Paternal microbiome perturbations impact offspring fitness

Ayele Argaw-Denboba, Thomas S. B. Schmidt, Monica Giacomo, Bobby Ranjan, Saravanan Devendran, Eleonora Mastrorilli, Catrin T. Lloyd, Danilo Pugliese, Violetta Paribeni, Juliette Dabin, Alessandra Pisaniello, Sergio Espinola, Alvaro Crevenna, Subhanita Ghosh, Neil Humphreys, Olga Boruc, Peter Sarkies, Michael Zimmermann, Peer Bork and Jamie A. Hackett ()
Additional contact information
Ayele Argaw-Denboba: Epigenetics & Neurobiology Unit
Thomas S. B. Schmidt: Structural & Computational Biology Unit
Monica Giacomo: Epigenetics & Neurobiology Unit
Bobby Ranjan: Epigenetics & Neurobiology Unit
Saravanan Devendran: Structural & Computational Biology Unit
Eleonora Mastrorilli: Structural & Computational Biology Unit
Catrin T. Lloyd: Epigenetics & Neurobiology Unit
Danilo Pugliese: Epigenetics & Neurobiology Unit
Violetta Paribeni: Epigenetics & Neurobiology Unit
Juliette Dabin: Epigenetics & Neurobiology Unit
Alessandra Pisaniello: Epigenetics & Neurobiology Unit
Sergio Espinola: Epigenetics & Neurobiology Unit
Alvaro Crevenna: Epigenetics & Neurobiology Unit
Subhanita Ghosh: MRC London Institute for Medical Science (LMS)
Neil Humphreys: Epigenetics & Neurobiology Unit
Olga Boruc: Epigenetics & Neurobiology Unit
Peter Sarkies: MRC London Institute for Medical Science (LMS)
Michael Zimmermann: Structural & Computational Biology Unit
Peer Bork: Structural & Computational Biology Unit
Jamie A. Hackett: Epigenetics & Neurobiology Unit

Nature, 2024, vol. 629, issue 8012, 652-659

Abstract: Abstract The gut microbiota operates at the interface of host–environment interactions to influence human homoeostasis and metabolic networks1–4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5–9. However, the systemic impact of the gut microbiome on the germline—and consequently on the F1 offspring it gives rise to—is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory ‘gut–germline axis’ in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.

Date: 2024
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DOI: 10.1038/s41586-024-07336-w

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