Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today1. The asthma-protective effect of farms appears to be associated with rich home dust microbiota2,3, which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts4 that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children2 and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention.
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The bacterial and fungal sequences from LUKAS have been deposited in the European Bioinformatics Institute European Nucleotide Archive database under accession number PRJEB29081. Other data supporting the findings of this study are available through direct communication with the corresponding author. Limitations apply to variables where too small subgroups may compromise research participant privacy/consent. In these cases amendment to the ethical approval will be required before data transfer.
All codes used in the study are available on the public repository https://github.com/PirkkaKirjavainen/FaRMI. Contact the corresponding author for more information.
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We thank J. Kauttio for the processing of LUKAS dust samples and P. Tiittanen and T. Kauppila for LUKAS data management; G. Humphrey and J. Gaffney for the processing of GABRIELA samples; A. Amir for assistance in bioinformatics; U. Naukkarinen and R. Tiihonen for cytokine stimulations; S. Illi for cytokine data processing; M. Martikainen for dendritic cell analyses; the participating families of the LUKAS and GABRIELA studies; the field workers in the LUKAS and GABRIELA studies; and the LUKAS and GABRIELA study groups. We acknowledge funding by the Academy of Finland grants 139021 (J.P.), 256375 (M.R.), 287675 (A.M.K.), 296814 (J.P.), 296817 (M.T.) and 308254 (P.V.K.); the Juho Vainio Foundation (P.V.K., M.T.); the Päivikki and Sakari Sohlberg Foundation (P.V.K., J.P.); The Finnish Cultural Foundation (J.P.); the Yrjö Jahnsson Foundation (P.V.K., J.P.); Kuopion seudun hengityssäätiö (B.J.); European Union QLK4-CT-2001-00250 (J.P., H.R., P.I.P., R.L., E.v.M); the National Institute for Health and Welfare, Finland (P.V.K., A.M.K., M.T., B.J., A.H., J.P.); Alfred P. Sloan Foundation G-2016-7076 R.A.; Deutsche Zentrum für Lungenforschung grants (M.J.E.) and 82DZL00502 (H.R.); Deutsche Forschungsgemeinschaft (DFG)-funded SFB 1021 (H.R.); SCHA 997/8-1 (B.S.); GILKUJ-39 (B.S.); Kühne Foundation, Schindellegi, Switzerland (R.L.); MU 891/5-1 Leibniz Prize, German Research Foundation (E.v.M.); ERC2009-AdG_20090506_250268 (E.v.M.); and LSHB-CT-2006-018996 (E.v.M.).
P.V.K., A.M.K., R.I.A., M.T., M.R., P.T., G.L., B.J., M.D., H.R., P.I.P., B.S., R.L., A.H., D.J.J.H. and J.P. do not have competing interests to disclose. M.J.E. and E.v.M. report patents EP2361632B1 and EP1964570B1 held by their institution LMU. E.v.M. reports being the recipient of funds from the European Commission for the conduct of the LUKAS (EFRAIM) and GABRIEL study and declares personal fees from Pharma Ventures, Peptinnovate Ltd, OM Pharma SA, the European Commission/European Research Council Executive Agency, Tampereen Yliopisto, the University of Turku, HAL Allergie GmbH, Ökosoziales Forum Oberösterreich and Mundipharma Deutschland GmbH & Co. KG; E.v.M. is an inventor on the patents EP1637147, EP1964570, LU101064 and EP1411977; E.v.M. is an inventor on and has received royalties from the patent EP2361632. R.K. is on the Scientific Advisory Board of Commense, Inc.
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In the LUKA1 farm homes, the bacterial/archaeal richness (n = 107), with median 652 OTUs (IQR 567–708), and Shannon entropy, with median 7.8 (IQR 7.2–8.2), were consistently higher than in the majority of the rural control homes (n = 96) where the respective values were 449 (IQR 384–555) for richness and 6.7 (IQR 5.9–7.2) for Shannon entropy (Wilcoxon, two-sided P < 0.0001). In fungal microbiota, there was a tendency for higher richness, with median 263 (217–306) fungal OTUs, and Shannon entropy, with median 3.9 (3.4–4.3), in the rural control (n = 97) than farm homes (n = 101) where the respective values were 252 (195–301; P = 0.12) for richness and 3.7 (3.3–4.1; Wilcoxon, two-sided P = 0.07) for Shannon entropy. The boxes represent the IQR with the median marked within the box, the whiskers represent the minimum/maximum value within 1.5 IQR below the lower quartile/above the upper quartile, respectively, and the dots represent outliers.
a,b, The relative abundance of bovine-associated (a) and human-associated (b) bacterial/archaeal OTUs in living room floor dust in farm (n = 107) and non-farm homes (n = 96) within LUKAS1 as determined by source tracking. Both comparisons (a,b) were significantly different with the Wilcoxon test at two-sided P < 0.0001. c, Relative abundance of soil-associated bacterial/archaeal OTUs was higher in the LUKAS (LUKAS1 and 2) non-farm homes that resembled more LUKAS1 farm homes (n = 179) than non-farm homes (n = 215) as defined by FaRMI (Wilcoxon test, two-sided P = 0.0003). The boxes represent IQR with median marked within the box, the whiskers represent minimum/maximum value within 1.5 IQR below the lower quartile/above the upper quartile, respectively, and the dots represent outliers.
Fungal taxa with significantly higher relative abundance in LUKAS1 farm (n = 101) than non-farm (orange circles) or in non-farm (n = 96) than farm homes (blue circles) as determined with ANCOM. Clades are colored up to genus level. Names are given for all phyla and for all taxa with significantly different relative abundance between farm and non-farm homes that have taxonomic assignment. The name of the highest taxonomic level is given for clades where the relative abundance between farm and non-farm homes is significantly different at several taxonomic levels. o, order.
Extended Data Fig. 4 Classification accuracy of the LUKAS1 farm-like microbiota model in the data it was trained in (LUKAS1).
Based on the receiver operating characteristics (ROC) curve, FaRMI had only moderate classification accuracy with area under the curve 0.74. This is a critical feature of FaRMI as it enables the detection of farm-like features also in non-farm homes.
That is, variables contributing to FaRMI and FaRMIGABRIELA, respectively (see also Supplementary Table 9). Taxa in both models are marked with yellow, taxa in LUKAS alone are marked with blue and taxa in GABRIELA alone are marked with red triangles. The direction of the triangle indicates negative (down-pointing triangle) or positive (up-pointing triangle) association with FaRMI and FaRMIGABRIELA. The size of the triangles is proportional to the variance explained by the taxa (adjusted partial R2); the size of the yellow triangles is proportional to the higher adjusted R2 in the FaRMI or FaRMIGABRIELA model. In three cases, the direction was opposite between the two models; also in these cases, the triangles represent the model where the taxa had higher adjusted R2. Clades are colored where the adjusted R2 was >1%.
Extended Data Fig. 6 Cytokine responses and serum CRP levels associated with farm-like indoor microbiota.
a,b, Quantile process plots of the quantile regression analysis showing the estimated change in cytokine concentration (pg ml−1) at a given percentile per IQR change in FaRMI at year 1 (a) and year 6 (b). The shaded areas show the 95% confidence intervals based on resampling with 1,000 repetitions and where these do not overlap with the horizontal zero-change line the decrease/increase at that percentile is statistically significant (two-sided P value without correction for multiple testing < 0.05). Plots are presented for all cytokines that show tendency for significant (P < 0.1) association with FaRMI between the 25th and 80th percentile without correction for multiple testing. Cytokines were measured from blood cultures stimulated with PI, LPS and PPG. CRP was measured from serum.
Extended Data Fig. 7 Proportion of ILT 4-expressing plasmacytoid dendritic cells is correlated with FaRMI.
The proportion of ILT 4-expressing plasmacytoid dendritic cells increased with increasing FaRMI within LUKAS1 children living in a non-farm home who were not diagnosed with asthma by 6 years of age (n = 26). In those children who had been diagnosed with asthma (n = 16) such a correlation did not exist. In logistic regression analysis modeling of the association between the ILT4 expression on plasmacytoid dendritic cells and FaRMI, the interaction term asthma ever by 6 years of age × FaRMI was significant (P = 0.03). The scatterplots were fitted with simple linear regression lines.
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Kirjavainen, P.V., Karvonen, A.M., Adams, R.I. et al. Farm-like indoor microbiota in non-farm homes protects children from asthma development. Nat Med 25, 1089–1095 (2019). https://doi.org/10.1038/s41591-019-0469-4
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