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Spontaneous preterm birth (sPTB) is a leading cause of maternal and neonatal morbidity and mortality, yet its prevention and early risk stratification are limited. Previous investigations have suggested that vaginal microbes and metabolites may be implicated in sPTB. Here we performed untargeted metabolomics on 232 second-trimester vaginal samples, 80 from pregnancies ending preterm. We find multiple associations between vaginal metabolites and subsequent preterm birth, and propose that several of these metabolites, including diethanolamine and ethyl glucoside, are exogenous. We observe associations between the metabolome and microbiome profiles previously obtained using 16S ribosomal RNA amplicon sequencing, including correlations between bacteria considered suboptimal, such as Gardnerella vaginalis, and metabolites enriched in term pregnancies, such as tyramine. We investigate these associations using metabolic models. We use machine learning models to predict sPTB risk from metabolite levels, weeks to months before birth, with good accuracy (area under receiver operating characteristic curve of 0.78). These models, which we validate using two external cohorts, are more accurate than microbiome-based and maternal covariates-based models (area under receiver operating characteristic curve of 0.55–0.59). Our results demonstrate the potential of vaginal metabolites as early biomarkers of sPTB and highlight exogenous exposures as potential risk factors for prematurity.

The enteric nervous system (ENS) forms a versatile sensory system along the gastrointestinal tract that interacts with most cell types in the bowel. Herein, we portray host-environment interactions at the intestinal mucosal surface through the lens of the enteric nervous system. We describe local cellular interactions as well as long-range circuits between the enteric, central, and peripheral nervous systems. Additionally, we discuss recently discovered mechanisms by which enteric neurons and glia respond to biotic and abiotic environmental changes and how they regulate intestinal immunity and inflammation. The enteric nervous system emerges as an integrative sensory system with manifold immunoregulatory functions under both homeostatic and pathophysiological conditions.

Innate lymphoid cells (ILCs) are well-characterized immune cells that play key roles in host defense and tissue homeostasis. Yet, how the three-dimensional (3D) genome organization underlies the development and functions of ILCs is unknown. Herein, we carried out an integrative analysis of the 3D genome structure, chromatin accessibility and gene expression in mature ILCs. Our results revealed that the local 3D configuration of the genome is rewired specifically at loci associated with ILC biology to promote their development and functional differentiation. Importantly, we demonstrated that the ontogenesis of ILC2s and the progression of allergic airway inflammation are determined by a unique local 3D configuration of the region containing the ILC-lineage-defining factor Id2, which is characterized by multiple interactions between the Id2 promoter and distal regulatory elements bound by the transcription factors GATA-3 and RORα, unveiling the mechanism whereby the Id2 expression is specifically controlled in group 2 ILCs.

Summary paragraphThe host-microbiota relationship has evolved to shape mammalian processes, including immunity, metabolism, and development1–3. Host phenotypes change in direct response to microbial exposures by the individual. Here we show that the microbiota induces phenotypic change not only in the individual but also in their succeeding generations of progeny. We found that germ-free mice exhibit a robust sebum secretion defect and transcriptional changes in various organs, persisting across multiple generations despite microbial colonization and breeding with conventional mice. Host-microbe interactions could be involved in this process, since T cell-deficient mice, which display defective sebum secretion4, also transgenerationally transmit their phenotype to progeny. These phenotypes are inherited by progeny conceived duringin vitrofertilization using germ-free sperm and eggs, demonstrating that epigenetic information in the gametes is required for phenotypic transmission. Accordingly, small non-coding RNAs that can regulate embryonic gene expression5were strikingly and similarly altered in gametes of germ-free and T cell-deficient mice. Thus, we have uncovered a novel mechanism whereby the microbiota and immune system induce phenotypic changes in successive generations of offspring. This epigenetic form of inheritance could be advantageous for host adaptation to environmental perturbation, where phenotypic diversity can be introduced more rapidly than by genetic mutation.

Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed

The SARS-CoV-2 virus has infected more than 261 million people and has led to more than 5 million deaths in the past year and a half

Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation ofKlf4expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants ofKLF4revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmicKlf4expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.

The microbiome modulates brain function, but the precise routes of gut-brain communication remain unclear. In a recent issue of Science, Gabanyi et al. discover that hypothalamic GABAergic neurons directly recognize microbial muropeptides via NOD2, leading to reduced neuronal activity, loss of appetite, and aberrant thermoregulation.

The microbial community colonizing the gastrointestinal tract, collectively termed the gut microbiota, is an important element of the host organism due to its impact on multiple aspects of health. The digestion of food, secretion of immunostimulatory molecules, performance of chemical reactions in the intestine, and production of metabolites by the microbiota contribute to host homeostasis and disease. Recent discoveries indicate that these major functions are not constantly performed over the course of a day, but rather undergo diurnal fluctuations due to compositional and biogeographical oscillations in the microbiota. Here, we summarize the characteristics and origins of diurnal microbiome rhythms as well as their functional consequences for the circadian biology of the host. We describe the major known pathways of circadian host-microbiome communication and discuss possible implications of altered diurnal microbiome rhythms for human disease.

Liver international 42(3), 640-650 (2022). doi:10.1111/liv.15161, Published by Wiley-Blackwell, Oxford

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in both mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome. We find that preferred dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports gut microbiome NAD synthesis. In addition, the microbiome converts nicotinamide, originating from the host circulation, into nicotinic acid. Host tissues uptake and utilize this microbiome-derived nicotinic acid for NAD synthesis, maintaining circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, NAD precursors cycle between the host and gut microbiome to maintain NAD homeostasis.

Antibiotic tolerance enables microorganisms to survive the exposure to antibiotics and serves as a precursor to antibiotic resistance. In a recent issue of Nature Microbiology, Liu et al. (2021) describe that high-fat-diet-induced changes in the intestinal microbiome and metabolome facilitate the development of antibiotic tolerance by bacterial pathogens.

The interaction between the metabolic activities of the intestinal microbiome and its host forms an important part of health. The basis of this interaction is in part mediated by the release of microbially-derived metabolites that enter the circulation. These products of microbial metabolism thereby interface with the immune, metabolic, or nervous systems of the host to influence physiology. Here, we review the interactions between the metabolic activities of the microbiome and the systemic metabolism of the host. The concept that the endocrine system includes more than just the eukaryotic host component enables the rational design of exogenous interventions that shape human metabolism. An improved mechanistic understanding of the metabolic microbiome-host interaction may therefore pioneer actionable microbiota-based diagnostics or therapeutics that allow the control of host systemic metabolism via the microbiome.

The ongoing COVID-19 pandemic has highlighted the dearth of approved drugs to treat viral infections, with only ∼90 FDA approved drugs against human viral pathogens. To identify drugs that can block SARS-CoV-2 replication, extensive drug screening to repurpose approved drugs is underway. Here, we screened ∼18,000 drugs for antiviral activity using live virus infection in human respiratory cells. Dose-response studies validate 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Amongst these drug candidates are 16 nucleoside analogs, the largest category of clinically used antivirals. This included the antiviral Remdesivir approved for use in COVID-19, and the nucleoside Molnupirivir, which is undergoing clinical trials. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral, and we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogs synergistically inhibits SARS-CoV-2 infection in vitro and in vivo suggesting a clinical path forward.

Exercise exerts a wide range of beneficial effects for healthy physiology

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, resulting millions of infections and deaths with few effective interventions available. Here, we demonstrate that SARS-CoV-2 evades interferon (IFN) activation in respiratory epithelial cells, resulting in a delayed response in bystander cells. Since pretreatment with IFNs can block viral infection, we reasoned that pharmacological activation of innate immune pathways could control SARS-CoV-2 infection. To identify potent antiviral innate immune agonists, we screened a panel of 75 microbial ligands that activate diverse signaling pathways and identified cyclic dinucleotides (CDNs), canonical STING agonists, as antiviral. Since CDNs have poor bioavailability, we tested the small molecule STING agonist diABZI, and found that it potently inhibits SARS-CoV-2 infection of diverse strains including variants of concern (B.1.351) by transiently stimulating IFN signaling. Importantly, diABZI restricts viral replication in primary human bronchial epithelial cells and in mice in vivo. Our study provides evidence that activation of STING may represent a promising therapeutic strategy to control SARS-CoV-2.

Targeted drug delivery is an attractive strategy for treatment of life-threatening inflammatory brain pathologies such as ischemic stroke. In these conditions, adhesion molecule expression (e.g. vascular cellular adhesion molecule-1, VCAM) is upregulated on endothelium. Hence, VCAM represents a relevant target for selective drug delivery. We have utilized αVCAM monoclonal antibodies to target therapeutic proteins and nanocarriers (liposomes and lipid nanoparticles, LNPs) to the pathologically-altered vasculature.To assess tissue biodistribution and therapeutic effects of VCAM-targeted agents, we used 2 mouse models: 1) acute inflammation induced by intra-striatal injection of tumor necrosis factor-α (TNF), and 2) ischemic stroke induced by transient middle cerebral artery occlusion (tMCAO). Biodistribution was assayed by measuring radioactivity in blood and organs 30 minutes after injection. Efficacy was determined by tracing radiolabeled albumin extravasation to assess edema.The results showed that VCAM targeting was increased by TNF injection, and that targeting to VCAM enhanced the cerebral accumulation of αVCAM conjugated thrombomodulin (TM) and nanocarriers by orders of magnitude (Fig A). It is noteworthy that αVCAM-TM and free αVCAM antibody had similar levels of brain uptake. Our data also demonstrated the protective effect of αVCAM-liposome loaded with dexamethasone on brain edema (Fig B), indicating the therapeutic potential of VCAM-targeting drug delivery strategies. Further, the results in tMCAO model recapitulated our findings in the TNF model that targeting to VCAM significantly improves delivery to the ischemic brain (Fig C). In summary, we have shown that targeting VCAM permits delivery of a diverse array of therapeutics to the inflamed vasculature in conditions such as ischemic stroke. Future work will focus on evaluating the therapeutic properties of VCAM-targeted drug delivery strategies.

Background & Aims Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF. Methods To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK BioBank population-based cohort. For functional studies, male Nlrp6-/- mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF. Results Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3–3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6-/- mice displayed exacerbated APAP- and LPS-induced liver injury, which was linked to significantly reduced gut and liver tissue microbiota diversity and correlated with increased intestinal permeability at baseline. Fecal microbiota transfer (FMT) from Nlrp6-/- mice into wild-type (WT) mice augmented liver injury on APAP treatment in recipient WT mice, resembling the inflammatory phenotype of Nlrp6-/- mice. Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6Chi inflammatory phenotype, suggesting a critical function of these cells as sensors of gut-derived signals orchestrating the inflammatory response. Conclusions Our data show an important yet unknown function of intestinal microbiota during ALF. Intestinal dysbiosis was transferrable to healthy WT mice via FMT and aggravated liver injury. Our study highlights intestinal microbiota as a targetable risk factor for ALF., Graphical abstract

Little is known about how interactions between diet, immune recognition, and intestinal stem cells (ISCs) impact the early steps of intestinal tumorigenesis. Here, we show that a high fat diet (HFD) reduces the expression of the major histocompatibility complex II (MHC-II) genes in ISCs. This decline in ISC MHC-II expression in a HFD correlates with an altered intestinal microbiome composition and is recapitulated in antibiotic treated and germ-free mice on a control diet. Mechanistically, pattern recognition receptor and IFNg signaling regulate MHC-II expression in ISCs. Although MHC-II expression on ISCs is dispensable for stem cell function in organoid cultures in vitro, upon loss of the tumor suppressor gene Apc in a HFD, MHC-II- ISCs harbor greater in vivo tumor-initiating capacity than their MHC-II+ counterparts, thus implicating a role for epithelial MHC-II in suppressing tumorigenesis. Finally, ISC-specific genetic ablation of MHC-II in engineered Apc-mediated intestinal tumor models increases tumor burden in a cell autonomous manner. These findings highlight how a HFD alters the immune recognition properties of ISCs through the regulation of MHC-II expression in a manner that could contribute to intestinal tumorigenesis.

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder with a very high prevalence rate and a chronic disease course beginning in early childhood. Despite the tremendous burden of ASD, there are currently no disease-modifying treatments. Like many neuropsychiatric illnesses ASD has a complex pathophysiology driven by genetic and environmental factors. There is interest in identifying modifiable environmental factors as potential translational research strategies for development of therapeutics for ASD. A rapidly growing body of research demonstrates that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, have profound influence on brain and behavior. This gut-brain signaling pathway is highly relevant to ASD as the microbiome begins to form at birth, is heavily influenced by environmental factors throughout early life, and begins to stabilize at the same stage of development that symptoms of ASD begin to develop. To investigate potential gene x microbiome interactions in a model of ASD, we utilized mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO), which clinically manifests as Phelan-McDermid syndrome, as a model for genetic risk of ASD. Analysis of the gut microbiome of Shank3KO mice demonstrated genotype effects on both microbiome composition and metabolite production. Behaviorally, Shank3KO mice demonstrate decreased social interactions and have altered anxiety and compulsive-like behaviors. Disruption of the microbiome with broad spectrum antibiotics lead to an exacerbation of all behavioral phenotypes in Shank3KO mice. Additionally, we found that Shank3KO mice had markedly increased changes in gene expression in the prefrontal cortex following microbiome depletion. Taken together, our results suggest a gene x microbiome interaction in this mouse model for ASD and raise the possibility that targeting the microbiome may be a valid translational research strategy in developing therapeutics for ASD.

The microbiome is critically involved in the regulation of systemic metabolism. An important but poorly understood facet of this regulation is the diurnal activity of the microbiome. Herein, we summarize recent developments in our understanding of the diurnal properties of the microbiome and their integration into the circadian regulation of organismal metabolism. The microbiome may be involved in the detrimental consequences of circadian disruption for host metabolism and the development of metabolic disease. At the same time, the mechanisms by which microbiome diurnal activity is integrated into host physiology reveal several translational opportunities by which the time of day can be harnessed to optimize microbiome-based therapies. The study of circadian microbiome properties may thus provide a new avenue for treating disorders associated with circadian disruption from the gut.

The intestinal commensal microbiome is an important component of host health, in part by contributing an abundance of metabolites that gain access to the systemic circulation. The microbiome thereby influences the physiology of numerous organ systems outside the gastrointestinal tract. The consequences of this signaling axis between the intestinal microbiome and host are profound, in particular for the modulation of organismal metabolism. Here, we review recent examples whereby the intestinal microbiome influences host metabolism by influencing the biology of adipose tissue. We place a special emphasis on metabolite-driven pathways by which adipose tissue responds to alterations in intestinal microbial colonization. Given its accessibility for therapeutic interventions, the gut microbiome is an attractive relay module for the remote control of systemic metabolism.

Background and Aims microRNAs regulate gene expression and influence the pathogenesis of human diseases. The present study investigated the role of microRNA-21 [miR-21] in the pathogenesis of intestinal inflammation, because miR-21 is highly expressed in inflammatory bowel disease. Inflammatory bowel disease is associated with intestinal barrier dysfunction and an altered gut microbiota. Recent studies have demonstrated that host microRNAs can shape the microbiota. Thus, we determined the influence of miR-21 on the gut microbiota and observed the subsequent impact in a dextran sodium sulphate [DSS]-induced colitis model. Methods The influence of miR-21 on the gut microbiota and inflammation was assessed in wild-type [WT] and miR-21–/– mice, in co-housed mice, following antibiotic depletion of the microbiota, or by colonization of germ-free [GF] mice with fecal homogenate, prior to DSS administration. We carried out 16S rRNA sequencing on WT and miR-21–/– mice to dissect potential differences in the gut microbiota. Results miR-21–/– mice have reduced susceptibility to DSS-induced colitis compared with WT mice. Co-housing conferred some protection to WT mice, while GF mice colonized with fecal homogenate from miR-21–/– were protected from DSS colitis compared with those colonized with WT homogenate. Further supporting a role for the microbiota in the observed phenotype, the protection afforded by miR-21 depletion was lost when mice were pre-treated with antibiotics. The 16S rRNA sequencing revealed significant differences in the composition of WT and miR-21–/– intestinal microbiota. Conclusions These findings suggest that miR-21 influences the pathogenesis of intestinal inflammation by causing propagation of a disrupted gut microbiota.

NAD(+) is an essential coenzyme for all living cells. NAD(+) concentrations decline with age, but whether this reflects impaired production or accelerated consumption remains unclear. We employed isotope tracing and mass spectrometry to probe age-related changes in NAD(+) metabolism across tissues. In aged mice, we observed modest tissue NAD(+) depletion (median decrease ~30%). Circulating NAD(+) precursors were not significantly changed, and isotope tracing showed the unimpaired synthesis of nicotinamide from tryptophan. In most tissues of aged mice, turnover of the smaller tissue NAD(+) pool was modestly faster such that absolute NAD(+) biosynthetic flux was maintained, consistent with more active NAD(+)-consuming enzymes. Calorie restriction partially mitigated age-associated NAD(+) decline by decreasing consumption. Acute inflammatory stress induced by LPS decreased NAD(+) by impairing synthesis in both young and aged mice. Thus, the decline in NAD(+) with normal aging is relatively subtle and occurs despite maintained NAD(+) production, likely due to increased consumption.

Little is known about how interactions of diet, intestinal stem cells (ISCs), and immune cells affect early-stage intestinal tumorigenesis. We show that a high-fat diet (HFD) reduces the expression of the major histocompatibility complex class II (MHC class II) genes in intestinal epithelial cells, including ISCs. This decline in epithelial MHC class II expression in a HFD correlates with reduced intestinal microbiome diversity. Microbial community transfer experiments suggest that epithelial MHC class II expression is regulated by intestinal flora. Mechanistically, pattern recognition receptor (PRR) and interferon-gamma (IFNγ) signaling regulates epithelial MHC class II expression. MHC class II-negative (MHC-II-) ISCs exhibit greater tumor-initiating capacity than their MHC class II-positive (MHC-II+) counterparts upon loss of the tumor suppressor Apc coupled with a HFD, suggesting a role for epithelial MHC class II-mediated immune surveillance in suppressing tumorigenesis. ISC-specific genetic ablation of MHC class II increases tumor burden cell autonomously. Thus, HFD perturbs a microbiome-stem cell-immune cell interaction that contributes to tumor initiation in the intestine.

Background & Aims Previous studies have identified physical activity as an important lifestyle factor in the pathogenesis of chronic liver diseases (CLD). However, most studies were short in follow-up, and based on self-reported activity. Moreover, it is unknown whether physical activity affects the risk of liver disease development in the general population. Herein, we aimed to clarify the association between physical activity and CLD by examining the risk of liver disease and progression in relation to accelerometer-based physical activity in a large subset of prospectively recruited participants in the UK Biobank. Methods We analysed data from 96,688 participants that recorded their physical activity through the use of a wrist accelerometer. Relative risks for development of liver diseases were calculated using multivariable-adjusted Cox regression models. In a subgroup of participants without any previously diagnosed liver disease (n = 95,974), a total of 374 liver disease cases were diagnosed during follow-up (mean = 5.5 years). Results Participants in the top compared with the bottom quartile of physical activity had a reduced risk of both overall CLD (hazard ratio [HR]: 0.41 [0.29–0.59]) and NAFLD (HR: 0.39 [0.21–0.70]). An activity increase of an additional 2,500 steps per day, was associated with a 38% reduction in CLD and a 47% reduction in NAFLD development, independent of adiposity. In the subgroup of participants with previously diagnosed liver disease (n = 714), participants in the top compared with the bottom quartile of physical activity had a striking 89% risk reduction in liver-related death (HR: 0.11 [0.02–0.86]), and 85% risk reduction in all-cause mortality (adjusted HR: 0.15 [0.05–0.44]). Walking an additional 2,500 steps per day was associated with 44% reduction in liver disease progression. Conclusions Greater physical activity is associated with a dose-dependent reduction in liver disease, which appears to be independent of adiposity. Lay summary In this study, we aimed to clarify the association between accelerometer-measured physical activity and chronic liver disease by examining risk of overall and specific liver diseases and their progression in relation to accelerometer-based physical activity in 96,688 participants in the UK Biobank. Our results show a clear, dose-dependent protective association between accelerometer-measured physical activity and liver disease development and progression. The linkage of device-measured activity could therefore create a framework for using wearables for personalised prevention of liver diseases., Graphical abstract, Highlights • Physical activity is associated with a dose-dependent reduction in liver disease that appears to be independent of adiposity. • An increase of 2,500 steps per day was associated with a 38% reduction in liver disease and a 47% reduction in NAFLD. • In patients with liver disease, activity was associated with a reduction in liver disease progression and cirrhosis development. • In patients with liver disease, increased physical activity significantly reduced the risk of liver-related death.

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intra-tumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by co-treatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intra-tumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.

Microbial infection poses a threat to organismal homeostasis and therefore must be efficiently counteracted by host defense mechanisms. It has been recently demonstrated that the immune system may anticipate an emerging pathogenic exposure through a heightened inflammatory state. Such anticipatory responses to fluctuating environmental conditions are typically orchestrated by the circadian clock, an intrinsic time-keeping system that adapts tissue physiology to diurnal variations in external influences. Here, we review current knowledge about the interplay between the circadian clock and antimicrobial responses. We summarize the molecular strategies employed by the circadian system against specific pathogens, the core-clock proteins as well as cells in which they are expressed that mediate host defense, and the consequences of circadian variations on immune function. Furthermore, we highlight the possible implications of such circadian gating in immune reactions against pathogenic infections for the chronopharmacology of antibacterial and antiviral therapies.

The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX(3)CR1 reduced expansion of intestinal microbe-specific T helper-1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CX(3)CR1(+) APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss indicating that, while microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis.

Several cytokines maintain intestinal health, but precise inter-cellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue, critical for gut homeostasis. Here we show that in a murine IBD model based on macrophage-restricted Interleukin 10 (IL-10) receptor deficiency (Cx3cr1(Cre):Il10ra(fl/fl) mice), pro-inflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition of children carrying IL10R mutations. We establish macrophage-derived IL-23 as the driving factor of this pathology. Specifically, we report that Cx3cr1(Cre): Il10ra(fl/fl):Il23a(fl/fl) mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis. By analyzing the epithelial response to pro-inflammatory macrophages, we provide evidence that T cells of colitic animals produce deleterious IL-22 that induces epithelial chemokine expression and detrimental neutrophil recruitment. Collectively, we define critical cell-type-specific contributions to the induction and effector mechanism of macrophage-driven colitis, as manifested in mice harboring IL-10R deficiencies and human IBD pathologies.

Metabolites have emerged as the quintessential effectors mediating the impact of the commensal microbiome on human physiology, both locally at the sites of microbial colonization and systemically. The endocrine activity of the microbiome and its involvement in a multitude of complex diseases has made microbiome-modulated metabolites an attractive target for the development of new therapies. Several properties make metabolites uniquely suited for interventional strategies: natural occurrence in a broad range of concentrations, functional pleiotropy, ease of administration, and tissue bioavailability. Here, we provide an overview of recently discovered physiological effects of microbiome-associated small molecules that may serve as the first examples of metabolite-based therapies. We also highlight challenges and obstacles that the field needs to overcome on the path toward successful clinical trials of microbial metabolites for human disease. Keywords: Microbiome, Disease, Metabolites, Therapies, Post-biotics

Recruited blood monocytes contribute to the establishment, perpetuation, and resolution of tissue inflammation. Specifically, in the inflamed intestine, monocyte ablation was shown to ameliorate colitis scores in preclinical animal models. However, the majority of intestinal macrophages that seed the healthy gut are also monocyte derived. Monocyte ablation aimed to curb inflammation would therefore likely interfere with intestinal homeostasis. In this study, we used a TLR2 trans-membrane peptide that blocks TLR2 dimerization that is critical for TLR2/1 and TLR2/6 heterodimer signaling to blunt inflammation in a murine colitis model. We show that although the TLR2 peptide treatment ameliorated colitis, it allowed recruited monocytes to give rise to macrophages that lack the detrimental proinflammatory gene signature and reduced potentially damaging neutrophil infiltrates. Finally, we demonstrate TLR blocking activity of the peptide on in vitro cultured human monocyte-derived macrophages. Collectively, we provide a significantly improved anti-inflammatory TLR2 peptide and critical insights in its mechanism of action toward future potential use in the clinic.