Search Results (186)

NLRP6 is a member of the NOD-like receptor family that was initially characterized as an inflammasome-forming sensor in the intestine. However, accumulating evidence over the past decade has revealed that the functions of NLRP6 extend far beyond this canonical role. NLRP6 operates in a wide range of tissues, including the intestine, liver, lung, and immune system, where it exerts context-dependent effects that can be either protective or detrimental. In the intestine, NLRP6 is most consistently associated with host protection, contributing to antiviral defense, epithelial barrier integrity, and the maintenance of microbial and metabolic homeostasis through both inflammasome-dependent and -independent mechanisms. In contrast, in systemic infection models and in certain inflammatory settings, NLRP6 can also promote pathology by suppressing NF-κB signaling; inducing IL-18–mediated lymphocyte death, or enhancing inflammatory cell death pathways. Moreover, studies using both conventional and tissue-specific knockout models have highlighted the importance of the gut–organ axis; particularly the gut–liver axis, in shaping NLRP6-dependent disease outcomes. Here, we summarize recent advances in understanding the upstream regulation, downstream signaling, and tissue-specific functions of NLRP6. Full article

Background: Kai-Bi-Bu-Fei Decoction (KBD) is derived from the canonical Traditional Chinese Medicine formulas Xuan-Bai-Cheng-Qi and Ma-Xing-Shi-Gan. It has been employed for decades in the treatment of severe pneumonia with significant clinical efficacy. This study aimed to evaluate the protective effects of KBD against influenza virus-induced severe pneumonia in a murine model and to elucidate the underlying molecular mechanisms. Methods: The chemical profile of KBD was characterized using UPLC-Q-TOF-MS. A severe pneumonia model was established in C57BL/6J mice via intranasal infection with influenza A/Puerto Rico/8/34 (H1N1, PR8). Multiple parameters, including 14-day survival rate, body weight, lung index, histopathological changes, viral load, and pulmonary cytokine/chemokine levels, were assessed. Furthermore, multi-omics analyses were integrated to characterize the gut microbiota and metabolic profiles. Fecal microbiota transplantation (FMT) was subsequently performed to validate the functional role of the gut microbiota and its metabolites. Results: KBD treatment significantly improved the survival rate by 40%, reduced the lung index by 27.85%, and alleviated lung injury. It also markedly lowered the viral load by 80.88%, suppressed pro-inflammatory cytokine levels, and restored intestinal barrier integrity. Mechanistically, KBD restored gut microbiota diversity by increasing the abundance of Firmicutes and Bacteroidetes, enriching beneficial genera such as Bifidobacterium and Faecalibaculum, and reducing Verrucomicrobiota. Integrated transcriptomic and metabolomic analyses revealed that KBD enhanced short-chain fatty acid (SCFA) metabolism and up-regulated pyruvate metabolism. Finally, FMT confirmed that the therapeutic benefits of KBD were transferable via the microbiota to microbiota-depleted mice. Conclusions: KBD exerts robust protection against severe influenza pneumonia, a process primarily mediated by the gut microbiota–SCFA axis. The enhancement of mitochondrial energy metabolism also appears to play a critical role in its therapeutic mechanism. Full article

Background/Objectives: Probiotic and synbiotic supplementation has been proposed as a preventive strategy against respiratory tract infections (RTIs) in early childhood, although evidence in infants and young children remains inconsistent. This systematic review and meta-analysis aimed to evaluate the effects of probiotic or synbiotic supplementation administered during the first 24 months of life on respiratory infection outcomes. Methods: PubMed/MEDLINE, Embase, and Scopus were systematically searched for randomized controlled trials published between January 2015 and 30 September 2025. Eligible studies included infants and children aged ≤24 months receiving oral probiotics or synbiotics compared with placebo, no intervention, or standard care. The primary outcome was the incidence of at least one upper respiratory tract infection (URTI), while the secondary outcome was the incidence of any RTI. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence was evaluated according to the GRADE approach. Results: Nine randomized controlled trials were included. Probiotic or synbiotic supplementation did not significantly reduce the risk of URTI (OR 0.95, 95% CI 0.47–1.95; I² = 78%). A non-significant trend toward a reduced risk of any RTI was observed (OR 0.66, 95% CI 0.35–1.25; I² = 69%). Exploratory subgroup analyses suggested possible strain-specific effects, with signals observed for Bifidobacterium longum subsp. infantis in relation to URTI prevention and Lactiplantibacillus plantarum ATCC 202195 for reduction in any RTI. However, these findings were based on a limited number of studies and should be interpreted cautiously. No serious adverse events attributable to supplementation were reported. Conclusions: Current evidence does not support the routine use of probiotic or synbiotic supplementation for the prevention of respiratory infections in children aged ≤24 months. However, potential strain-specific benefits warrant further investigation in adequately powered randomized trials. Full article

Lung cancer, particularly non-small cell lung cancer (NSCLC), remains the leading cause of cancer mortality worldwide. While immune checkpoint inhibitors (ICIs) have revolutionized treatment, primary and acquired resistance, and immune-related adverse events (irAEs) limit their therapeutic efficacy. Recent evidence highlights the gut and local microbial communities as a modifiable determinant of NSCLC outcomes, especially in the context of ICI use. Emerging data support the concept of a gut–lung-immune axis, a tridirectional communication pathway, in which gut and lung microbial communities influence local and systemic antitumor immunity through immune cell trafficking, cytokine signaling, and microbial-derived metabolites. In this review, we synthesize current clinical and mechanistic studies examining the role of gut, tumor-resident, and circulating microbiota in shaping ICI efficacy and toxicity in NSCLC. Distinct gut and tumor microbial signatures, such as the abundance of Akkermansia muciniphila and Bifidobacterium, correlate with improved ICI response, whereas dysbiosis promotes immune suppression, resistance, and irAEs. Additionally, we highlight emerging microbial-based biomarkers, including fecal microbial profiles, circulating microbial DNA, and composite tools such as TOPOSCORE, which show promise for predicting response, toxicity, and optimal treatment duration. Overall, these findings underscore the gut–lung-immune axis as a key regulator of immunotherapy outcomes in NSCLC and suggest that microbiome-informed strategies may enable more precise, effective, and safer personalization of ICI therapy. Full article

Upper respiratory tract infections (URTI) are highly prevalent worldwide. Although probiotics have shown potential in preventing URTI, evidence in healthy adults remains limited. Lacticaseibacillus rhamnosus CRL 1505 is a strain with immunomodulatory effects in preclinical studies and benefits in healthy children. Based on this evidence, a randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted in healthy adults, receiving either L. rhamnosus CRL 1505 (1 bln/day) or placebo for 12 weeks, with a 4-week follow-up. The primary endpoint was the proportion of participants experiencing URTI episodes (at least one, two, or three episode(s)). The secondary endpoints included: number and duration of URTI episodes, URTI-free time, symptom severity, use of symptomatic medication, salivary IgA levels, and safety outcomes. Results show that L. rhamnosus CRL 1505 significantly reduced the number of participants experiencing ≥3 URTI episodes at 16 weeks compared with placebo. The probiotic group experienced fewer URTI episodes per participant, a shorter cumulative duration of URTIs, and a higher URTI-free time rate. Probiotic supplementation significantly reduced the use of symptomatic medications. In conclusion, daily supplementation with L. rhamnosus CRL 1505 reduced the burden of URTI in healthy adults, specifically of those experiencing more episodes, by decreasing infection frequency, duration, and medication use. Full article

Both the gut and the lungs possess a microbiome, a community of commensal bacteria, archaea, fungi, and viruses that perform important housekeeping functions in those organs. The colonic microbiome primarily ferments indigestible dietary fibers into essential short-chain fatty acids, synthesizes essential vitamins, regulates the mucosal immune system, and forms a protective barrier against pathogenic colonization. The lung microbiome maintains respiratory health primarily by regulating mucosal immunity, providing a physical barrier against invading pathogens, and producing beneficial metabolites. Several colonic microbiota metabolites, including the short-chain fatty acids acetate, propionate, and butyrate, together with the tryptophan metabolites indole-3-acetate and indole-3-propionate, secondary bile acids, and the polyamines spermidine and putrescine, are transported to the lungs via the gut–lung axis. These colonic microbiota biomolecules suppress lung inflammation, strengthen immune homeostasis, and reduce the severity of respiratory diseases. In contrast, lung microorganisms and their metabolites can travel to the gut via the gut–lung axis, influencing intestinal immune responses and potentially leading to an imbalance of gut microorganisms or dysbiosis. This means that respiratory diseases may lead to digestive issues, intestinal inflammation and chronic diseases. Here, we have reviewed this crosstalk and its impact on the principal pulmonary diseases: asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchogenic carcinoma, COVID-19, interstitial lung diseases, pneumonia, and tuberculosis. It is concluded that the gut microbiome plays a significant part in lung health and disease. Diet, tobacco smoking and electronic cigarette vaping all impact both the gut and lung microbiomes. Full article

Antimicrobial resistance in Mycoplasma gallisepticum (MG), a primary causative agent of chronic respiratory disease in poultry, has reached alarming levels, underscoring the urgent need for alternative strategies. Natural products have emerged as promising candidates owing to their multi-target mechanisms of action. This review synthesizes current evidence on natural anti-MG agents, critically appraising their in vitro and in vivo efficacy, molecular mechanisms, and translational potential. A mechanistic taxonomy is proposed for distinguishing direct pathogen-directed mechanisms (membrane disruption, adhesion inhibition, virulence factor neutralization) from indirect host-directed mechanisms, notably NF-κB/MAPK pathway modulation and gut–lung axis immunoregulation. Emphasis is placed on anti-infective polypharmacology, exemplified by luteolin’s dual inhibition of the TatD virulence factor and host inflammatory cascades. The gut–lung axis represents a novel therapeutic frontier, with Bacillus subtilis KC1 controlling respiratory mycoplasmosis through intestinal microbiome remodeling and systemic AhR activation. Despite encouraging efficacy data, critical knowledge gaps persist, including a scarcity of rigorous in vivo trials under commercial conditions, incomplete mechanistic characterization, and challenges in standardizing complex natural product formulations. Natural products are best positioned not as wholesale antibiotic replacements but as integral components of integrated, antibiotic-sparing strategies aligned with antimicrobial stewardship and One Health principles. Full article

Micro- and nanoplastics (MNPs) are widespread environmental pollutants, with increasing evidence of human exposure through multiple routes. Their detection in human tissues, including the lungs, raises concerns about their potential impact on respiratory health, including lung cancer (LC). This review synthesizes current evidence on the biological effects of MNP exposure, with a focus on mechanisms potentially relevant to LC. In particular, extracellular vesicles (EVs) are discussed as mediators potentially linking environmental exposure to cellular responses. Experimental studies suggest that MNPs may induce oxidative stress, inflammation, and genotoxicity, and may alter EV biogenesis and cargo, thereby influencing pathways involved in epithelial–mesenchymal transition, angiogenesis, and immune modulation. We also explore the potential contribution of the gut–lung axis, where MNP-induced dysbiosis and intestinal barrier disruption may promote systemic inflammatory responses, with bacterial EVs acting as additional mediators. However, evidence directly linking MNP exposure, EV-mediated signaling, and LC is limited and largely derived from experimental models. Key challenges include the lack of standardized detection methods, insufficient dose–response data, and scarce epidemiological evidence. Integrating exposomic and multi-omic approaches, including EV-omics, lipidomics, and metabolomics, is needed to clarify the relevance of these mechanisms and support the identification of potential biomarkers in human disease. Full article

Background/Objectives: Respiratory tract infections (RTIs) are a leading cause of morbidity in children under five, with over 75% experiencing recurrent episodes and an increased risk of asthma by school age, particularly following respiratory syncytial virus (RSV) and rhinovirus (RV) infections. While current therapies primarily address acute symptoms, effective preventive strategies remain limited. Bacterial-derived immunomodulators have emerged as promising interventions, but their mechanisms and pediatric clinical evidence remain incompletely characterized. This narrative review examines preclinical mechanisms and clinical findings for four such agents, contextualizing current evidence and identifying key gaps. Methods: A targeted narrative review of PubMed-indexed literature (inception to September 2025) was conducted. Mechanistic studies, pediatric (0–18 years) clinical trials, and meta-analyses evaluating OM-85, polyvalent mechanical bacterial lysates (PMBL/Ismigen), MV130, and Lactobacillus rhamnosus CRL1505 were included. Outcomes of interest comprised immunological mechanisms, RTI incidence, wheezing, and asthma-related outcomes. Results: All four agents share convergent immunomodulatory mechanisms involving epithelial barrier reinforcement, innate immune activation, and adaptive immune modulation. OM-85 has the most extensive preclinical evidence. PMBL enhances epithelial repair via the IL-23/IL-22 axis, MV130 induces trained immunity, and CRL1505 acts through the gut–lung axis. Clinical evidence varies markedly, with OM-85 showing the most comprehensive data (18 RCTs and 7 meta-analyses), followed by PMBL and MV130, while evidence for CRL1505 remains predominantly preclinical. Conclusions: Despite variable evidence maturity, these agents share a coherent mechanistic rationale and favorable safety profiles, with ongoing studies expected to clarify their clinical role in early-life respiratory prevention. Full article

The gut microbiota, often referred to as the “forgotten organ”, plays an indispensable role in maintaining host physiological metabolism, immune function, and nutrient absorption. Moreover, the gut microbiome serves as a critical biological barrier against viral infections and is increasingly recognized as a potential target to augment antiviral therapies. Recent studies have revealed that microbial ligands and metabolites derived from the gut microbiota are pivotal in modulating respiratory immune responses, providing compelling evidence of the complex interaction network between microorganisms and the host, particularly the signaling pathways linking the gut to distal organs such as the lungs. This review examines the communication and regulatory mechanisms between the gut microbiota and pulmonary mucosal surfaces during influenza virus infection, emphasizing how gut microbial communities and probiotics influence host immune responses, promote the production of immune-related molecules, and enhance antiviral defenses. The aim is to provide comprehensive insights into the gut–lung axis and its implications for respiratory health. Full article

Sensory neurons at barrier tissues were once seen as passive detectors of environmental stimuli. However, in the last five years, increasing evidence has challenged this view, redefining these cells as active immune sentinels that directly affect tissue immunity in the skin, lungs, and gastrointestinal tract. Nociceptors and pruriceptors express various immune-sensing receptors, including Toll-like receptors, cytokine receptors, and alarmin sensors, which allow them to directly detect pathogens, allergens, and tissue damage. When activated, sensory neurons quickly release neuropeptides such as calcitonin gene-related peptide (CGRP), substance P, vasoactive intestinal peptide (VIP), and PACAP (pituitary adenylate cyclase-activating polypeptide), which guide immune cell recruitment, activation, and resolution. Reciprocally, immune-derived mediators, including IL-33, IL-31, thymic stromal lymphopoietin (TSLP), IL-4/IL-13, and TNF-α, modulate neuronal excitability and plasticity, forming bidirectional neuroimmune circuits that control inflammation, host defense, pain, and itch. Landmark studies published in 2024–2025, including neuronal control of gut Treg function and the identification of sensory nerve immune niches, have further refined this framework and revealed tissue-specific circuit specialization. This review synthesizes recent insights from molecular, cellular, and systems levels into the sensory neuroimmune axis, emphasizes its protective versus pathogenic roles, and critically evaluates emerging therapeutic strategies and safety concerns, positioning sensory neuroimmunology as a unifying framework for tissue barrier homeostasis and disease. Full article

The gut–lung axis is important in Chronic Obstructive Pulmonary Disease (COPD) pathogenesis; however, most studies rely on low-resolution 16S rRNA sequencing, and integrated multi-omics investigations in Chinese COPD populations are scarce. A total of 104 participants including 74 stable COPD patients and 30 healthy controls from northern China were recruited, and shotgun metagenomic sequencing and untargeted metabolomics were performed. Results showed that alpha diversity of the gut microbiota did not differ significantly between COPD patients and healthy controls, whereas beta diversity showed clear separation. Marked differences in microbial composition from phylum to species levels (e.g., Oscillospiraceae) and altered microbial functions (signal transduction, antibiotic resistance, etc.) were observed in COPD patients. Metabolomic profiling identified 497 differential fecal metabolites and 1260 differential serum metabolites in COPD patients. Importantly, serum riboflavin levels were significantly reduced and positively correlated with pulmonary function indices as well as the key differential gut microbial functional gene K11752. Serum metabolite eremopetasinorol exhibited high diagnostic accuracy for COPD (AUC = 0.947, 95% CI: 0.8–0.98), surpassing fecal metabolites and microbial features. This study provides integrated metagenomic and metabolomic characterization of gut microbiota alterations in Chinese COPD patients, offering novel insights for biomarker discovery and targeted intervention strategies. Full article

(1) Airborne fine particulate matter (PM_2.5) poses a growing threat to poultry production by impairing intestinal health, disturbing microbial balance, and reducing growth performance. Rosmarinic acid (RA), a natural polyphenol with antioxidant, anti-inflammatory, and gut microbiota-regulating properties, can effectively maintain intestinal homeostasis. To date, its protective effects against PM_2.5-induced intestinal injury in broilers remain largely unclear. This study investigated whether dietary RA supplementation mitigates intestinal damage and microbiota dysbiosis caused by PM_2.5 in broilers and explored the related mechanisms. (2) A total of 144 21-day-old broilers were randomly allocated to three groups, control (CON), PM_2.5 exposure (PM), and PM_2.5 exposure plus rosmarinic acid (RA), with six replicates of eight broilers each. (3) Results indicated that PM_2.5 exposure severely impaired growth performance, whereas dietary RA significantly increased average daily feed intake and average daily gain, decreased the feed-to-gain ratio, and elevated final body weight in broilers. RA significantly attenuated PM_2.5-induced intestinal inflammation, as evidenced by reduced expression of inflammatory cytokines (IL-6 and IFN-γ) and downregulation of key components in the TLR4 signaling pathway (TLR4, MyD88, and NF-κB). Inhaled PM_2.5 exposure impaired the intestinal epithelial barrier, marked by decreased mRNA levels of MUC2 and CLDN1 and increased caspase3 expression. Dietary RA treatment effectively restored these indicators, suggesting its role in maintaining epithelial integrity. Furthermore, RA reshaped the gut microbiota structure, altering both α- and β-diversity. Notably, RA led to a higher proportion of potentially health-promoting bacterial taxa, including Lactobacillus, V9D2013_group, and Oscillospirales, while reducing opportunistic pathogens like Shuttleworthia. (4) In conclusion, RA alleviates PM_2.5-induced intestinal inflammation, reinforces the epithelial barrier, and modulates the intestinal microbiota in broilers, likely through inhibition of the TLR4/NF-κB signaling. These findings reveal a novel mechanism by which RA mitigates pollutant-induced intestinal injury via gut microbiota modulation and TLR4/NF-κB suppression, offering new insights into the gut–lung axis in avian species. Full article

Background: Upper respiratory tract infections (URTIs), allergic rhinitis (AR), and chronic rhinosinusitis (CRS) are prevalent and burdensome inflammatory disorders. Probiotics may modulate immune responses via gut–respiratory axis signaling, but their clinical efficacy across these conditions remains uncertain and highly heterogeneous. Methods: We conducted a PRISMA-guided systematic review and random-effects meta-analysis of randomized controlled trials (RCTs) evaluating oral or topical probiotics for URTIs, AR, or CRS (MEDLINE, EMBASE, CENTRAL, and Web of Science; inception to July 2025). Disease severity category (acute, subacute, chronic), episode incidence, and duration of illness were extracted alongside symptom scores. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence was graded using the GRADE framework. Results: Thirty-two RCTs were included. In URTIs, certain strains [e.g., Lactiplantibacillus plantarum DR7, Lactobacillus rhamnosus GG] reduced symptom duration and antibiotic use; however, the pooled incidence reduction was non-significant (RD = −0.07; 95% CI: −0.23 to 0.09; p = 0.38), with very high heterogeneity (I² = 93.12%), limiting interpretability. In AR, probiotics reduced TNSS and improved quality of life (SMDs −0.72 to −2.30) in individual trials supported by immune marker changes [e.g., increased IL-10, decreased IgE]. In CRS, only two small trials—differing in delivery route (topical vs. oral), CRS phenotype, and publication era (2009 and 2017)—with conflicting effect directions were identified; formal meta-analysis was not performed given insufficient and methodologically heterogeneous data, and CRS findings are reported descriptively only. GRADE certainty ranged from very low (URTI incidence) to low (AR symptoms, URTI illness burden). Conclusions: Probiotic effects appear strain- and condition-specific. URTI pooled incidence data are unreliable due to extreme heterogeneity; individual strains show consistent benefits on illness burden and AR symptoms/quality of life. Evidence for CRS is insufficient for meta-analytic conclusions; findings are reported descriptively pending adequately powered dedicated trials. Strain-targeted RCTs with standardized outcomes, formal GRADE appraisal, and adequate power are needed before clinical recommendations can be made. Full article

Allergic asthma is a prevalent chronic inflammatory disease of the airways whose pathogenesis has traditionally been attributed to localized immune dysfunction within the lung. However, accumulating evidence from microbiome research supports a broader system-level perspective in which cross-organ interactions contribute to disease susceptibility and progression. In particular, the gut–lung axis has emerged as a key regulatory pathway linking intestinal microbial ecology, immune development, and respiratory health. This review synthesizes current epidemiological, mechanistic, and experimental evidence supporting the role of gut microbiota dysbiosis in allergic asthma. We examine how early-life environmental and nutritional exposures and gut microbiota establishment during critical developmental windows shape long-term immune tolerance and asthma susceptibility. We then summarize characteristic features of asthma-associated gut dysbiosis and discuss how microbial-derived metabolites, including short-chain fatty acids, tryptophan metabolites, pro-allergic lipid mediators such as 12,13-dihydroxy-9Z-octadecenoic acid, and bacterial-derived histamine, modulate distal airway immune responses through epigenetic, receptor-mediated, and immune trafficking mechanisms. Particular emphasis is placed on the role of diet as a key upstream regulator of gut microbiota composition and metabolic function. Finally, we evaluate experimental and translational studies targeting the gut–lung axis, including dietary modulation, microbiome-targeted interventions such as fecal microbiota transplantation, and emerging postbiotic approaches. Collectively, current evidence indicates that gut microbial composition and metabolic function are critical determinants of respiratory immune homeostasis. Targeting the gut–lung axis through nutrition- and microbiome-based strategies offers a promising avenue for the prevention and precision treatment of allergic asthma. Full article