Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection
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Abstract
Abstract The whipworm Trichuris trichiura is a soil-transmitted helminth that dwells in the epithelium of the caecum and proximal colon of their hosts causing the human disease, trichuriasis. Trichuriasis is characterized by colitis attributed to the inflammatory response elicited by the parasite while tunnelling through intestinal epithelial cells (IECs). The IL-10 family of receptors, comprising combinations of subunits IL-10Rα, IL-10Rβ, IL-22Rα and IL-28Rα, modulates intestinal inflammatory responses. Here we carefully dissected the role of these subunits in the resistance of mice to infection with T. muris, a mouse model of the human whipworm T. trichiura. Our findings demonstrate that whilst IL-22Rα and IL-28Rα are dispensable in the host response to whipworms, IL-10 signalling through IL-10Rα and IL-10Rβ is essential to control caecal pathology, worm expulsion and survival during T. muris infections. We show that deficiency of IL-10, IL-10Rα and IL-10Rβ results in dysbiosis of the caecal microbiota characterised by expanded populations of opportunistic bacteria of the families Enterococcaceae and Enterobacteriaceae. Moreover, breakdown of the epithelial barrier after whipworm infection in IL-10, IL-10Rα and IL-10Rβ-deficient mice, allows the translocation of these opportunistic pathogens or their excretory products to the liver causing organ failure and lethal disease. Importantly, bone marrow chimera experiments indicate that signalling through IL-10Rα and IL-10Rβ in haematopoietic cells, but not IECs, is crucial to control worm expulsion and immunopathology. These findings are supported by worm expulsion upon infection of conditional mutant mice for the IL-10Rα on IECs. Our findings emphasize the pivotal role of systemic IL-10Rα signalling on immune cells in promoting microbiota homeostasis and maintaining the intestinal epithelial barrier, thus preventing immunopathology during whipworms infections. Author summary The human gut is home to millions of bacteria, collectively called the microbiota, and also to parasites that include whipworms. The interactions between gut cells, the microbiota and whipworms define conditions for balanced parasitism. Cells lining the gut host whipworms but also interact with gut immune cells to deploy measures that control or expel whipworms whilst maintaining a barrier to prevent microbial translocation. Whipworms affect the composition of the microbiota, which in turn impacts the condition of the gut lining and the way in which immune cells are activated. In order to avoid tissue damage and disease, these interactions are tightly regulated. Here we show that signalling through a member of the IL-10 receptor family, IL-10Rα, in gut immune cells is critical for regulating of these interactions. Lack of this receptor on gut immune cells results in persistence of whipworms in the gut accompanied by an uncontrolled inflammation that destroys the gut lining. This tissue damage is accompanied by the overgrowth of members of the microbiota that act as opportunistic pathogens. Furthermore, the destruction of the gut barrier allows these bacteria to reach the liver where they cause organ failure and fatal disease.
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Accelerated Cellular Uptake and Metabolism of L-Thyroxine during Acute Salmonella typhimurium Sepsis
DeRubertis, F. R., & Woeber, K. A. (1973) · Journal of Clinical Investigation · doi:10.1172/jci107176 · Cited by 25 · see citing works
The Response of the Thyroid Gland and Thyroid Hormone Metabolism to Infectious Disease
Wartofsky, L. (2008) · Hormone Research · doi:10.1159/000178623 · Cited by 19 · see citing works
Fasnacht, N., Greweling‐Pils, M. C., Bollati‐Fogolín, M., Schippers, A., & Müller, W. (2009) · European Journal of Immunology · doi:10.1002/eji.200838710 · Cited by 18 · see citing works
Self-citationKopper, J. J., Patterson, J. S., & Mansfield, L. S. (2015) · Veterinary Parasitology · doi:10.1016/j.vetpar.2015.07.038 · Cited by 3 · see citing works
Flagged first, then by citations
1 of the 93 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Whipworm and roundworm infections
Else, K. J., Keiser, J., Holland, C. V., Grencis, R. K., Sattelle, D. B., Fujiwara, R. T., Bueno, L. L., Asaolu, S. O., Sowemimo, O. A., & Cooper, P. J. (2020) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-0171-3 · Cited by 308 · see citing works
Willers, M., Ulas, T., Völlger, L., Vogl, T., Heinemann, A. S., Pirr, S., Pagel, J., Fehlhaber, B., Halle, O., Schöning, J., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.08.019 · Cited by 145 · see citing works
Chiriac, M. T., Buchen, B., Wandersee, A., Hundorfean, G., Günther, C., Bourjau, Y., Doyle, S. E., Frey, B., Ekici, A. B., Büttner, C., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.03.015 · Cited by 103 · see citing works
Helminth-microbiota cross-talk – A journey through the vertebrate digestive system
Cortés, A., Peachey, L., Scotti, R., Jenkins, T. P., & Cantacessi, C. (2019) · Molecular and Biochemical Parasitology · doi:10.1016/j.molbiopara.2019.111222 · Cited by 63 · see citing works
Self-citationImmunity to Soil-Transmitted Helminths: Evidence From the Field and Laboratory Models
Colombo, S. A. P., & Grencis, R. K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01286 · Cited by 48 · see citing works
Self-citationFermentable Dietary Fiber Promotes Helminth Infection and Exacerbates Host Inflammatory Responses
Myhill, L. J., Stolzenbach, S., Mejer, H., Jakobsen, S. R., Hansen, T. V. A., Andersen, D., Brix, S., Hansen, L. H., Krych, Ł., Nielsen, D. S., et al. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1901149 · Cited by 36 · see citing works
Webster, H. C., Gamino, V., Andrusaite, A. T., Ridgewell, O. J., McCowan, J., Shergold, A. L., Heieis, G. A., Milling, S. W. F., Maizels, R. M., & Perona‐Wright, G. (2022) · Mucosal Immunology · doi:10.1038/s41385-022-00513-y · Cited by 36 · see citing works
Oyesola, O. O., Souza, C. O. S., & Loke, P. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.869163 · Cited by 30 · see citing works
Kang, K., Sun, Y., Pan, D., Sang, L.-X., Sun, M., Li, Y., & Chang, B. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.9862 · Cited by 28 · see citing works
Yousefi, Y., Haq, S., Banskota, S., Kwon, Y. H., & Khan, W. I. (2021) · Pathogens · doi:10.3390/pathogens10080925 · Cited by 28 · see citing works
Dietary Inulin and Trichuris suis Infection Promote Beneficial Bacteria Throughout the Porcine Gut
Stolzenbach, S., Myhill, L. J., Andersen, L. O., Krych, Ł., Mejer, H., Williams, A. R., Nejsum, P. L., Stensvold, C. R., Nielsen, D. S., & Thamsborg, S. M. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.00312 · Cited by 26 · see citing works
Mayer, J. U., Brown, S. L., MacDonald, A. S., & Milling, S. W. F. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.592325 · Cited by 22 · see citing works
Zhang, P., & Hill, G. R. (2019) · Seminars in Immunology · doi:10.1016/j.smim.2019.101322 · Cited by 21 · see citing works
Trichuris murisand comorbidities – within a mouse model context
Hayes, K. S., & Grencis, R. K. (2021) · Parasitology · doi:10.1017/s0031182021000883 · Cited by 21 · see citing works
Self-citationPeng, Y., Xu, J., Zeng, C.-F., Zhao, X., Li, L., & Qi, L. (2022) · Annals of Translational Medicine · doi:10.21037/atm-22-1958 · Cited by 18 · see citing works
Hatching of whipworm eggs induced by bacterial contact is serine-protease dependent
Goulding, D., Tolley, C., Mkandawire, T. T., Doyle, S. R., Hart, E., Airs, P. M., Grencis, R. K., Berriman, M., & Correa, M. A. D. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1012502 · Cited by 10 · see citing works
Self-citationYousefi, Y., Haider, Z., Grondin, J. A., Wang, H., Haq, S., Banskota, S., Seto, T. C., Surette, M. G., & Khan, W. I. (2025) · Mucosal Immunology · doi:10.1016/j.mucimm.2025.03.007 · Cited by 10 · see citing works
Darlan, D. M., Rozi, M. F., & Yulfi, H. (2021) · Life · doi:10.3390/life11030188 · Cited by 11 · see citing works
Duan, C., Abudureheman, T., Wang, S., Suo, J., Yu, Y., Shi, F., Liu, X., Salama, D. B., Srivastav, R. K., Gupta, N., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1435702 · Cited by 9 · see citing works
Another decade of research: An update and application of key discoveries
Hubbard, I. C., Thompson, J., Else, K. J., & Shears, R. K. (2023) · Advances in Parasitology/Advances in parasitology · doi:10.1016/bs.apar.2023.05.002 · Cited by 8 · see citing works
Mair, I., Else, K. J., & Forman, R. A. (2021) · Parasitology · doi:10.1017/s003118202100069x · Cited by 9 · see citing works
Ranjitkar, S., Krajewski, D., Garcia, C., Tedeschi, C., Polukort, S., Rovatti, J., Mire, M. M., Blesso, C. N., Jellison, E. R., Schneider, S. S., et al. (2024) · The Journal of Immunology · doi:10.4049/jimmunol.2300884 · Cited by 6 · see citing works
Meli, A. P., Russell, G. A., Swaminathan, S., Weichselbaum, L., MacMahon, C. A., Pernet, E., Karo‐Atar, D., Rogers, D., Rochette, A., Fontès, G., et al. (2023) · Mucosal Immunology · doi:10.1016/j.mucimm.2023.08.004 · Cited by 5 · see citing works
Zhang, H., Bednář, L., Heitlinger, E. G., Hartmann, S., & Rausch, S. (2022) · International Journal for Parasitology · doi:10.1016/j.ijpara.2022.03.006 · Cited by 5 · see citing works
An optimised faecal microRNA sequencing pipeline reveals fibrosis in Trichuris muris infection
Layton, E., Goldsworthy, S., Yang, E., Ong, W. Y., Sutherland, T. E., Bancroft, A. J., Thompson, S., Au, B. V., Griffiths‐Jones, S., Grencis, R. K., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56698-w · Cited by 4 · see citing works
Self-citationTangkawattana, S., Suyapoh, W., Taiki, N., Tookampee, P., Chitchak, R., Thongrin, T., & Tangkawattana, P. (2023) · Veterinary World · doi:10.14202/vetworld.2023.2303-2312 · Cited by 4 · see citing works
Host microbiome determines host specificity of the human whipworm, Trichuris trichiuraPreprint
Stark, K. A., Mkandawire, T. T., Tolley, C., Thompson, S., Fortune‐Grant, R., Brandt, C., Clare, S., Lawley, T. D., Cantacessi, C., Almeida, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.09.653168 · Cited by 2 · see citing works
Self-citationVeteriner Bilimlerinde Probiyotiklerin Terapötik, Profilaktik ve Fonksiyonel Kullanımı
Karadağoğlu, Ö., Rıaz, R., Çıldır, Ö. Ş., Makav, M., Kaya, K., Küçükoflaz, M., AYDIN, E., Ölmez, M., Şahin, T., Sezer, M., et al. (2023) · Özgür Yayınları eBooks · doi:10.58830/ozgur.pub358
Helmint Kaynaklı Enfeksiyonların Kontrolünde Probiyotikler
Aydın, N., Ölmez, N., & Barış, S. A. R. I. (2023) · Özgür Yayınları eBooks · doi:10.58830/ozgur.pub358.c1524
Köpek ve Kedilerde Yeni Gelişmeler: Probiyotikler
Batı, Y. U., Sezer, M., & Akyüz, E. (2023) · Özgür Yayınları eBooks · doi:10.58830/ozgur.pub358.c1523
Obezitede Probiyotiklerin Glukoz ve Lipid Metabolizması Üzerine Etkisi
Aygörmez, S. (2023) · Özgür Yayınları eBooks · doi:10.58830/ozgur.pub358.c1526
Genetiği Değiştirilmiş Probiyotikler
Çıldır, Ö. Ş. (2023) · Özgür Yayınları eBooks · doi:10.58830/ozgur.pub358.c1516
Optimisation of single-nuclei isolation and RNA sequencing of parasitic nematodes
Buddenborg, S. K., Morrison, A. A., Bewsher, A. C., Kieninger, M. R., Ng, B. L., Maitland, K., Hart, E., Bartley, D. J., Correa, M. A. D., & Doyle, S. R. (2026) · International Journal for Parasitology · doi:10.1101/2024.11.13.623282
Immunomodulatory effects of nematode-microbiota interactions in cancer therapy
Oksenych, V., Rashidan, M., Khazaei, M., & Tahmasebi, H. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1803276 · Cited by 1 · see citing works
Zhang, Y., Liu, X., Wang, B., Yin, H., Tian, X., Zhao, J., Xin, S., Wang, H., Ren, Y., Liu, X., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27219472
- Authors
- Duque-Correa, M. A., Karp, N. A., McCarthy, C., Forman, S., Goulding, D., Sankaranarayanan, G., Jenkins, T. P., Reid, A. J., Cambridge, E. L., Ballesteros Reviriego, C., The Sanger Mouse Genetics Project, The 3i consortium, Müller, W., Cantacessi, C., Dougan, G., Grencis, R. K., & Berriman, M.
- Affiliations
- Wellcome Sanger Institute (GB)
- Wellcome Centre for Cell-Matrix Research (GB)
- University of Cambridge (GB)
- ORCID
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2019-01-14
- Volume
- 15
- Issue
- 1
- Pages
- e1007265
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC6347331
- OpenAlex
- W2885095388
- Cited by
- 35
- References
- 93
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 8 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 2 · 2017: 1
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Update notices
- new_version (2019-01-25)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- H2020 Marie Skłodowska-Curie Actions (656347)
- Wellcome Trust (100156)
- Topics
- Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
- Keywords
- Trichuris muris, trichuriasis, dysbiosis, Enterococcaceae, Enterobacteriaceae, intestinal epithelial barrier, immunopathology, worm expulsion, hematopoietic cells, bone marrow chimeras, intestinal inflammation
- MeSH terms
- Gastrointestinal Microbiome, Interferon Lambda, Interleukin-22, Animals, Disease Models, Animal, Homeostasis, Interleukins, Intestines, Mice, Inbred C57BL, Trichuriasis, Trichuris, Signal Transduction, Cytokines, Interleukin-10, Mice, Receptors, Interleukin-10
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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