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Chronic low-grade inflammation, also called metaflammation, is associated with prevalent non-communicable diseases, such as atherosclerosis. Anti-inflammatory therapy provides a clinical benefit in patients, but the triggers that incite metaflammation remain largely unknown. To uncover non-genetic inflammatory factors influencing atherosclerosis severity, we performed an unbiased in vivo screen measuring thousands of host- and microbe-derived molecules in a mouse model of atherosclerosis. Machine learning-supported analyses identified, next to known pro- and anti-atherogenic factors, the medium fatty acid-chain sphingomyelin d18:1/14:0 (S14) as highly positively associated with atherogenesis. S14 activated macrophage innate immune signalling, immune-metabolic reprogramming and pro-inflammatory gene transcription. The inflammatory activity of S14 was TLR4- and MD-2-dependent, consistent with biochemical and molecular dynamics simulation analyses showing that S14 promoted the formation of active TLR4/MD-2 dimers. Human interventional and observational trials demonstrated that dietary changes altered concentrations of S14 and that increased circulating S14 was associated with carotid plaque development in obese individuals. Collectively, these findings identify an inducible endogenous ligand for TLR4 that drives metaflammation, providing the rationale for preventative approaches and pharmacological interventions that may curb detrimental inflammation secondary to Western-type lifestyle habits.

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 magnitude and time evolution of shrinkage are influenced by numerous factors which are implemented in the design codes often in a different way. The time-dependent behavior of concrete in structures sensitive to creep and shrinkage should be verified by means of short-term laboratory measurements. Extrapolation of drying shrinkage from short-term measurements is an illposed problem. The process is extremely slow but can be accelerated by reducing the specimen size. The knowledge of the size-effect on drying shrinkage is a necessity to establish the transition from the laboratory to the structural size. In the literature, the experimental data on such size-effect are insufficient. For this reason a new experiment was developed to study this phenomenon on small-scale specimens made of cement mortar and the results from the first year are summarized in this paper. The measured data are validated by coupled FEM hygro-mechanical simulations.

The design and behavior of creep-sensitive structures can be to a large extent dependent on the evolution of drying shrinkage. Drying shrinkage of concrete measured on standard laboratory specimens is very time demanding, furthermore, the extrapolation based on the short-term measurements is an ill-posed problem and can lead to large errors. Additionally, the final magnitude of shrinkage is size-dependent which makes the transition from the laboratory data to real structure even more challenging. The present paper evaluates this size effect based on the data gathered in the Creep and shrinkage database developed at the Northwestern university and the data from the literature. Finally, this size effect is compared against the current codes of practice and recommendations.

Exercise exerts a wide range of beneficial effects for healthy physiology

The aim of this paper is to show and compare the time evolution of drying shrinkage and drying creep in concrete from three different perspectives. The first one analyzes the basic equations defined in the most common design codes and prediction models for the description of the long-term behavior of concrete (ACI 209, EC2, Model Code 2010, B3, B4). Next, the evolution of drying creep and shrinkage is examined by processing suitable experimental data available from the database developed at the Northwestern University. Finally, the last point of view investigates the results obtained from the finite element simulations employing the material point approach, in particular, the material model based on the Microprestress-Solidification theory.

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.

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.

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.

The intestinal microbiota contains trillions of commensal microorganisms that shape multiple aspects of host physiology and disease. In contrast to the host’s genome, the microbiome is amenable to change over the course of an organism’s lifetime, providing an opportunity to therapeutically modulate the microbiome’s impact on human pathophysiology., The intestinal microbiota contains trillions of commensal microorganisms that shape multiple aspects of host physiology and disease. In contrast to the host’s genome, the microbiome is amenable to change over the course of an organism’s lifetime, providing an opportunity to therapeutically modulate the microbiome’s impact on human pathophysiology. In this Perspective, we highlight environmental factors that regulate the temporal dynamics of the intestinal microbiome, with a particular focus on the different time scales at which they act. We propose that the identification of transient and intermediate states of microbiome responses to perturbations is essential for understanding the rules that govern the behavior of this ecosystem. The delineation of microbiome dynamics is also helpful for distinguishing cause and effect in microbiome responses to environmental stimuli. Understanding the dimension of time in host-microbiome interactions is therefore critical for therapeutic strategies that aim at short-term or long-term engineering of the intestinal microbial community.

In tackling the obesity pandemic, considerable efforts are devoted to the development of effective weight reduction strategies, yet many dieting individuals fail to maintain a long-term weight reduction, and instead undergo excessive weight regain cycles. The mechanisms driving recurrent post-dieting obesity remain largely elusive. Here we identify an intestinal microbiome signature that persists after successful dieting of obese mice and contributes to faster weight regain and metabolic aberrations upon re-exposure to obesity-promoting conditions. Faecal transfer experiments show that the accelerated weight regain phenotype can be transmitted to germ-free mice. We develop a machine-learning algorithm that enables personalized microbiome-based prediction of the extent of post-dieting weight regain. Additionally, we find that the microbiome contributes to diminished post-dieting flavonoid levels and reduced energy expenditure, and demonstrate that flavonoid-based 'post-biotic' intervention ameliorates excessive secondary weight gain. Together, our data highlight a possible microbiome contribution to accelerated post-dieting weight regain, and suggest that microbiome-targeting approaches may help to diagnose and treat this common disorder.

SummaryElevated postprandial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postprandial glycemic response to real-life meals. We validated these predictions in an independent 100-person cohort. Finally, a blinded randomized controlled dietary intervention based on this algorithm resulted in significantly lower postprandial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postprandial blood glucose and its metabolic consequences.Video Abstract

The intestinal microbiota undergoes diurnal compositional and functional oscillations that affect metabolic homeostasis, but the mechanisms by which the rhythmic microbiota influences host circadian activity remain elusive. Using integrated multi-omics and imaging approaches, we demonstrate that the gut microbiota features oscillating biogeographical localization and metabolome patterns that determine the rhythmic exposure of the intestinal epithelium to different bacterial species and their metabolites over the course of a day. This diurnal microbial behavior drives, in turn, the global programming of the host circadian transcriptional, epigenetic, and metabolite oscillations. Surprisingly, disruption of homeostatic microbiome rhythmicity not only abrogates normal chromatin and transcriptional oscillations of the host, but also incites genome-wide de novo oscillations in both intestine and liver, thereby impacting diurnal fluctuations of host physiology and disease susceptibility. As such, the rhythmic biogeography and metabolome of the intestinal microbiota regulates the temporal organization and functional outcome of host transcriptional and epigenetic programs.

SummaryHost-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted “postbiotic” metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases.