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Chitooligosaccharides (COSs) have various physiological activities and broad application prospects; however, their pharmacokinetics and tissue distribution remain unclear. In this study, a sensitive and selective ultra-performance liquid chromatography–mass spectrometry (UPLC–MS) method for determining chitobiose (COS 2) and chitotriose (COS 3) in rat serum and tissues was developed. This method was successfully validated based on FDA guidelines in terms of selectivity, calibration curves (lower limit of quantification was 0.002 µg/mL for COS 2 and 0.02 µg/mL for COS 3), precision (intra-day relative standard deviation of 0.04%–3.55% and inter-day relative standard deviation of 1.94%–11.63%), accuracy (intra-day relative error of − 1.81%–11.06% and inter-day relative error of − 9.41%–8.63%), matrix effects, recovery (97.10%–101.29%), stability, dilution integrity, and carry-over effects. Then, the method was successfully applied to the pharmacokinetics and tissue distribution study of COS 2 and COS 3 after intragastric and intravenous administration. After intragastric administration, COS 2 and COS 3 were rapidly absorbed, reached peak concentrations in the serum after approximately 0.45 h, and showed rapid elimination with clearances greater than 18.82 L/h/kg and half-lives lower than 6 h. The absolute oral bioavailability of COS 2 and COS 3 was 0.32%–0.52%. COS 2 and COS 3 were widely distributed in Wistar rat tissues and could penetrated the blood–brain barrier without tissue accumulation. Graphic Abstract

Background: The role of bacteria in different courses of chronic obstructive pulmonary disease (COPD) has not been very clarified. In this study, sputum samples from patients at different courses of COPD were collected to analyze the differences of the structure and function of respiratory microbiome in different courses of COPD.Results: Our study involved 38 patients with acute exacerbation of COPD (AECOPD). Among them, 42 sputum samples were collected from the acute exacerbation of COPD (Of these 38 patients, 4 patients also collected sputum from the second acute exacerbation phase), and 12 sputum samples were collected from the stable phase of COPD (6 of the above 38 patients). Firmicutes, Proteobacteria, Bacteroidetes and Actinobacteria dominated the phylum in all the COPD samples, while Streptococcus, Neisseria, Haemophilus and Prevotella is the top 4 species in the cohort. Salmonella, Salmonella, Pseudomonas and Proteobacteria achieved higher abundance in AECOPD group. Samples from AECOPD patients showed higher α diversity. Moreover, genes annotated to K07481(the function is related to transposase) and K16087(the function is related to hemoglobin/transferrin/lactoferrin receptor protein) in stable subgroup showed higher abundance than that in acute exacerbation subgroup. Compared to samples from stable COPD, Proteobacteria contributed the most antibiotic resistance genes. Conclusions: There are differences in the function and metabolism of respiratory microbiome in patients with different course of COPD. Word count: 218/350

Chitooligosaccharides (COSs) have various physiological activities and broad application prospects; however, their pharmacokinetics and tissue distribution remain unclear. In this study, a sensitive and selective ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method for determining chitobiose (COS 2) and chitotriose (COS 3) in rat serum and tissues was developed. This method was successfully validated based on FDA guidelines in terms of selectivity, calibration curves (lower limit of quantification was 0.002 µg/mL for COS 2 and 0.02 µg/mL for COS 3), precision (intra-day relative standard deviation of 0.04–3.55% and inter-day relative standard deviation of 1.94–11.63%), accuracy (intra-day relative error of -1.81–11.06% and inter-day relative error of -9.41–8.63%), matrix effects, recovery (97.10–101.29%), stability, dilution integrity, and carry-over effects. Then, the method was successfully applied to the pharmacokinetics and tissue distribution study of COS 2 and COS 3 after intragastric and intravenous administration. After intragastric administration, COS 2 and COS 3 were rapidly absorbed, reached peak concentrations in the serum after approximately 0.45 h, and showed rapid elimination with clearances greater than 18.82 L/h/kg and half-lives lower than 6 h. The absolute oral bioavailability of COS 2 and COS 3 was 0.32–0.52%. COS 2 and COS 3 were widely distributed in Wistar rat tissues and could penetrated the blood-brain barrier without tissue accumulation.