Fuentes Susana, den Hartog Gerco, Nanlohy Nening M, Wijnands Lucas, Ferreira José A, Nicolaie Mioara A, Pennings Jeroen L A, Jacobi Ronald, de Wit Jelle, van Beek Josine, van Baarle Debbie
Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands.
Department of Statistics, Informatics and Mathematical Modelling, National Institute for Public Health and the Environment, Bilthoven, Netherlands.
Lancet Healthy Longev. 2021 Jan;2(1):e13-e23. doi: 10.1016/S2666-7568(20)30034-9.
People aged 60 years or older are at high risk for respiratory infections, one of the leading causes of mortality worldwide. Vaccination is the main way to protect against these infections; however, vaccination is less effective in older adults than in younger adults due to ageing of the immune system, so innovative strategies that improve vaccine responses could provide a major public health benefit. The gut microbiota regulates host immune homoeostasis and response against pathogens, but human studies showing the effects of the gut microbiota on respiratory infections in older adults are sparse. We aimed to investigate the composition of the microbiota in relation to respiratory infections and local and systemic immune markers in older adults during an influenza season.
In this observational study, participants were selected from an influenza-like illness (ILI) prospective surveillance cohort in which community-dwelling adults aged 60 years and older in the Netherlands were recruited through their general practitioner or the Civil Registry. Inclusion criteria have been described elsewhere. Participants completed questionnaires and self-reported symptoms. To measure microbiota composition, faecal samples were collected from participants registering an ILI event, with a follow-up (recovery) sample collected 7-9 weeks after the ILI event, and from asymptomatic participants not reporting any event throughout the season. We tested associations between microbiota profiles and a set of health-related variables, patient characteristics, and local and systemic immune markers. We cultured identified bacterial biomarkers for ILI with CaCo-2 cells in an in vitro intestinal epithelial model and measured the induced immune response. This study is registered with http://www.trialregister.nl, NL4666.
Between Oct 1, 2014, and April 30, 2015, 2425 older adults were recruited into the ILI surveillance cohort. From Oct 1, 2014, to June 15, 2015, faecal samples were collected from 397 participants, of whom 213 (54%) reported an ILI event once throughout the season and 184 (46%) did not. 192 ILI participants recovered and provided follow-up samples. Microbiota composition was altered during an ILI event. The Bacteroidetes (mean relative abundance 17·51% [SD 11·41] in the ILI group and 14·19% [10·02] in the control group; adjusted p=0·014) and the Proteobacteria (3·40% [8·10] in the ILI group and 1·57% [3·69] in the control group; adjusted p=0·015) were more abundant in the ILI group than in the control group. The abundance of Ruminococcus torques was positively associated with ILI and the abundance of Escherichia/Shigella, negatively correlated with alpha diversity, and negatively co-occurred with beneficial taxa, including butyrate producers. R torques was associated with pro-inflammatory profiles, both locally in faeces and systemically in blood. ILI-associated taxa (R torques and Escherichia coli) had symbiotic effects on the cellular immune response when cultured together in an in vitro model.
The abundances of specific bacteria could be used as potential biomarkers for susceptibility to respiratory infections and as targets for intervention in the ageing population.
The Dutch Ministry of Health, Welfare and Sport, and the Strategic Program of the National Institute for Public Health and the Environment.
60岁及以上的人群面临呼吸道感染的高风险，呼吸道感染是全球主要死因之一。接种疫苗是预防这些感染的主要方式；然而，由于免疫系统衰老，疫苗接种在老年人中的效果不如年轻人，因此，能够改善疫苗反应的创新策略可能会带来重大的公共卫生效益。肠道微生物群调节宿主免疫稳态及对病原体的反应，但关于肠道微生物群对老年人呼吸道感染影响的人体研究较少。我们旨在调查流感季节老年人中微生物群的组成与呼吸道感染以及局部和全身免疫标志物之间的关系。
在这项观察性研究中，参与者选自流感样疾病（ILI）前瞻性监测队列，荷兰60岁及以上的社区居住成年人通过其全科医生或民事登记处招募。纳入标准已在其他地方描述。参与者完成问卷并自我报告症状。为了测量微生物群组成，从报告ILI事件的参与者中收集粪便样本，并在ILI事件发生7 - 9周后收集随访（恢复）样本，同时从整个季节未报告任何事件的无症状参与者中收集样本。我们测试了微生物群谱与一系列健康相关变量、患者特征以及局部和全身免疫标志物之间的关联。我们在体外肠道上皮模型中用CaCo - 2细胞培养已鉴定的ILI细菌生物标志物，并测量诱导的免疫反应。本研究已在http://www.trialregister.nl注册，注册号为NL4666。
2014年10月1日至2015年4月30日期间，2425名老年人被纳入ILI监测队列。2014年10月1日至2015年6月15日期间，从397名参与者中收集了粪便样本，其中213名（54%）在整个季节报告了一次ILI事件，184名（46%）未报告。192名ILI参与者康复并提供了随访样本。在ILI事件期间，微生物群组成发生了改变。拟杆菌门（ILI组平均相对丰度为17.51% [标准差11.41]，对照组为14.19% [10.02]；校正p = 0.014）和变形菌门（ILI组为3.40% [8.10]，对照组为1.57% [3.69]；校正p = 0.015）在ILI组中的丰度高于对照组。扭链瘤胃球菌的丰度与ILI呈正相关，大肠埃希菌/志贺菌属的丰度与α多样性呈负相关，且与包括丁酸盐产生菌在内的有益类群呈负共现。扭链瘤胃球菌在粪便局部和血液全身均与促炎谱相关。在体外模型中共同培养时，与ILI相关的类群（扭链瘤胃球菌和大肠杆菌）对细胞免疫反应具有共生效应。
特定细菌的丰度可作为呼吸道感染易感性的潜在生物标志物，并作为老年人群干预的靶点。
荷兰卫生、福利与体育部以及国家公共卫生和环境研究所战略计划。
