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Metagenomic analysis of animal, environmental and human microbiomes in the context of excess pneumonia risk around livestock production farms in the Netherlands: effects in humans

Group and collaboration

Dick Heederik & Lidwien Smit (IRAS,UU), Debby Bogaert (UMCU) Arjan Stegeman (DGK, UU) Marion Koopmans & Matt Cotton (Department of Viroscience, Erasmus MC)

Collaboration: Wageningen Bioveterinary Research (Alex Bossers), RIVM and others.

PhD student: Warner van Kersen (linked to project P6)

Project description

Recent results of the VGO (‘Veehouderij en Gezondheid Omwonenden’) study showed a clear and consistent association between poultry and goat farming and pneumonia in individuals living in a radius of 1-2 km of poultry and goat farms (Freidl et al., 2017; Smit et al., 2017). This observation could be reproduced over a period of five years from 2009-2013 using general practitioner electronic medical records of approximately 120000 individuals living in the East of Noord Brabant and the North of Limburg, areas know for the presence of intensive livestock farming. Health impact calculations suggest that these associations seem responsible for several 1000s of avoidable pneumonia cases per year.

The likelihood for an individual to develop pneumonia differs clearly near a goat or a poultry farm. The risk is 35-50% higher near a goat farm and only 10% elevated near a poultry farm while poultry farms are known as high dust and endotoxin emitting point sources. Indications exist that pneumonia cases who live near poultry farms have a shifted microbiome and an abundance of Streptococcus pneumoniae, compared to pneumonia cases from more distant locations, most likely the result of elevated dust and endotoxin exposure (Smit et al., 2017). This observation fits with elevated pneumonia risk in individuals with elevated dust exposure and with experimental data showing host defences affected by elevated environmental dust exposure. The consistently higher likelihood to develop pneumonia around goat farms probably points to a different etiology, either zoonotic infections or manure management-related microbial exposure (potential thermophilic micro-organisms related to composting). This makes it relevant to contrast groups of pneumonia cases and controls around these two types of livestock farming and study different exposure and health characteristics in these groups.

We therefore propose to investigate the possible causes of this association between poultry and goats and excess pneumonia risk in a combined project with two PhD students, one focusing on the virome (including the phageome) and the other on the microbiome (jointly named: metagenome). The PhD students will be funded by Erasmus MC (1.0 fte) and Utrecht University (1.0 fte).

In this project we aim to:

  1. Study the etiology of respiratory disease in humans living in intensive livestock farming areas by systematic assessment of known infectious etiologies and indirect effects of dust, endotoxin and/or irritant gas exposures leading to host-mediated mechanisms of disease.
  2. Analyse the respiratory metagenome of persons with unexplained respiratory disease near goat or poultry farms and controls.
  3. Characterize emissions from livestock farms by fingerprinting the livestock faecal and respiratory microbiome and virome in animal populations on the farm level, and in farm dust samples and relate emissions to farm management and if relevant zoonotic disease dynamics.
  4. Analyse metagenome datasets for potential farm- and / or farm-animal specific signatures amenable to exposure studies in residents exposed to farm emissions
  5. Measure the relevant microbes and viruses in different production/age groups of the farm aiming to model the population dynamics of infection/colonization by these agents in time, space and production stage. This can feed the model of exposure to residents/workers and enables to draw hypotheses on reducing the within farm amplification of these agents
  6. Measure and model movement of microbes and viruses to exposed neighbouring residents by combining existing emission models which make use of "classical" emission data and dispersion modelling after modification for microbial emissions.

This will be done by metagenomics analysis of the phageome/virome and microbiome at the animal human interface by analysing animal samples, airborne dust samples from stables and outside, and human samples of incident pneumonia patients and controls from a sufficiently powered case-control study. The animal samples will involve faeces and respiratory samples (nasal swabs) from 10-20 farms. The human samples will involve nose and throat swabs from cases and controls. The aim is to use metagenomics sequencing to enable studying correlations between the genomic composition of farm animal faeces, farm dust and microbiomes in nearby residents.

Full metagenomics analysis will reveal the composition of bacterial DNA present in each sample, and the RNA and DNA virome from samples enriched for virus detection. Exploration of the metagenome will include evaluation of potential presence of pathogens (bacterial, viral, fungal), as well as antimicrobial resistance genes and virulence genes.

Elements of the proposal are also included in project proposals included in a research program proposal which will be submitted to the Ministries of Health and Economic Affairs (VGO III). Full NCOH partners have committed themselves to operate as one partner in the submitted proposal for the so-called VGO phase III studies, which will be conducted with RIVM.

Complex Systems & Metagenomics is the overarching theme for more than 10 PhD tracks in NCOH projects to create new interdisciplinary, inter-thematic, and inter-institutional research collaborations.

PhD student interview

Interview: Yearning to see the bigger picture

‘I have a stutter. Because of this, I’ve always had a curiosity for disease-related topics and how they develop. In order to avoid speaking situations, I hid in the lab as a medical microbiology technician. But analysing materials of individual patients left me yearning to see the bigger picture. After all, why were these people getting sick in the first place and what can we do about it? I completed my masters in evolutionary biology, with a thesis on disease in invasive parakeets, got control of my stutter and landed my dream job as a PhD student.’