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The interplay between the commensal microbiota and the mammalian immune system development and function includes multifold interactions in homeostasis and disease. The microbiome plays critical roles in the training and development of major components of the host’s innate and adaptive immune system, while the immune system orchestrates the maintenance of key features of host-microbe symbiosis. In a genetically susceptible host, imbalances in microbiota-immunity interactions under defined environmental contexts are believed to contribute to the pathogenesis of a multitude of immune-mediated disorders. Here, we review features of microbiome-immunity crosstalk and their roles in health and disease, while providing examples of molecular mechanisms orchestrating these interactions in the intestine and extra-intestinal organs. We highlight aspects of the current knowledge, challenges and limitations in achieving causal understanding of host immune-microbiome interactions, as well as their impact on immune-mediated diseases, and discuss how these insights may translate towards future development of microbiome-targeted therapeutic interventions.

Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1β and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases.

Conceptual scientific and medical advances have led to a recent realization that there may be no single, one-size-fits-all diet and that differential human responses to dietary inputs may rather be driven by unique and quantifiable host and microbiome features. Integration of these person-specific host and microbiome readouts into actionable modules may complement traditional food measurement approaches in devising diets that are of benefit to the individual. Although many host-derived factors are hardwired and difficult to modulate, the microbiome may be more readily reshaped by environmental factors such as dietary exposures and is increasingly recognized to potentially impact human physiology by participating in digestion, the absorption of nutrients, shaping of the mucosal immune response and the synthesis or modulation of a plethora of potentially bioactive compounds. Thus, diet-induced microbiota alterations may be harnessed in order to induce changes in host physiology, including disease development and progression. However, major limitations in ‘big-data’ processing and analysis still limit our interpretive and translational capabilities concerning these person-specific host, microbiome and diet interactions. In this Review, we describe the latest advances in understanding diet–microbiota interactions, the individuality of gut microbiota composition and how this knowledge could be harnessed for personalized nutrition strategies to improve human health.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of cardiometabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. It is rapidly becoming the most prevalent liver disease worldwide. A sizable minority of NAFLD patients develop nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, cirrhosis, and hepatocellular carcinoma. Recent studies have shown that in addition to genetic predisposition and diet, the gut microbiota affects hepatic carbohydrate and lipid metabolism as well as influences the balance between pro‐inflammatory and anti‐inflammatory effectors in the liver, thereby impacting NAFLD and its progression to NASH. In this review, we will explore the impact of gut microbiota and microbiota‐derived compounds on the development and progression of NAFLD and NASH, and the unexplored factors related to potential microbiome contributions to this common liver disease. Graphical Abstract In this review, Kolodziejczyk, Elinav and colleagues explore the impact that the gut microbiota may have on the development and progression of nonalcoholic liver diseases (i.e. NAFLD and NASH), and discuss the unexplored factors related to potential microbiome contributions to this common disorder.

Metabolic syndrome often accompanies obesity and hyperglycemia and is associated with a breakdown in the integrity of the intestinal barrier and increased risk of systemic infection. Thaiss et al. found that mice with systemic infection of a Salmonella analog, Citrobacter rodentium , also exhibited hyperglycemia. Deletion of the glucose transporter GLUT2 altered sensitivity to chemically induced epithelial permeability and protected mice from pathogen invasion. The authors also found a correlation in humans between glycated hemoglobin (an indicator of hyperglycemia) and serum levels of pathogen recognition receptor ligands. Science , this issue p. 1376 High blood sugar levels cause epithelial reprogramming, compromising gut barrier integrity and increasing susceptibility to pathogens. Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial–specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.

Polyporaceae is an important fungal family that has been a source of natural products with a range of pharmaceutical activities in China. In our previous study, two polysaccharides, PCWPW and PCWPS, with significant antioxidant and antidepressant activity were obtained from Poria cocos. In this study, we evaluated their potential molecular mechanisms in the immunomodulation of macrophages. PCWPW and PCWPS were characterized by GC–MS analysis to contain 1,3-linked Glcp. ELISA assays results demonstrated that the secretion of TNF-α was significantly enhanced by PCWPW/PCWPS. RNA-seq data demonstrated that PCWPS treatment modulated the expression of immune-related genes in macrophages, which was further confirmed by RT-qPCR assays. The activation of TNF-α secretion was found to be mannose receptor (MR) dependent and suppressed by MR inhibitor pretreatment. Moreover, the amount of TNF-α cytokine secretion in PCWPW/PCWPS-induced RAW264.7 cells was decreased when pretreated with NF-κB or MAPK signaling pathway inhibitors. Collectively, our results suggested that PCWPW and PCWPS possessed immunomodulatory activity that regulates TNF-α expression through the NF-κB/MAPK signaling pathway by binding to mannose receptors. Therefore, PCWPW and PCWPS isolated from Poria cocos have potential as drug candidates for immune-related disease treatment.

Background This study evaluates WHO guidelines, particularly those integrating health systems guidance (HSG) and clinical practice guideline (CPG), by comparing the AGREE Ⅱ and AGREE-HS tools to identify differences in assessing integrated guidelines (IGs). Methods This exploratory evaluation used WHO epidemic guidelines. A comprehensive search in the WHO Institutional Repository for Information Sharing (IRIS) identified CPGs, HSGs, and IGs, which were assessed using AGREE Ⅱ and/or AGREE-HS tools. Results A total of 157 guidelines (20 CPGs, 101 HSGs, and 36 IGs) were included. CPGs scored significantly higher than IGs with AGREE Ⅱ ( P  < 0.001), but no significant difference was found using AGREE-HS ( P  = 0.185). Significant differences were found in multiple domains of AGREE Ⅱ ( P  < 0.05), including Scope and Purpose , Stakeholder Involvement , and Editorial Independence. AGREE-HS also revealed differences in cost-effectiveness and ethical criteria ( P  < 0.05). Conclusion CPGs were of significantly higher quality than IGs when assessed with AGREE Ⅱ, while IGs and HSGs showed similar quality with AGREE-HS. Despite consistent overall scores for IGs across both tools, specific item scores varied. These findings underscore the need for more transparent reporting in IGs, particularly regarding developer information, conflicts of interest, and patient guidance. Future work should focus on developing tools that integrate both AGREE Ⅱ and AGREE-HS to improve guideline evaluation.

Background Previous studies indicated that excessive engagement in digital devices could lead to negative psychological impacts in general population. We aimed to determine the association of electronic screen exposure with depression among women in early pregnancy. Methods A cross-sectional study was conducted from June 2021 to June 2022. A total of 665 women in early pregnancy were recruited and the information included socio-demographic characteristics, screen exposure and Patient Health Questionnaire − 9 depression scale. Results Among the women in early pregnancy, the total daily smartphone viewing time was the longest (median [P25-P75], 5 [3–6] hours/day) in the three types of electronic screen exposure. The total daily smartphone viewing time ( P  = 0.015, OR [95% CI ] = 1.09[1.11–1.18]), smartphone ( P  = 0.016, OR [95% CI ] = 1.24[1.04–1.47]) and television viewing time ( P  = 0.006, OR [95% CI ] = 1.35[1.09–1.67]) before nocturnal sleep were significantly associated with depression among women in early pregnancy. The thresholds calculated by receiver operator characteristic curves were 7.5 h/day, 1.5 h/day and 1.5 h/day, respectively. In addition, women with higher scores of smartphone addiction were more susceptible to depression ( P <0.001, OR [95% CI ] = 1.11[1.07–1.16]). The top three smartphone usages in women with depression were watching videos (22.0%), listening to music (20.9%) and playing games (16.7%). Conclusions In conclusion, electronic screen exposure, including screen viewing time, smartphone addiction and problematic smartphone use was associated with depression among women in early pregnancy. Further studies are warranted to verify the conclusions.

Taste and odor compounds (T&Os), which is often associated with plankton in water sources, pose significant challenges to water quality in the world. Identifying the potential producers and understanding the driving factors are critical for effective treatment. While most studies focused on outbreak of T&Os linked with summer cyanobacterial blooms, questions remain about the mechanisms and environmental factors driving spring outbreaks when cyanobacteria are typically in low abundance. Therefore, changes in the concentrations of T&Os, i.e., 2-methylisoborneol (2-MIB) and three others, in relation to the phytoplankton community, the physico-chemical and hydrological conditions in a mesotrophic reservoir surrounded by hills in East China were investigated from March to June 2023. Results show that 2-MIB was the main T&O during the spring outbreak of phytoplankton, and peaked at 96.10 ng/L, which is nearly 10 times of its odor threshold concentration (OTC) of 10 ng/L. The filamentous cyanobacterium Pseudanabaena sp. was identified as the primary producer of 2-MIB, and the cell concentration of 4 000 cells/mL of Pseudanabaena sp. could potentially result in 10 ng/L of 2-MIB in this reservoir. The abundance of Pseudanabaena sp. and 2-MIB were correlated significantly with turbidity, suggesting that a lower light environment might be critical to promote the dominance of Pseudanabaena sp. and the subsequent production of 2-MIB. Moreover, the combination of consistently decreased water level, moderate water stratification, optimal water temperature ranging ~14–23 °C, the increase of permanganate index (COD Mn ) and total nitrogen (TN) concentration were likely to drive the accumulation and outbreak of 2-MIB. The hydrodynamic disturbance (i.e., a sudden rapid flow of water) triggered the abrupt disappearance of both Pseudanabaena sp. and 2-MIB. This study suggests that proliferation of Pseudanabaena sp. in spring is important in contributing to 2-MIB outbreak, and flushing may be an effective approach to mitigate T&O issues in water sources.

This systematic review and meta-analysis aimed to compare the efficacy of novel bioceramic sealers versus traditional epoxy resin-based sealers (AH Plus) used with the single-cone technique in root canal treatment, focusing on postoperative pain, apical sealing, overfilling, retreatment difficulty, and clinical success. Following PRISMA guidelines, a comprehensive search was conducted across PubMed, Embase, Cochrane CENTRAL, Web of Science, CNKI, and Wanfang databases from January 2014 to December 2024. Randomized controlled trials (RCTs) and cohort studies comparing bioceramic sealers (e.g., iRoot SP, Bio-C Sealer) to AH Plus were included. Two reviewers independently extracted data and assessed quality using Cochrane RoB 2.0 and Newcastle-Ottawa tools. Meta-analyses were performed using RevMan 5.4, employing fixed- or random-effects models based on heterogeneity ( ). Fifteen studies (11 RCTs, 4 cohorts; 1,528 teeth) were included. Bioceramic sealers significantly reduced postoperative pain (OR = 0.48, 95% CI: 0.35-0.66,  < 0.001;  = 22%) and improved apical sealing (SMD = -1.35, 95% CI: -1.78 to -0.92,  < 0.001;  = 71%). However, they increased overfilling risk (OR = 1.85, 95% CI: 1.25-2.74,  = 0.002;  = 18%) and retreatment difficulty (SMD = 0.88, 95% CI: 0.25-1.51,  = 0.006;  = 45%). Mid-term clinical success rates showed no significant difference (OR = 1.12, 95% CI: 0.85-1.47,  = 0.41;  = 15%). Bioceramic sealers outperform AH Plus in reducing pain and enhancing sealing but carry higher overfilling and retreatment challenges. Mid-term success rates are comparable. Clinicians should prioritize bioceramics for cases demanding superior sealing and comfort while employing careful technique to mitigate risks. Long-term studies are needed to validate durability and retreatment protocols. PROSPERO, identifier (CRD420261285302).