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Urban living in healthy Tanzanians is associated with an inflammatory status driven by dietary and metabolic changes

Abstract

Sub-Saharan Africa currently experiences an unprecedented wave of urbanization, which has important consequences for health and disease patterns. This study aimed to investigate and integrate the immune and metabolic consequences of rural or urban lifestyles and the role of nutritional changes associated with urban living. In a cohort of 323 healthy Tanzanians, urban as compared to rural living was associated with a pro-inflammatory immune phenotype, both at the transcript and protein levels. We identified different food-derived and endogenous circulating metabolites accounting for these differences. Serum from urban dwellers induced reprogramming of innate immune cells with higher tumor necrosis factor production upon microbial re-stimulation in an in vitro model of trained immunity. These data demonstrate important shifts toward an inflammatory phenotype associated with an urban lifestyle and provide new insights into the underlying dietary and metabolic factors, which may affect disease epidemiology in sub-Sahara African countries.

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Fig. 1: Schematic depiction of the study population and distribution.
Fig. 2: Associations of blood transcriptomes, ex vivo cytokine immune responses and plasma cytokines with urban or rural living.
Fig. 3: Impact of age and sex on cytokine production capacity.
Fig. 4: Differences in plasma metabolite abundance in rural- versus urban-living individuals.
Fig. 5: Relation of plasma metabolites with ex vivo cytokine production capacity.
Fig. 6: Impact of annual seasonality on blood transcriptome and cytokine immune responses.
Fig. 7: Association of urban individuals’ food-derived metabolome on cytokine immune responses and blood transcriptome.

Data availability

Data that support the findings of this study are available from the corresponding author upon request. Sequence data have been deposited at the European Genome–phenome Archive, which is hosted by the EBI and the CRG, under accession number EGAS00001004284. In addition to the deposition of the raw sequencing data on the European Genome–phenome Archive, we provide an interactive platform for data inspection and analysis via FASTGenomics (https://beta.fastgenomics.org/p/Temba_300FG_NatureImmun). In this platform, we provide processed count tables of the datasets generated in this study as well as key analytical results and the code written to analyze the respective data. Metabolomics data have been deposited to the EMBL-EBI MetaboLights database65 with study identifier MTBLS2267. Code analysis scripts are available at: https://github.com/schultzelab/Temba-Kullaya-Pecht-et-al.- and https://beta.fastgenomics.org/p/Temba_300FG_NatureImmun. Publicly available databases used for this study include NCBI’s Gene Expression Omnibus G3 under accession code GSE110749 and differential gene analysis results from the study of Arango et al. (Biochem. Pharmacol., https://doi.org/10.1016/j.bcp.2012.09.005, 2012). Other databases are KEGG (https://www.genome.jp/kegg/), HMDB (https://www.hmdb.ca/) and ChEBI (https://www.ebi.ac.uk/chebi/). All other data are available in the main text, supplementary materials and auxiliary supplemental tables.

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Acknowledgements

The authors thank all volunteers in the Human Functional Genomics in Healthy Tanzanian Individuals study for their participation. We thank J. Njau, J. Kwayu and E. Kimaro for help in sample collection; H. Lemmers and H. Toenhake-Dijkstra for help in laboratory analysis; Y. Li for help in statistics; and M. Miclaus for help with metabolome data processing. We also thank M. Kraut and K. Händler for their great contribution to RNA sequencing. This study was funded by the following grants: the European Union’s Horizon 2020 Research and Innovation Program under the ERA-Net Cofund action no. 727565; the Joint Programming Initiative, A Healthy Diet for a Healthy Life (JPI-HDHL; project 529051018) awarded to M.G.N., Q.d.M., A.V. and J.L.S.; ZonMw (the Netherlands Organisation for Health Research and Development) awarded to M.G.N., Q.dM. and A.V.; Radboud Revolving Research Funds (3R-Fund) awarded to G.S.T.; Spinoza Prize (NWO SPI94-212) and ERC Advanced grant (no. 833247) awarded to M.G.N.; and the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy (EXC2151) 390873048 awarded to M.G.N. and J.L.S.

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Contributions

Q.d.M., A.V., M.G.N., L.A.B.J., G.K., J.L.S. and B.T.M. contributed to the conceptualization, study design and data interpretation and led the project; G.S.T., V.K., B.T.M. and F.L. contributed to participant recruitment, data collection and laboratory analyses; G.S.T. designed and performed functional validation experiments and analysis of immunological and metabolome data; T.P., T.U., A.C.A. and J.L.S. contributed to RNA-seq analysis and analytical integration with metabolome data and interpretation; C.K.B. and V.K. contributed to genetics analysis and interpretation; G.S.T., T.P. and Q.d.M. wrote the original draft of the manuscript; and G.S.T., T.P., V.K., C.K.B., B.T.M., A.C.A., T.U., G.K., F.L., V.K., L.A.B.J., J.L.S., A.V., M.G.N. and Q.d.M. contributed to writing and editing the manuscript.

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Correspondence to Mihai G. Netea or Quirijn de Mast.

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Peer reviewer information Nature Immunology thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available. Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Schematic depiction of the study parameters.

Schematic depiction of the study recruitment procedure. b, collected samples for blood transcriptome measured in unstimulated blood and circulating inflammatory mediators and metabolome were measured in EDTA plasma. c, Cytokine production capacity of the circulating immune cells in the ex vivo whole blood stimulation experimental setup.

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Supplementary Figs. 1–7 and Tables 7 and 16.

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Temba, G.S., Kullaya, V., Pecht, T. et al. Urban living in healthy Tanzanians is associated with an inflammatory status driven by dietary and metabolic changes. Nat Immunol 22, 287–300 (2021). https://doi.org/10.1038/s41590-021-00867-8

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