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2026

Cell 2026 Aug 3:S0092-8674(26)00820-2. doi: 10.1016/j.cell.2026.07.022. Online ahead of print.

Milk osteopontin alters the infant microbiome to drive DC hematopoiesis and disease tolerance

Daniel R Howard, Ridwan B Rashid, Tufael Ahmed, Patricia Namubiru, Md Sohel Rana, Tyler Wilkins, Joshua Morrow, Darren J Creek, Rose Ann Franco, Mark C Allenby, Declan L Turner, Rhiannon B Werder, Sam Manna, Catherine Satzke, Yenkai Lim, Jiarui Sun, Paul G Dennis, Anushka Yadav, Andrew J Kueh, Cheong Kwong Chung, Elizabeth Forbes-Blom, Mario Noti, Jonathan O'Regan, Luis Pedro Coelho, Chrysothemis C Brown, Mark Morrison, Simon Phipps

QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia. QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4000, Australia. Monash Institute of Pharmaceutical Sciences, Parkville, VIC 3800, Australia. BioMimetic Systems Engineering Laboratory, School of Chemical Engineering, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; Australian Red Cross Lifeblood, Kelvin Grove, Brisbane, QLD 4059, Australia. BioMimetic Systems Engineering Laboratory, School of Chemical Engineering, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Novo Nordisk Foundation Centre for Stem Cell Medicine, reNEW Melbourne, Melbourne, VIC 3052, Australia. Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia. Frazer Institute, Faculty of Health, Medicine, and Behavioural Sciences, University of Queensland, Brisbane, QLD 4072, Australia. School of the Environment, The University of Queensland, Brisbane, QLD, Australia. School of the Environment, The University of Queensland, Brisbane, QLD, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia. Immune Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Olivia Newton-John Cancer Research Institute, Heidelberg, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Bundoora, Melbourne, VIC, Australia. Nestlé SA, Nestlé Research, Nestlé Institute of Health Sciences, Health Benefit Department, Vers-Chez-les-Blancs, Lausanne, Switzerland. Research & Development, Nestlé Product Technology Center - Nutrition, Vevey, Switzerland. Nestlé Development Centre Nutrition, Askeaton, County Limerick, Ireland. Centre for Microbiome Research, School of Biomedical Sciences, Queensland University of Technology, Translational Research Institute, Brisbane, QLD, Australia. Immune Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Frazer Institute, Faculty of Health, Medicine, and Behavioural Sciences, University of Queensland, Brisbane, QLD 4072, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia. QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4000, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia

Service type: Stock strains

Abstract

Breastfeeding reduces the risk of severe lower respiratory infections (sLRIs), a leading cause of infant mortality; however, the protective mechanisms remain elusive. Here, we demonstrated that the absence of milk-derived osteopontin (OPN), highly expressed in colostrum, predisposes neonatal mice to viral and bacterial sLRI, consequent to disrupted dendritic cell (DC) hematopoiesis in the developing liver and lung. Amelioration of disease severity by oral OPN supplementation was associated with increased enteric abundance of Lactobacillaceae and elevated levels of serum 3-phenyllactic acid (PLA), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist. Supplementation with PLA or the PPARγ agonist rosiglitazone restored lung DC hematopoiesis via airway epithelium-derived chemokine ligand 25 (CCL25)-mediated recruitment of lymphoid-myeloid primed progenitors and induction of a supportive lung niche. PLA-induced DC hematopoiesis and disease tolerance were attenuated by plasmacytoid DC depletion, immunoneutralization of stem cell factor, or genetic deletion of airway epithelial Flt3L. Our findings elucidate a microbiome-host interaction by which milk OPN confers protection against sLRI.