鼻腔及口腔微生物菌叢在氣喘的角色

Abstract

背景：氣喘是呼吸道對許多過敏原反應過度而發生慢性反覆性的呼吸道發炎疾病。微生物菌叢與呼吸道黏膜上皮細胞緊密接觸，微生物菌叢失調可能是導致呼吸道慢性發炎的重要原因之一。上下呼吸道不論結構上或功能上皆緊密相關，因此，鼻腔及口腔微生物菌叢失調，亦可能對於下呼道慢性發炎，如氣喘的疾病控制，造成顯著的影響。微生物菌叢在氣喘病患急性發作易感性上所扮演的角色。 方法：本研究在國立臺灣大學醫學院附設醫院及其新竹分院進行。收案診斷為氣喘的成人病患，並追蹤三個月。所有病患在收案後均接受鼻腔和口腔微生物菌叢的檢查。 結果：本研究一共收案61名氣喘病患。病患年齡中位數為44歲（範圍：21–72歲）。男性佔所有病患比例的18%。回歸分析發現：鼻腔細菌叢的alpha多樣性與ACT分數呈負相關和eosinophil數量呈正相關，但與IgE濃度跟FEV1/FVC數值的相關性不顯著。收案後三個月內，34%的病患曾經有氣喘急性惡化。曾經發生氣喘急性惡化病患的鼻腔細菌叢的alpha多樣性(alpha diversity)有低於無急性惡化病患的傾向。兩組間鼻腔細菌叢組成不同。相較於未發生氣喘急性惡化病患，曾經發生急性惡化的患者鼻腔在種的層級有較低比例的Cutibacterium acnes (1.44±2.14% vs. 4.11±6.34%, P = 0.019)、Anaerococcus Octavius (0.06±0.26% vs. 0.54±1.31%, P = 0.029)、 Pseudomonas yamanorum (0.02±0.08% vs. 0.40±0.97%, P = 0.019)、Acinetobacter johnsonii (0.02±0.08% vs. 0.07±0.19%, P = 0.015)、Pseudobdellovibrio exovorus (0.01±0.03% vs. 0.13±0.27%, P = 0.037)和 Brevibacillus marinus (0.002±0.01% vs. 0.05±0.14%, P = 0.032)；在屬的層級有較低比例的Cutibacterium (1.55±2.19% vs. 4.36±6.42%, P = 0.015), Anaerococcus (0.09±0.36% vs. 1.02±2.36%, P = 0.018), Lactobacillus (0.00±0.00% vs. 0.34±0.95%, P = 0.031), Blautia (0.001±0.004% vs. 0.11±0.34%, P = 0.039), Pseudobdellovibrio (0.01±0.03% vs. 0.07±0.19%, P = 0.036), Brevibacillus (0.003±0.01% vs. 0.06±0.13%, P = 0.016)；在門的層級有較低比例的 Cyanobacteria (0.00±0.00% vs. 0.02±0.07%, P = 0.046)。在口腔細菌叢方面，我們發現口腔細菌叢的alpha多樣性與ACT分數、eosinophil數量、IgE濃度和FEV1/FVC數值的相關性不顯著。兩組間，口腔細菌叢的alpha多樣性和beta多樣性皆無顯著差異。然而，相較於未發生氣喘急性惡化病患，曾經發生急性惡化的患者口腔在種的層級有較低比例的Streptococcus sanguis (0.29±0.32% vs. 0.69±1.08%, P = 0.036)、 Streptococcus gwanjuense (0.02±0.05% vs. 0.16±0.43%, P = 0.041)、Actinomyces graevenitzii (0.04±0.06% vs. 0.17±0.38%, P = 0.033)、Butyrivibrio hungatei (0.01±0.02% vs. 0.04±0.06%, P = 0.047)和Leptotrichia buccalis (0.004±0.01% vs. 0.02±0.05%, P = 0.035)；在屬的層級有較低比例的Butyrivibrio (0.02±0.02% vs. 0.04±0.06%, P = 0.048)。 結論：曾急性惡化的氣喘病患，其鼻腔細菌叢的alpha多樣性似乎低於未曾氣喘急性惡化病患。曾氣喘急性惡化患者的鼻腔中，在屬的層級有較低比例的Cutibacterium、Anaerococcus、Lactobacillus、Blautia、Pseudobdellovibrio 和 Brevibacillus。口腔細菌叢的alpha多樣性和beta多樣性在曾急性發作與未曾急性發作病患中皆無顯著差異。本研究未收案健康人做比較，且收案人數較少。鼻腔微生物和氣喘急性發作易感性的機轉，需要進一步以動物介入實驗探討。

Background: Asthma is a chronic and recurrent inflammatory disease of the airways, triggered by an overreaction of the respiratory system to various allergens. The microbiome is in close contact with the respiratory mucosal epithelial cells, and its dysbiosis may be one of the key factors contributing to chronic airway inflammation. The upper and lower respiratory tracts are closely related both structurally and functionally. Therefore, dysbiosis of the nasal and oral microbiota may also significantly impact the control of chronic lower airway inflammation, such as in asthma. The role of the microbiome in the susceptibility to acute exacerbations in asthma patients is also noteworthy. Methods: The study conducted at National Taiwan University Hospital in Taipei and its Hsinchu Branch in Taiwan. Adult patients diagnosed with asthma were recruited at 3-month follow-up. All patients underwent nasal and oral microbiome examinations after enrollment. Results: A total of 61 patients with asthma were enrolled. The mean patient age was 44 years (range: 21–72 years). Men comprised 18% (11/61) of all patients. Within the 3-month period, 34% of the patients experienced exacerbations. Patients with exacerbated asthma tended to have lower nasal alpha diversity than those without exacerbations. Nasal alpha diversity may correlate negatively with ACT scores and positively with eosinophil counts, but not with IgE levels or value of FEV1/FVC. The nasal bacterial composition differed between the two groups. Compared to patient with non-exacerbated asthma, those with exacerbated asthma had a lower proportion of nasal Cutibacterium acnes (1.44±2.14% vs. 4.11±6.34%, P value = 0.019), Anaerococcus octavius (0.06±0.26% vs. 0.54±1.31%, P value = 0.029), Pseudomonas yamanorum (0.02±0.08% vs. 0.40±0.97%, P value = 0.019), Acinetobacter johnsonii (0.02±0.08% vs. 0.07±0.19%, P value = 0.015), Pseudobdellovibrio exovorus (0.01±0.03% vs. 0.13±0.27%, P value = 0.037), and Brevibacillus marinus (0.002±0.01% vs. 0.05±0.14%, P value = 0.032) at species level, had a lower proportion of nasal Cutibacterium (1.55±2.19% vs. 4.36±6.42%, P value = 0.015), Anaerococcus (0.09±0.36% vs. 1.02±2.36%, P value = 0.018), Lactobacillus (0.00±0.00% vs. 0.34±0.95%, P value = 0.031), Blautia (0.001±0.004% vs. 0.11±0.34%, P value = 0.039), Pseudobdellovibrio (0.01±0.03% vs. 0.07±0.19%, P value = 0.036), Brevibacillus (0.003±0.01% vs. 0.06±0.13%, P value = 0.016) at the genus level, and had a lower proportion of nasal Cyanobacteria (0.00±0.00% vs. 0.02±0.07%, P value = 0.046) at the phylum level. There were no differences in oral alpha diversity and beta diversity between the two groups. Oral alpha diversity index was not associated with ACT score, eosinophil count, IgE level or value of FEV1/FVC. However, compared with patients with non-exacerbated asthma, those with exacerbated asthma had a lower proportion of oral Streptococcus sanguis (0.29±0.32% vs. 0.69±1.08%, P value = 0.036), Streptococcus gwanjuense (0.02±0.05% vs. 0.16±0.43%, P value = 0.041), Actinomyces graevenitzii (0.04±0.06% vs. 0.17±0.38%, P value = 0.033), Butyrivibrio hungatei (0.01±0.02% vs. 0.04±0.06%, P value = 0.047), and Leptotrichia buccalis (0.004±0.01% vs. 0.02±0.05%, P value = 0.035) at the species level, and had a lower proportion of oral Butyrivibrio (0.02±0.02% vs. 0.04±0.06%, P value = 0.048) at the genus level. Discussion: The nasal microbiome may be an important factor influencing susceptibility to asthma exacerbations. Patients with exacerbated asthma seemed to have lower alpha diversity in their nasal microbiome compared to those with non-exacerbated asthma. Patients with exacerbated asthma had a lower proportion of nasal Cutibacterium, Anaerococcus, Lactobacillus, Blautia, Pseudobdellovibrio, and Brevibacillus at the genus level. There were no significant differences in the alpha diversity and beta diversity of the oral microbiome between patients who had experienced exacerbations and those who had not. This study did not include healthy individuals for comparison, and the sample size was relatively small. Further animal interventional studies are needed to explore the mechanisms by which nasal microbiome may influence susceptibility to asthma exacerbations.