short-chain fatty acids, bile acid derivatives, indole metabolites, polyamines, trimethylamine-N-oxide, formate, and hydrogen sulfide. These metabolites regulate various cell types in the intestine, leading to an altered intestinal barrier, immunity, chronic inflammation, and tumorigenesis. The physical, chemical, and metabolic properties of these metabolites along with their distinct functions to trigger host receptors appear to largely determine their effects in regulating CRC development. In this review, we will discuss the current advances in our understanding of the major CRC-regulating microbial metabolites, focusing on their production and interactive effects on immune responses and tumorigenesis in the colon.

Identification of the niche and mobilization mechanism for tissue-protective multipotential bone marrow ILC progenitors.

Innate lymphoid cells (ILCs) play crucial roles in maintenance and defense of peripheral tissues but would undergo natural and inflammation-induced attrition over time. A potential solution to counteract the peripheral ILC attrition would be regulated mobilization of bone marrow (BM) ILC progenitors. The major multipotential ILC progenitors (ILCPs) are divided into two subsets in distinct niches of the BM. Sinusoid ILCPs emigrate from the BM to circulate the peripheral blood. In contrast, parenchyma ILCPs are more likely in cell cycling and less likely to emigrate BM. The mobilization of BM ILCPs is internally and externally controlled by the coordinated expression of the BM retention receptors (Itg-α4 and CXCR4) and the emigration receptors sphingosine-1-phosphate (S1P) receptors. The expression of the BM retention and emigration receptors is developmentally regulated in the steady state and by the inflammasome-derived IL-18. Upon infusion, sinusoid ILCPs can effectively restore peripheral ILC insufficiency and tissue integrity during inflammatory responses.

Cutting Edge: The Expression of Transcription Inhibitor GFI1 Is Induced by Retinoic Acid to Rein in Th9 Polarization.

IL-9, produced mainly by specialized T cells, mast cells, and group 2 innate lymphoid cells, regulates immune responses, including anti-helminth and allergic responses. Polarization of naive CD4 T cells into IL-9-producing T cells (Th9s) is induced by IL-4 and TGF-ß1 or IL-1ß. In this article, we report that the transcription factor growth factor-independent 1 transcriptional repressor (GFI1) plays a negative role in mouse Th9 polarization. Moreover, the expression of GFI1 is controlled by liganded RARα, allowing GFI1 to mediate the negative effect of retinoic acid on IL-9 expression. The Gfi1 gene has multiple RARα binding sites in the promoter region for recruiting nuclear coactivator steroid receptor coactivator-3 and p300 for histone epigenetic modifications in a retinoic acid-dependent manner. Retinoic acid-induced GFI1 binds the Il9 gene and suppresses its expression. Thus, GFI1 is a novel negative regulator of Il9 gene expression. The negative GFI1 pathway for IL-9 regulation provides a potential control point for Th9 activity.

Machine Learning Estimation of Low-Density Lipoprotein Cholesterol in Women With and Without HIV.

INTRODUCTION: Low-density lipoprotein cholesterol (LDL-C) is typically estimated from total cholesterol, high-density lipoprotein cholesterol, and triglycerides. The Friedewald, Martin-Hopkins, and National Institutes of Health equations are widely used but may estimate LDL-C inaccurately in certain patient populations, such as those with HIV. We sought to investigate the utility of machine learning for LDL-C estimation in a large cohort of women with and without HIV. METHODS: We identified 7397 direct LDL-C measurements (5219 from HIV-infected individuals, 2127 from uninfected controls, and 51 from seroconvertors) from 2414 participants (age 39.4 ± 9.3 years) in the Women's Interagency HIV Study and estimated LDL-C using the Friedewald, Martin-Hopkins, and National Institutes of Health equations. We also optimized 5 machine learning methods [linear regression, random forest, gradient boosting, support vector machine (SVM), and neural network] using 80% of the data (training set). We compared the performance of each method using root mean square error, mean absolute error, and coefficient of determination (R2) in the holdout (20%) set. RESULTS: SVM outperformed all 3 existing equations and other machine learning methods, achieving the lowest root mean square error and mean absolute error, and the highest R2 (11.79 and 7.98 mg/dL, 0.87, respectively, compared with those obtained using the Friedewald equation: 12.45 and 9.14 mg/dL, 0.87). SVM performance remained superior in subgroups with and without HIV, with nonfasting measurements, in LDL <70 mg/dL and triglycerides > 400 mg/dL. CONCLUSIONS: In this proof-of-concept study, SVM is a robust method that predicts directly measured LDL-C more accurately than clinically used methods in women with and without HIV. Further studies should explore the utility in broader populations.

Differential Risk of Cancer Associated with Glucagon-like Peptide-1 Receptor Agonists: Analysis of Real-world Databases.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1Ra) are commonly used in type 2 diabetes mellitus (T2DM). However, differential risk of various cancers among GLP1Ra recipients is unknown. METHODS: We inquired an aggregated electronic health record database, Explorys, and compared the adjusted odds ratio (aOR) of cancers between GLP1Ra and metformin users. Findings were validated in the FDA Adverse Event Reporting System (FDA FAERS). RESULTS: From 1/2005 to 6/2019, we identified 619 340 and 64 230 patients in the metformin and GLP1Ra group, respectively. Within 5 years of starting antidiabetic medications, GLP1Ra was associated with significantly lower incident risk of prostate (aOR 0.81, p = .03), lung (aOR 0.81, p = .05), and colon cancer (aOR 0.85, p = .03), while the risk of thyroid cancer was significantly higher (aOR 1.65, p < .01). Similar findings were seen in the FDA FAERS database, where GLP1Ra was associated with lower risk of prostate (aOR 0.72, p = .08), lung (aOR 0.52, p < .01), colon cancer (aOR 0.82, p = .31), and higher risk of thyroid cancer (aOR 4.33, p < .01). In addition, with longer duration of GLP1Ra use, the risk of prostate, lung, and colon cancer further decreased, suggesting an exposure duration-response relationship. CONCLUSIONS: GLP1Ra is associated with lower risks of prostate, lung, and colon cancer, but higher risk of thyroid cancer.

Regulation of common neurological disorders by gut microbial metabolites.

The gut is connected to the CNS by immunological mediators, lymphocytes, neurotransmitters, microbes and microbial metabolites. A mounting body of evidence indicates that the microbiome exerts significant effects on immune cells and CNS cells. These effects frequently result in the suppression or exacerbation of inflammatory responses, the latter of which can lead to severe tissue damage, altered synapse formation and disrupted maintenance of the CNS. Herein, we review recent progress in research on the microbial regulation of CNS diseases with a focus on major gut microbial metabolites, such as short-chain fatty acids, tryptophan metabolites, and secondary bile acids. Pathological changes in the CNS are associated with dysbiosis and altered levels of microbial metabolites, which can further exacerbate various neurological disorders. The cellular and molecular mechanisms by which these gut microbial metabolites regulate inflammatory diseases in the CNS are discussed. We highlight the similarities and differences in the impact on four major CNS diseases, i.e., multiple sclerosis, Parkinson's disease, Alzheimer's disease, and autism spectrum disorder, to identify common cellular and molecular networks governing the regulation of cellular constituents and pathogenesis in the CNS by microbial metabolites.

Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids.

A mounting body of evidence indicates that dietary fiber (DF) metabolites produced by commensal bacteria play essential roles in balancing the immune system. DF, considered nonessential nutrients in the past, is now considered to be necessary to maintain adequate levels of immunity and suppress inflammatory and allergic responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are the major DF metabolites and mostly produced by specialized commensal bacteria that are capable of breaking down DF into simpler saccharides and further metabolizing the saccharides into SCFAs. SCFAs act on many cell types to regulate a number of important biological processes, including host metabolism, intestinal functions, and immunity system. This review specifically highlights the regulatory functions of DF and SCFAs in the immune system with a focus on major innate and adaptive lymphocytes. Current information regarding how SCFAs regulate innate lymphoid cells, T helper cells, cytotoxic T cells, and B cells and how these functions impact immunity, inflammation, and allergic responses are discussed.

Incidence and Risk of Various Types of Arterial Thromboembolism in Patients With Cancer.

OBJECTIVE: To describe the temporal association and identify risk factors between cancer diagnosis and various types of arterial thromboembolism (ATE). PATIENTS AND METHODS: We inquired an aggregated electronic health record database (Explorys, IBM Corp., Armonk, New York) and identified patients with cancer from January 1999 to October 2019, with various types of ATE, including myocardial infarction, acute ischemic stroke, acute limb ischemia, acute mesenteric ischemia, acute renal infarction, and retinal artery occlusion. We investigated the temporal relationship between cancer diagnosis and ATE events by examining the incidence ratio (IR) of ATE before and after diagnosis of cancer. RESULTS: We identified 305,384 patients with cancer and ATE. The 30-day interval IR of total ATE was elevated shortly before and after cancer diagnosis, which was consistent among different ATE and cancer types. The incidence was highest within a 330-day window (90 days before and 240 days after cancer diagnosis), and IR peaked at 13.9 (95% confidence interval [CI], 13.6 to 14.2) in the first 30 days following diagnosis of cancer. Compared with patients with cancer who never developed ATE, patients with ATE had more cardiovascular risk factors at baseline. Patients with brain cancer, lung cancer, colorectal cancer, and pancreatic cancer had the highest risk of developing ATE, whereas ATE type was anatomically associated with cancer type. CONCLUSION: In this observational study of an aggregated US patient population, those with newly diagnosed cancer had increased risk of ATE events. This risk was most elevated in a 330-day window around cancer diagnosis and was consistent across different types of ATE and cancer.

The Butyrate-Producing Bacterium Clostridium butyricum Suppresses Clostridioides difficile Infection via Neutrophil- and Antimicrobial Cytokine-Dependent but GPR43/109a-Independent Mechanisms.

Short-chain fatty acids, such as butyrate, are major gut microbial metabolites that are beneficial for gastrointestinal health. Clostridium butyricum MIYAIRI588 (CBM588) is a bacterium that produces a robust amount of butyrate and therefore has been used as a live biotherapeutic probiotic in clinical settings. Clostridioides difficile causes life-threatening diarrhea and colitis. The gut resident microbiota plays a critical role in the prevention of C. difficile infection (CDI), as the disruption of the healthy microbiota by antibiotics greatly increases the risk for CDI. We report that CBM588 treatment in mice significantly improved clinical symptoms associated with CDI and increased the number of neutrophils and Th1 and Th17 cells in the colonic lamina propria in the early phase of CDI. The protective effect of CBM588 was abolished when neutrophils, IFN-γ, or IL-17A were depleted, suggesting that induction of the immune reactants is required to elicit the protective effect of the probiotic. The administration of tributyrin, which elevates the concentration of butyrate in the colon, also increased the number of neutrophils in the colonic lamina propria, indicating that butyrate is a potent booster of neutrophil activity during infection. However, GPR43 and GPR109a, two G protein-coupled receptors activated by butyrate, were dispensable for the protective effect of CBM588. These results indicate that CBM588 and butyrate suppress CDI, in part by boosting antimicrobial innate and cytokine-mediated immunity.

Performance of Methods to Estimate Low-Density Lipoprotein Cholesterol in Women With and Without HIV Infection.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is estimated from total cholesterol, high-density lipoprotein cholesterol and triglycerides using predefined equations which assume fixed or varying relationships between these parameters and may underestimate or overestimate LDL-C. Data on the performance of these equations in persons with HIV are limited. We sought to investigate the utility of the 3 most widely used methods (Friedewald, Hopkins, and the recently proposed NIH equation) to predict LDL-C in persons with HIV. METHODS: We identified 7397 direct LDL-C (5219 HIV, 2127 uninfected controls, 51 seroconvertors) measurements in the Women's Interagency HIV Study, and used the 3 equations (Friedewald, Hopkins, and NIH) to calculate LDL-C. We compared the performance of the 3 equations using root mean square error and coefficient of determination (R2). RESULTS: Overall, the Friedewald equation had the best performance characteristics, outperforming Hopkins and NIH methods with lower root mean square error and higher R2 at lower triglyceride levels. However, this association did not hold true at higher triglyceride levels (quartiles 3 and 4), whereas the Hopkins equation had better performance characteristics in quartile 3, none of the 3 equations were optimal in quartile 4. After adjusting for fasting status and triglycerides levels, HIV+ had larger mean difference compared with directly measured LDL using all 3 methods. CONCLUSIONS: All 3 methods have lower accuracy in HIV+ vs HIV- women, even after adjusting for triglyceride levels and fasting status. Further research should focus on identifying methods to estimate LDL-C in HIV.

IL-4-BATF signaling directly modulates IL-9 producing mucosal mast cell (MMC9) function in experimental food allergy.

BACKGROUND: This study group has previously identified IL-9-producing mucosal mast cell (MMC9) as the primary source of IL-9 to drive intestinal mastocytosis and experimental IgE-mediated food allergy. However, the molecular mechanisms that regulate the expansion of MMC9s remain unknown. OBJECTIVES: This study hypothesized that IL-4 regulates MMC9 development and MMC9-dependent experimental IgE-mediated food allergy. METHODS: An epicutaneous sensitization model was used and bone marrow reconstitution experiments were performed to test the requirement of IL-4 receptor α (IL-4Rα) signaling on MMC9s in experimental IgE-mediated food allergy. Flow cytometric, bulk, and single-cell RNA-sequencing analyses on small intestine (SI) MMC9s were performed to illuminate MMC9 transcriptional signature and the effect of IL-4Rα signaling on MMC9 function. A bone marrow-derived MMC9 culture system was used to define IL-4-BATF signaling in MMC9 development. RESULTS: Epicutaneous sensitization- and bone marrow reconstitution-based models of IgE-mediated food allergy revealed an IL-4 signaling-dependent cell-intrinsic effect on SI MMC9 accumulation and food allergy severity. RNA-sequencing analysis of SI-MMC9s identified 410 gene transcripts reciprocally regulated by IL-4 signaling, including Il9 and Batf. Insilico analyses identified a 3491-gene MMC9 transcriptional signature and identified 2 transcriptionally distinct SI MMC9 populations enriched for metabolic or inflammatory programs. Employing an in vitro MMC9-culture model system showed that generation of MMC9-like cells was induced by IL-4 and this was in part dependent on BATF. CONCLUSIONS: IL-4Rα signaling directly modulates MMC9 function and exacerbation of experimental IgE-mediated food allergic reactions. IL-4Rα regulation of MMC9s is in part BATF-dependent and occurs via modulation of metabolic transcriptional programs.

Dietary fiber metabolites regulate innate lymphoid cell responses.

Innate lymphoid cells (ILCs) rapidly undergo expansion in population size and functional maturation in response to cytokines that signal infection, tissue damage, or changes in physiology. Optimal ILC responses are shaped, in part, by the microbiota but the mechanisms remain unclear. We report that short-chain fatty acids (SCFAs), produced by the commensal microbiota from dietary fibers, support optimal expansion of ILCs, including ILC1, ILC2, and ILC3 in the intestines through their G-protein-coupled receptors (GPCRs). While this function is primarily important for intestinal ILC populations, it can also boost ILC responses in other tissues depending on host condition. ILCs express multiple GPCRs that detect SCFAs. Interestingly, we found that the expression of SCFA receptors, such as Ffar2 and Ffar3, by ILCs is induced by SCFAs. GPCR triggering by SCFAs co-stimulates the activation of phosphoinositide 3-kinase (PI3K), Stat3, Stat5, and mammalian target of rapamycin (mTOR), which is important for ILC proliferation. While Ffar2 signaling promotes ILC2 proliferation, SCFAs can suppress ILC2 proliferation through a non-Ffar2-mediated mechanism. In conclusion, our findings indicate that SCFAs, as the major mediator of healthy microbiota and nutritional status, function to maintain optimal numbers of ILCs in peripheral tissues during infection and inflammatory responses.