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Prior research has indicated that the gut-lung-axis can be influenced by the intestinal microbiota, thereby impacting lung immunity. Rifaximin is a broad-spectrum antibacterial drug that can maintain the homeostasis of intestinal microflora. In this study, we established an influenza A virus (IAV)-infected mice model with or without rifaximin supplementation to investigate whether rifaximin could ameliorate lung injury induced by IAV and explore the molecular mechanism involved. Our results showed that IAV caused significant weight loss and disrupted the structure of the lung and intestine. The analysis results of 16S rRNA and metabolomics indicated a notable reduction in the levels of probiotics Lachnoclostridium, Ruminococcaceae_UCG-013, and tryptophan metabolites in the fecal samples of mice infected with IAV. In contrast, supplementation with 50 mg/kg rifaximin reversed these changes, including promoting the repair of the lung barrier and increasing the abundance of Muribaculum, Papillibacter and tryptophan-related metabolites content in the feces. Additionally, rifaximin treatment increased ILC3 cell numbers, IL-22 level, and the expression of RORγ and STAT-3 protein in the lung. Furthermore, our findings demonstrated that the administration of rifaximin can mitigate damage to the intestinal barrier while enhancing the expression of AHR, IDO-1, and tight junction proteins in the small intestine. Overall, our results provided that rifaximin alleviated the imbalance in gut microbiota homeostasis induced by IAV infection and promoted the production of tryptophan-related metabolites. Tryptophan functions as a signal to facilitate the activation and movement of ILC3 cells from the intestine to the lung through the AHR/STAT3/IL-22 pathway, thereby aiding in the restoration of the barrier. KEY POINTS: • Rifaximin ameliorated IAV infection-caused lung barrier injury and induced ILC3 cell activation. • Rifaximin alleviated IAV-induced gut dysbiosis and recovered tryptophan metabolism. • Tryptophan mediates rifaximin-induced ILC3 cell activation via the AHR/STAT3/IL-22 pathway.

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Background: The diagnosis and treatment of lung, colon, and gastric cancer through the histologic characteristics and genomic biomarkers have not had a strong impact on the mortality rates of the top three global causes of death by cancer. Methods: Twenty-five transcriptomic analyses (10 lung cancer, 10 gastric cancer, and 5 colon cancer datasets) followed our own bioinformatic pipeline based on the utilization of specialized libraries from the R language and DAVID´s gene enrichment analyses to identify a regulatory metafirm network of transcription factors and target genes common in every type of cancer, with experimental evidence that supports its relationship with the unlocking of cell phenotypic plasticity for the acquisition of the hallmarks of cancer during the tumoral process. The network's regulatory functional and signaling pathways might depend on the constant crosstalk with the microbiome network established in the oral-gut-lung axis. Results: The global transcriptomic network analysis highlighted the impact of transcription factors (SOX4, TCF3, TEAD4, ETV4, and FOXM1) that might be related to stem cell programming and cancer progression through the regulation of the expression of genes, such as cancer-cell membrane receptors, that interact with several microorganisms, including human T-cell leukemia virus 1 (HTLV-1), the human papilloma virus (HPV), the Epstein-Barr virus (EBV), and SARS-CoV-2. These interactions can trigger the MAPK, non-canonical WNT, and IFN signaling pathways, which regulate key transcription factor overexpression during the establishment and progression of lung, colon, and gastric cancer, respectively, along with the formation of the microbiome network. Conclusion: The global transcriptomic network analysis highlights the important interaction between key transcription factors in lung, colon, and gastric cancer, which regulates the expression of cancer-cell membrane receptors for the interaction with the microbiome network during the tumorigenic process.

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This comprehensive review undertakes a multidisciplinary exploration of the gut-lung axis, from the foundational aspects of anatomy, embryology, and histology, through the functional dynamics of pathophysiology, to implications for clinical science. The gut-lung axis, a bidirectional communication pathway, is central to understanding the interconnectedness of the gastrointestinal- and respiratory systems, both of which share embryological origins and engage in a continuous immunological crosstalk to maintain homeostasis and defend against external noxa. An essential component of this axis is the mucosa-associated lymphoid tissue system (MALT), which orchestrates immune responses across these distant sites. The review delves into the role of the gut microbiome in modulating these interactions, highlighting how microbial dysbiosis and increased gut permeability ("leaky gut") can precipitate systemic inflammation and exacerbate respiratory conditions. Moreover, we thoroughly present the implication of the axis in oncological practice, particularly in lung cancer development and response to cancer immunotherapies. Our work seeks not only to synthesize current knowledge across the spectrum of science related to the gut-lung axis but also to inspire future interdisciplinary research that bridges gaps between basic science and clinical application. Our ultimate goal was to underscore the importance of a holistic understanding of the gut-lung axis, advocating for an integrated approach to unravel its complexities in human health and disease.

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The gastrointestinal tract contains a diverse microbiome consisting of bacteria, fungi, viruses and archaea. Although these microbes usually reside as commensal organisms, it is now well established that higher abundance of specific bacterial or fungal species, or loss of diversity in the microbiome can significantly affect development, progression and outcomes in disease. Studies have mainly focused on the effects of bacteria, however, the impact of other microbes, such as fungi, has received increased attention in the last few years. Fungi only represent around 0.1% of the total gut microbial population. However, key fungal taxa such as Candida, Aspergillus and Wallemia have been shown to significantly impact health and disease. The composition of the gut mycobiome has been shown to affect immunity at distal sites, such as the heart, lung, brain, pancreas, and liver. In the case of the lung this phenomenon is referred to as the 'gut-lung axis'. Recent studies have begun to explore and unveil the relationship between gut fungi and lung immunity in diseases such as asthma and lung cancer, and lung infections caused by viruses, bacteria and fungi. In this review we will summarize the current, rapidly growing, literature describing the impact of the gut mycobiome on respiratory disease and infection.

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Group 2 innate lymphoid cells (ILC2s) play a crucial role in the progression of asthma, yet the regulatory mechanisms modulating ILC2 responses in asthma remain underexplored. Human milk oligosaccharides (HMOs), vital non-nutritive components of breast milk, are known to significantly shape immune system development and influence the incidence of allergic diseases. However, their impact on ILC2-driven asthma is not fully understood. Our research reveals that dietary HMOs act as potent inhibitors of ILC2 responses and allergic airway inflammation. Treatment with 2'-fucosyllactose (2'-FL) and 6'-sialyllactose (6'-SL) significantly reduced ILC2-related airway inflammation induced by papain or Alternaria alternata in mice, evidenced by decreased eosinophil (EOS) infiltration and lower IL-5 and IL-13 levels in BALF. Notably, while ILC2 expresses HMO receptors, HMO did not act directly on ILC2 but potentially modulated their activity through alterations in gut microbiota derived SCFAs. HMO treatments alleviated airway inflammation in SCFA-dependent manners, with SCFA depletion or receptor blocking reversing these beneficial effects. This study reveals the potential of dietary HMOs in managing asthma through modulation of ILC2 activity and the gut-lung axis, proposing a new therapeutic avenue that utilises the immunomodulatory capacities of nutritional components to combat respiratory diseases.

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Introduction: Introduction: The influenza virus primarily targets the respiratory tract, yet both the respiratory and intestinal systems suffer damage during infection. The connection between lung and intestinal damage remains unclear. Methods: Our experiment employs 16S rRNA technology and Liquid Chromatography-Mass Spectrometry (LC-MS) to detect the impact of influenza virus infection on the fecal content and metabolites in mice. Additionally, it investigates the effect of influenza virus infection on intestinal damage and its underlying mechanisms through HE staining, Western blot, Q-PCR, and flow cytometry. Results: Our study found that influenza virus infection caused significant damage to both the lungs and intestines, with the virus detected exclusively in the lungs. Antibiotic treatment worsened the severity of lung and intestinal damage. Moreover, mRNA levels of Toll-like receptor 7 (TLR7) and Interferon-b (IFN-b) significantly increased in the lungs post-infection. Analysis of intestinal microbiota revealed notable shifts in composition after influenza infection, including increased Enterobacteriaceae and decreased Lactobacillaceae. Conversely, antibiotic treatment reduced microbial diversity, notably affecting Firmicutes, Proteobacteria, and Bacteroidetes. Metabolomics showed altered amino acid metabolism pathways due to influenza infection and antibiotics. Abnormal expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the colon disrupted the balance between helper T17 cells (Th17) and regulatory T cells (Treg cells) in the intestine. Mice infected with the influenza virus and supplemented with tryptophan and Lactobacillus showed reduced lung and intestinal damage, decreased Enterobacteriaceae levels in the intestine, and decreased IDO1 activity. Discussion: Overall, influenza infection caused damage to lung and intestinal tissues, disrupted intestinal microbiota and metabolites, and affected Th17/Treg balance. Antibiotic treatment exacerbated these effects. Supplementation with tryptophan and Lactobacillus improved lung and intestinal health, highlighting a new understanding of the lung-intestine connection in influenza-induced intestinal disease.

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BACKGROUND: The gut-lung axis, pivotal for respiratory health, is inadequately explored in pulmonary and critical care medicine (PCCM) inpatients. METHODS: Examining PCCM inpatients from three medical university-affiliated hospitals, we conducted 16S ribosomal RNA sequencing on stool samples (inpatients, n = 374; healthy controls, n = 105). We conducted statistical analyses to examine the gut microbiota composition in PCCM inpatients, comparing it to that of healthy controls. Additionally, we explored the associations between gut microbiota composition and various clinical factors, including age, white blood cell count, neutrophil count, platelet count, albumin level, hemoglobin level, length of hospital stay, and medical costs. RESULTS: PCCM inpatients exhibited lower gut microbiota diversity than healthy controls. Principal Coordinates Analysis revealed marked overall microbiota structure differences. Four enterotypes, including the exclusive Enterococcaceae enterotype in inpatients, were identified. Although no distinctions were found at the phylum level, 15 bacterial families exhibited varying abundances. Specifically, the inpatient population from PCCM showed a significantly higher abundance of Enterococcaceae, Lactobacillaceae, Erysipelatoclostridiaceae, Clostridiaceae, and Tannerellaceae. Using random forest analyses, we calculated the areas under the receiver operating characteristic curves (AUCs) to be 0.75 (95% CIs 0.69-0.80) for distinguishing healthy individuals from inpatients. The four most abundant genera retained in the classifier were Blautia, Subdoligranulum, Enterococcus, and Klebsiella. CONCLUSIONS: Evidence of gut microbiota dysbiosis in PCCM inpatients underscores the gut-lung axis's significance, promising further avenues in respiratory health research.

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Introduction: Pulmonary neutrophilia is a hallmark of numerous airway diseases including Chronic Obstructive Pulmonary Disease (COPD), Neutrophilic asthma, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS) and COVID-19. The aim of the current study was to investigate the effect of dietary interventions on lung health in context of pulmonary neutrophilia. Methods: Male BALB/cByJ mice received 7 intra-nasal doses of either a vehicle or lipopolysaccharides (LPS). To study the effect of nutritional interventions they received 16 intra-gastric doses of either a vehicle (PBS) or the following supplements (1) probiotic Bifidobacterium breve (B. breve) M16-V; (2) a prebiotic fiber mixture of short-chain galacto-oligosaccharides, long-chain fructo-oligosaccharides, and low-viscosity pectin in a 9:1:2 ratio (scGOS/lcFOS/lvPectin); and (3) A synbiotic combination B. breve M16-V and scGOS/lcFOS/lvPectin. Parameters for lung health included lung function, lung morphology and lung inflammation. Parameters for systemic immunomodulation included levels of fecal short chain fatty acids and regulatory T cells. Results: The synbiotic supplement protected against the LPS induced decline in lung function (35% improved lung resistance at baseline p = 0.0002 and 25% at peak challenge, p = 0.0002), provided a significant relief from pulmonary neutrophilia (40.7% less neutrophils, p < 0.01) and improved the pulmonary neutrophil-to-lymphocyte ratio (NLR) by 55.3% (p = 0.0033). Supplements did not impact lung morphology in this specific experiment. LPS applied to the upper airways induced less fecal SCFAs production compared to mice that received PBS. The production of acetic acid between day -5 and day 16 was increased in all unchallenged mice (PBS-PBS p = 0.0003; PBS-Pro p < 0.0001; PBS-Pre, p = 0.0045; PBS-Syn, p = 0.0005) which upon LPS challenge was only observed in mice that received the synbiotic mixture of B. breve M16-V and GOS:FOS:lvPectin (p = 0.0003). A moderate correlation was found for butyric acid and lung function parameters and a weak correlation was found between acetic acid, butyric acid and propionic acid concentrations and NLR. Conclusion: This study suggests bidirectional gut lung cross-talk in a mouse model for pulmonary neutrophilia. Neutrophilic lung inflammation coexisted with attenuated levels of fecal SCFA. The beneficial effects of the synbiotic mixture of B. breve M16-V and GOS:FOS:lvPectin on lung health associated with enhanced levels of SCFAs.

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Recent experimental and epidemiological studies underscore the vital interaction between the intestinal microbiota and the lungs, an interplay known as the "gut-lung axis". The significance of this axis has been further illuminated following the identification of intestinal microbial metabolites, such as short-chain fatty acids (SCFA), as key mediators in setting the tone of the immune system. Through the gut-lung axis, the gut microbiota and its metabolites, or allergens, are directly or indirectly involved in the immunomodulation of pulmonary diseases, thereby increasing susceptibility to allergic airway diseases such as asthma. Asthma is a complex outcome of the interplay between environmental factors and genetic predispositions. The concept of the gut-lung axis may offer new targets for the prevention and treatment of asthma. This review outlines the relationships between asthma and the respiratory microbiome, gut microbiome, and environmental microbiome. It also discusses the current advancements and applications of microbiomics, offering novel perspectives and strategies for the clinical management of chronic respiratory diseases like asthma.

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The communication mechanism of the gut-lung axis has received increasing attention in recent years, particularly in acute respiratory infectious diseases such as influenza. The peripheral immune system serves as a crucial bridge between the gut and the lungs, two organs that are not in close proximity to each other. However, the specific communication mechanism involving gut microbiota, immune cells, and their anti-influenza effects in the lung remains to be further elucidated. In this study, the effects of 731 species of peripheral immune cells and 211 different gut microbiota on influenza outcomes were analyzed using a two-sample Mendelian randomization analysis. After identifying specific species of gut microbiota and peripheral immune cells associated with influenza outcomes, mediation analyses were conducted to determine the mediating effects of specific immune cells in the protective or injurious effects of influenza mediated by gut microbiota. 19 species of gut microbiota and 75 types of peripheral immune cells were identified as being associated with influenza susceptibility. After rigorous screening, 12 combinations were analyzed for mediated effects. Notably, the down-regulation of CD64 on CD14- CD16- cells mediated 21.10% and 18.55% of the protective effect of Alcaligenaceae and Dorea against influenza, respectively. In conclusion, focusing on influenza, this study genetically inferred different types of gut microbiota and peripheral immune cells to determine their protective or risk factors. Furthermore, mediation analysis was used to determine the proportion of mediating effects of peripheral immune cells in gut microbiota-mediated susceptibility to influenza. This helps elucidate the gut-lung axis mechanism by which gut microbiota affects influenza susceptibility from the perspective of regulation of peripheral immune cells.

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Asthma is, worldwide, the most frequent non-communicable disease affecting both children and adults, with high morbidity and relatively low mortality, compared to other chronic diseases. In recent decades, the prevalence of asthma has increased in the pediatric population, and, in general, the risk of developing asthma and asthma-like symptoms is higher in children during the first years of life. The "gut-lung axis" concept explains how the gut microbiota influences lung immune function, acting both directly, by stimulating the innate immune system, and indirectly, through the metabolites it generates. Thus, the process of intestinal microbial colonization of the newborn is crucial for his/her future health, and the alterations that might generate dysbiosis during the first 100 days of life are most influential in promoting hypersensitivity diseases. That is why this period is termed the "critical window". This paper reviews the published evidence on the numerous factors that can act by modifying the profile of the intestinal microbiota of the infant, thereby promoting or inhibiting the risk of asthma later in life. The following factors are specifically addressed in depth here: diet during pregnancy, maternal adherence to a Mediterranean diet, mode of delivery, exposure to antibiotics, and type of infant feeding during the first three months of life.

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The increased global prevalence of chronic respiratory diseases in recent years has caused a substantial public health burden. Lactiplantibacillus plantarum KC3 and Leonurus japonicus Houtt. (LJH) extracts can alleviate respiratory symptoms and improve lung function in vitro and in vivo. However, the clinical efficacy and safety profile of this combination in patients with respiratory diseases remain unclear. Therefore, this multicenter, randomized, double-blind, placebo-controlled clinical trial aimed to evaluate the efficacy and safety of L. plantarum KC3 and LJH extracts in adults with respiratory discomfort. This mixture was termed 'CKDB-315'. Participants, randomly assigned to the CKDB-315 or placebo groups, were treated for 12 weeks. Assessments included the St. George's Respiratory Questionnaire (SGRQ) and the Chronic Obstructive Pulmonary Disease Assessment Test (CAT). The CKDB-315 group showed considerably improved SGRQ and CAT scores compared with the placebo group. Secondary outcomes, including dyspnea, pulmonary function, total antioxidant status, and inflammatory cytokine levels, were consistent with the primary outcomes. Exploratory analyses of the gut microbiota and short-chain fatty acid contents revealed the potential mechanisms underlying the effects of CKDB-315. Finally, safety analysis indicated that CKDB-315 was well tolerated and caused few adverse events. Our findings indicate that CKDB-315 is a promising therapeutic option for respiratory discomfort in adults.

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Antibiotic use in early life disrupts microbial colonization and increases the risk of developing allergies and asthma. We report that mice given antibiotics in early life (EL-Abx), but not in adulthood, were more susceptible to house dust mite (HDM)-induced allergic airway inflammation. This susceptibility was maintained even after normalization of the gut microbiome. EL-Abx decreased systemic levels of indole-3-propionic acid (IPA), which induced long-term changes to cellular stress, metabolism, and mitochondrial respiration in the lung epithelium. IPA reduced mitochondrial respiration and superoxide production and altered chemokine and cytokine production. Consequently, early-life IPA supplementation protected EL-Abx mice against exacerbated HDM-induced allergic airway inflammation in adulthood. These results reveal a mechanism through which EL-Abx can predispose the lung to allergic airway inflammation and highlight a possible preventative approach to mitigate the detrimental consequences of EL-Abx.

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Preclinical evidence has firmly established a bidirectional interaction among the lung, gut, and gut microbiome. There are many complex communication pathways between the lung and intestine, which affect each other's balance. Some metabolites produced by intestinal microorganisms, intestinal immune cells, and immune factors enter lung tissue through blood circulation and participate in lung immune function. Altered gut-lung-microbiome interactions have been identified in rodent models and humans of several lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, asthma, etc. Emerging evidence suggests that microbial therapies can prevent and treat respiratory diseases, but it is unclear whether this association is a simple correlation with the pathological mechanisms of the disease or the result of causation. In this review, we summarize the complex and critical link between the gut microbiota and the lung, as well as the influence and mechanism of the gut microbiota on respiratory diseases, and discuss the role of interventions such as prebiotics and fecal bacteria transplantation on respiratory diseases. To provide a reference for the rational design of large-scale clinical studies, the direct application of microbial therapy to respiratory-related diseases can reduce the incidence and severity of diseases and accompanying complications.

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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization in March 2020. Since then, viral spread from humans to animals has occurred worldwide. Nonhuman primates (NHPs) have been found to be susceptible to reverse-zoonosis transmission of SARS-CoV-2, but initial research suggested that platyrrhine primates are less susceptible than catarrhine primates. Here we report the natural SARS-CoV-2 infection of a common woolly monkey (Lagothrix lagothricha) from a wildlife rehabilitation center in Ecuador. The course of the disease, the eventual death of the specimen, and the pathological findings are described. Our results show the susceptibility of a new platyrrhine species to SARS-CoV-2 and provide evidence for the first time of a COVID-19-associated death in a naturally infected NHP. The putative route of transmission from humans, and implications for captive NHPs management, are also discussed. Given that common woolly monkeys are at risk of extinction in Ecuador, further understanding of the potential threat of SARS-CoV-2 to their health should be a conservation priority. A One Health approach is the best way to protect NHPs from a new virus in the same way that we would protect the human population.

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The gut microbiota is a complex community of microorganisms inhabiting the intestinal tract, which plays a vital role in human health. It is intricately involved in the metabolism, and it also affects diverse physiological processes. The gut-lung axis is a bidirectional pathway between the gastrointestinal tract and the lungs. Recent research has shown that the gut microbiome plays a crucial role in immune response regulation in the lungs and the development of lung diseases. In this review, we present the interrelated factors concerning gut microbiota and the associated metabolites in pulmonary hypertension (PH), a lethal disease characterized by elevated pulmonary vascular pressure and resistance. Our research team explored the role of gut-microbiota-derived metabolites in cardiovascular diseases and established the correlation between metabolites such as putrescine, succinate, trimethylamine N-oxide (TMAO), and N, N, N-trimethyl-5-aminovaleric acid with the diseases. Furthermore, we found that specific metabolites, such as TMAO and betaine, have significant clinical value in PH, suggesting their potential as biomarkers in disease management. In detailing the interplay between the gut microbiota, their metabolites, and PH, we underscored the potential therapeutic approaches modulating this microbiota. Ultimately, we endeavor to alleviate the substantial socioeconomic burden associated with this disease. This review presents a unique exploratory analysis of the link between gut microbiota and PH, intending to propel further investigations in the gut-lung axis.

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Chronic obstructive pulmonary disease (COPD) is the world's leading lung disease and lacks effective and specific clinical strategies. Probiotics are increasingly used to support the improvement of the course of inflammatory diseases. In this study, we evaluated the potential of a lactic acid bacteria (LAB) combination containing Limosilactobacillus reuteri GMNL-89 and Lacticaseibacillus paracasei GMNL-133 to decrease lung inflammation and emphysema in a COPD mouse model. This model was induced by intranasal stimulation with elastase and LPS for 4 weeks, followed by 2 weeks of oral LAB administration. The results showed that the LAB combination decreased lung emphysema and reduced inflammatory cytokines (IL-1ß, IL-6, TNF-α) in the lung tissue of COPD mice. Microbiome analysis revealed that Bifidobacterium and Akkermansia muciniphila, reduced in the gut of COPD mice, could be restored after LAB treatment. Microbial α-diversity in the lungs decreased in COPD mice but was reversed after LAB administration, which also increased the relative abundance of Candidatus arthromitus in the gut and decreased Burkholderia in the lungs. Furthermore, LAB-treated COPD mice exhibited increased levels of short-chain fatty acids, specifically acetic acid and propionic acid, in the cecum. Additionally, pulmonary emphysema and inflammation negatively correlated with C. arthromitus and Adlercreutzia levels. In conclusion, the combination of L. reuteri GMNL-89 and L. paracasei GMNL-133 demonstrates beneficial effects on pulmonary emphysema and inflammation in experimental COPD mice, correlating with changes in gut and lung microbiota, and providing a potential strategy for future adjuvant therapy.

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BACKGROUND: Gut microbiota (GM) have been implicated as important regulators of gastrointestinal symptom which is commonly occurred along with respiratory influenza A virus (IAV) infection, suggesting the involvement of the gut-to-lung axis in a host's response to IAV. IAV primarily destroys airway epithelium tight junctions (TJs) and consequently causes acute respiratory disease syndrome. It is known that GM and their metabolism produce an anti-influenza effect, but their role in IAV-induced airway epithelial integrity remains unknown. METHODS: A mouse model of IAV infection was established. GM were analyzed using 16S rRNA gene sequencing, and short-chain fatty acids (SCFAs) levels were measured. GM depletion and fecal microbiota transplantation (FMT) were conducted to validate the role of GM in IAV infection. A pair-feeding experiment was conducted to reveal whether IAV-induced GM dysbiosis is attributed to impaired food intake. Furthermore, human bronchial epithelial (HBE) cells were cocultured with IAV in the presence or absence of acetate. TJs function was analyzed by paracellular permeability and transepithelial electronic resistance (TEER). The mechanism of how acetate affects TJs integrity was evaluated in HBE cells transfected with G protein-coupled receptor 43 (GPR43) short hairpin RNA (shRNA). RESULTS: IAV-infected mice exhibited lower relative abundance of acetate-producing bacteria (Bacteroides, Bifidobacterium, and Akkermansia) and decreased acetate levels in gut and serum. These changes were partly caused by a decrease in food consumption (due to anorexia). GM depletion exacerbated and FMT restored IAV-induced lung inflammatory injury. IAV infection suppressed expressions of TJs (occludin, ZO-1) leading to disrupted airway epithelial barrier function as evidenced by decreased TEER and increased permeability. Acetate pretreatment activated GPR43, partially restored IAV-induced airway epithelial barrier function, and reduced inflammatory cytokines levels (TNF-α, IL-6, and IL-1ß). Such protective effects of acetate were absent in HBE cells transfected with GPR43 shRNA. Acetate and GPR43 improved TJs in an AMP-activated protein kinase (AMPK)-dependent manner. CONCLUSION: Collectively, our results demonstrated that GM protected airway TJs by modulating GPR43-AMPK signaling in IAV-induced lung injury. Therefore, improving GM dysbiosis may be a potential therapeutic target for patients with IAV infection.

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