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Background Salidroside (SAL) has a protective effect on multiple organ systems. Exposure to fine particulate matter (PM2.5) in the atmosphere may lead to disruptions in gut microbiota and impact intestinal health. The regulatory effect of SAL on the gut microbiota of mice exposed to PM2.5 requires further investigation. Objective To evaluate gut microbiota disruption in mice after being exposed to PM2.5 and the potential effect of SAL. Methods Forty male C57BL/6 mice, aged 6 to 8 weeks, were randomly divided into four groups: a control group, an SAL group, a PM2.5 group, and an SAL+PM2.5 group, each containing 10 mice. In the SAL group and the SAL+PM2.5 group, the mice were administered SAL (60 mg·kg−1) by gavage, while in the control group and the PM2.5 group, sterile saline (10 mL·kg−1) was administered by gavage. In the PM2.5 group and the SAL+PM2.5 group, PM2.5 suspension (8 mg·kg−1) was intratracheally instilled, and in the control group and SAL group, sterile saline (1.5 mL·kg−1) was intratracheally administered. Each experiment cycle spanned 2 d, with a total of 10 cycles conducted over 20 d. Histopathological changes in the ileum tissue of the mice were observed after HE staining. Colon contents were collected for gut microbiota sequencing and short-chain fatty acids (SCFAs) measurements. Results The PM2.5 group showed infiltration of inflammatory cells in the ileum tissue, while the SAL+PM2.5 group exhibited only a small amount of inflammatory cell infiltration. Compared to the control group, the PM2.5 group showed decreased Shannon index (P<0.05) and increased Simpson index (P<0.05), indicating that the diversity of gut microbiota in this group was decreased; the SAL+PM2.5 group showed increased Shannon index compared to the PM2.5 group (P<0.05) and decreased Simpson index (P<0.05), indicating that the diversity of gut microbiota in mice intervened with SAL was increased. The principal coordinates analysis (PCoA) revealed a significant separation between the PM2.5 group and the control group, while the separation trend was less evident among the control group, the SAL group, and the SAL+PM2.5 group. The unweighted pair-group method with arithmetic means (UPGMA) clustering tree results showed that the control group and the SAL group clustered together first, followed by clustering with the SAL+PM2.5 group, and finally, the three groups clustered with the PM2.5 group. The PCoA and UPGMA clustering results indicated that the uniformity and similarity of the microbiota in the PM2.5 group were significantly decreased. Compared to the control group, the PM2.5 group showed decreased abundance of phylum Bacteroidetes and Candidatus_Saccharimonas (P<0.05) and increased abundance of phylum Proteobacteria, genus Escherichia, genus Bacteroides, genus Prevotella, genus Enterococcus, and genus Proteus (P<0.05). Compared to the PM2.5 group, the SAL+PM2.5 group showed decreased abundance of phylum Proteobacteria, phylum Actinobacteria, genus Prevotella, and genus Proteus (P<0.05), and increased abundance of Candidatus_Saccharimonas (P<0.05). The PM2.5 group showed reduced levels of propionic acid, valeric acid, and hexanoic acid compared to the control group (P<0.05), while the SAL+PM2.5 group showed increased levels of propionic acid, isobutyric acid, butyric acid, valeric acid, and hexanoic acid compared to the PM2.5 group (P<0.05). Conclusion Exposure to PM2.5 can cause pathological alterations, microbial dysbiosis, and disturbing production of SCFAs in intestinal tissue in mice. However, SAL can provide a certain degree of protective effect against these changes.
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ObjectiveTo investigate the effect of Bufeitang on intestinal flora of rats with lung Qi-deficiency syndrome of chronic obstructive pulmonary disease（COPD）， and to explore the mechanism of traditional Chinese medicine in regulating intestinal flora and thus restoring the balance of lung-gut axis. MethodA total of 84 rats were randomly divided into 7 groups， including blank group， model group， fecal bacterial transplantation（FMT） group， dexamethasone group and low， medium and high dose groups of Bufeitang， 12 rats in each group. Except for the blank group， cigarette and sawdust fumigation combined with intratracheal instillation of lipopolysaccharide（LPS） were used to establish the COPD rat model with lung Qi-deficiency syndrome in all other groups. The low， medium and high dose groups of Bufeitang were intragastric administrated with Bufeitang（3.645， 7.29， 14.58 g·kg-1）， the FMT group was given fecal bacteria liquid enema（10 mL·kg-1）， dexamethasone group was given dexamethasone acetate tablet suspension by gavage（0.135 mg·kg-1）， the blank group and model group were given equal amount of distilled water. Fresh feces were collected after 28 d of continuous intervention for 16S rRNA gene sequencing. Lung and colon tissues were stained with hematoxylin-eosin（HE） for pathomorphological observation， and enzyme-linked immunosorbent assay （ELISA） was performed to detect the contents of tumor necrosis factor-α（TNF-α） and interleukin-8（IL-8） in lung tissues. ResultCompared with the blank group， the model group showed severe abnormal lung tissue structure with alveolar atrophy and collapse accompanied by severe inflammatory cell infiltration. Compared with the model group， the extent of injury was significantly improved， and inflammatory cell infiltration was reduced with basically normal alveolar structure in the high dose group of Bufeitang. Compared with the blank group， the model group had severely abnormal colonic tissue structure， the epithelial cells in the mucosal layer were eroded and shed， the number of inflammatory cells increased， the submucosal layer was edematous and the gap was enlarged. Compared with the model group， the extent of damage was significantly improved in the medium and high dose groups of Bufeitang， the epithelial cells in the mucosal layer were neatly and closely arranged， with only a small amount of inflammatory cell infiltration and no significant degeneration. Compared with the blank group， the TNF-α and IL-8 levels of lung tissue in the model group were significantly increased（P<0.01）. Compared with the model group， the TNF-α and IL-8 levels of lung tissues in the low， medium and high dose groups of Bufeitang were significantly decreased（P<0.01）. Bufeitang significantly modulated the number of bacteria species as well as alpha and beta diversity of model rats， corrected the return of intestinal flora to normal abundance and diversity， and positively regulated 4 differential phyla（such as Firmicutes， Proteobacteria） and 13 differential genera（such as Turicibacter， Lactobacillus， Anaerobiospirillum， Intestinimonas） in COPD model rats with lung Qi-deficiency syndrome， and down-regulated 2 carbohydrate metabolic pathway functions， including the pentose phosphate pathway（non-oxidative branch） Ⅰ and the Calvin-Benson-Bassham cycle. ConclusionBufeitang can modulate the abundance and diversity of intestinal flora species， affect the function of metabolic pathways， repair the structure of lung and colon tissues， regulate the level of inflammatory factors， and thus improve COPD with lung Qi-deficiency syndrome. The mechanism may be related to its regulation of inflammation-related intestinal flora to restore the balance of lung-gut axis in COPD with lung Qi-deficiency syndrome.
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ObjectiveTo explore the possible mechanism of Yupingfeng Granules （玉屏风散） in preventing and treating chronic obstructive pulmonary disease （COPD） from the perspective of “lung-gut axis”. MethodsThirty-two male Wistar rats were randomly divided into normal group，model group， roxithromycin group and Yupingfeng Granules group， with 8 rats in each group. Except for the normal group， the rat model of COPD was prepared by intratracheal instillation of lipopolysaccharide （LPS） combined with smoking for 12 weeks. Since the fifth week of modeling，the roxithromycin group and the Yupingfeng Granules group were given 31.5 mg/（kg·d） and 1.575 g/（kg·d） of corresponding drugs respectively by gavage，and normal group and model group were given 10 ml/（kg·d） physiolo-gical saline. Sample was collected 24 hours after the last administration. The pathological changes of lung tissue were observed using HE staining； Ultrahigh performance liquid chromatography quadrupole time of flight mass spectrometry （UHPLC-QTOFMS） was used to detect the differential metabolites in alveolar lavage fluid （BALF） in all groups but roxithromycin group；16S rDNA sequencing technology was used to detect the changes of intestinal flora， and the association analysis was conducted between the differential metabolites and the differential flora. ResultsCompared with the normal group， the model group showed an increase in goblet cells in the small bronchial wall， disappearance of the smooth muscle layer of the bronchial wall， and infiltration of inflammatory cells； compared with the model group， roxithromycin group showed slight alveolar interstital edema， and obviously reduced inflammatory cell， while no obvious alveolar interstital edema was observed in the Yupingfeng Granules group， showing a small amout of inflammatory cell infiltration. The results of the BALF differential metabolite screening showed that compared with the normal group， 12 substances were upregulated and 19 substances were downregulated in the model group； compared with the model group， 37 substances in the Yupingfeng Granules group were upregulated and 43 substances were downregulated KEGG analysis yielded a total of 2 metabolic pathways， glycerophospholipid metabolism， and unsaturated fatty acid biosynthetic metabolism； compared with the model group， choline， acetylcholine， glycerol-3-phosphate， glycerophosphate choline， palmitic acid， and arachidonic acid showed an upward trend， while stearic acid and docosahexaenoic acid showed a downward trend in Yupingfeng Granules group （P＜0.05）. The results of the intestinal flora showed that， there are 80 different species between the normal group and the model group， and 65 different species between the model group and Yupingfeng Granules group. Among the top 5 species with relative abundance levels，compared with the model group， the level of Prevotella_9，Ruminococcaceae_UCG-005，Ruminiclostridium_6 increase，and Lactobacillus，Bacteroides decrease（P＜0.05）.The results of the correlation analysis showed that， in the normal and model groups， arachidonic acid was negatively correlated with Oribacterium（r=-0.753，P＜0.01）； in the Yupingfeng Granules group and model group， stearic acid and Bacteroides（r=0.788）， Mycobacterium（r=0.826），［Eubacterium］_Ruminantium_Group（r=0.770） was positively correlated（P＜0.01）， Arachidic acid was negatively correlated with Roseiarcus（r=-0.779）， glycerol-3-phosphate was negatively correlated with Desulfovibrio（r=-0.758）， Arachidonic acid was negatively correlated with Oribacterium（r=-0.753）， and Palmitic acid was negatively correlated with Pseudolabs（r=-0.750，P＜0.01）. ConclusionYupingfeng Granules can affect the metabolism of BALF and the flora structure of intestinal microorganisms， and regulating the balance of “lung-gut axis” may be one of the mechanisms of Yupingfeng Granules in treatment of COPD.
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In China， about 100 million people currently have chronic obstructive pulmonary disease （COPD）. At the same time， COPD is a multisystem disease， not only affecting the function of musculoskeletal， cardiovascular， kidney and immune systems in patients， but also causing intestinal dysfunction as its extrapulmonary manifestations. From the perspective of traditional Chinese medicine （TCM）， after COPD is formed， deficiency， phlegm stasis and toxicity were accumulated in the lungs， which leads to dysfunction of lung in dispersing and descending， and eventually causes ascending and descending disorder of Qi activities， disorder of fluid supply and distribution， and stagnation of blood stasis. The viscera disease would affect the bowels， and the large intestine is thus affected. Modern medical discovers that， the lungs and intestines have common origins and similar physiological structures， in pathological circumstances， their common mucosal immune system may lead to similar immune factors and inflammatory manifestations in the lungs and intestines. At the same time， the studies have confirmed that there is also a close relationship between intestinal flora and lung， that is "lung-gut axis". These theories partially illustrate the mechanism of COPD in inducing intestinal injury. The specific manifestations of COPD intestinal dysfunction， ① Flora disorder， with increased abundance of intestinal gram-negative bacilli， and inhibited reproduction of Bifidobacterium， Lactobacillus and short-chain fatty acid-producing bacteria. ② Intestinal barrier damage： characterized by the destruction of intestinal epithelium tight connectivity， increased intestinal permeability， and thinning of the mucus layer. ③ Intestinal motility disorder： mostly manifested as weight loss and malnutrition. At present， for the intestinal dysfunction in COPD patients， most of the relevant discussions and targeted treatment methods in TCM are scattered and unsystematic. Guided by the idea of treating different diseases with the same treatment， we summarized the etiology and pathogenesis of COPD intestinal dysfunction by learning from the experience of TCM in treating intestinal flora disorders and inflammatory bowel disease， and proposed preliminary formulation with Tiaoqi Qushi，Tongfu Tongluo as its basic treatment principles in this paper， hoping to provide new ideas for the treatment of COPD.
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The "lung and large intestine being interior-exteriorly related" is one of the classical theories in traditional Chinese medicine, which indicates a close correlation between the lung and large intestine in physiology and pathology, and plays a pivotal role in guiding the treatment of the lung and bowel diseases. Modern medicine has revealed some connections between the lung and large intestine in tissue origin and mucosal immunity, and preliminarily illuminated the material basis and possible regulatory mechanism of the theory. Recently, this theory has been applied to guide the treatment of refractory lung and intestine diseases such as COVID-19 and ulcerative colitis and has obtained reliable efficacy. Existing research results show that the anatomical homogeneity of lung and large intestine promotes the correlation between lung-bowel mucosal immunity, and mucosal immunity and migration and homing of innate lymphocytes are one of the physiological and pathological mechanisms for lung and large intestine to share. Under the guidance of this theory, Chinese medicines with heat-clearing and detoxifying or tonic effects are commonly used in the treatment of the lung and intestinal diseases by regulating lung-bowel mucosal immunity and they can be candidate drugs to treat lung/intestinal diseases simultaneously. However, the existing studies on immune regulation are mainly focused on the expression levels of sIgA and cytokines, as well as the changes in the number of immune cells such as innate lymphocytes and B lymphocytes. While the following aspects need further investigation: the airway/intestinal mucous hypersecretion, the functional changes of pulmonary and intestinal mucosal barrier immune cells, the dynamic process of lung/intestinal mucosal immune interaction, the intervention effect of local pulmonary/intestinal microecology, the correlation and biological basis between the heat-clearing and detoxifying effect and the tonic effect, and its regulation of pulmonary/intestinal mucosal immunity. In this paper, we try to analyze the internal relationship between lung and intestine related diseases from the point of view of the common mucosal immune system of lung and intestine, and summarize the characteristics and rules of traditional Chinese medicine compound and its active ingredients, which have regulatory effect on lung and intestine mucosal immune system, so as to further explain the theoretical connotation of "lung and large intestine being interior-exteriorly related" and provide reference for the research and development of drugs for related diseases.
Subject(s)
Humans , COVID-19/immunology , Colitis, Ulcerative/immunology , Intestine, Large/immunology , Lung/immunology , Medicine, Chinese TraditionalABSTRACT
The common mucosal immunological system is an important anatomical basis of the allergic disorders.Its function is not only regulated by the susceptibility gene,but also affected the development because of the early life exposure to antibiotics.It is the tangible that early life antibiotic-driven changes in mucosal immune enhance susceptibility to allergic disorders of respiratory system.A holistic approach to study the mucosal immune system as an integrated global organ is imperative for future advances in understanding mucosal immunology and for future treatment of the allergic disorders.This review will be focus on the latest evidence and the mechanisms in driving the lung-gutcross-talk.