{ "abstract": "Lysosome-rich enterocytes (LREs) are a specialized population of intestinal cells that mediate the uptake and absorption of dietary proteins in fish and neonatal mammals. Loss of LRE function causes inhibited growth and poor survival due to protein malnutrition. Previously, we reported that in zebrafish loss of Plasmolipin (pllp), an endosomal membrane protein highly expressed in LREs, impairs LRE differentiation and dietary protein absorption, resulting in marked reduction in survival rates. Raising pllp homozygous mutants surviving to adulthood and in-crossing them for multiple generations resulted in a recovery of survival and growth, even when fed a low protein diet. To uncover mechanisms underlying this phenomenon, we compared the older adapted pllp allele with genetically related wild type (WT) fish and a newly generated pllp mutant allele. Using transcriptome profiling and quantitative protein absorption assays, we found that the adapted pllp mutants exhibit upregulation of LRE endocytic components associated with a capacity for protein absorption that exceeds that of WT. This hyperactivation of LRE endocytic and absorptive activity is accompanied by transcriptional regulation of immune genes that may contribute to the enhanced survival of pllp mutants in the face of increased exposure to environmental antigens. Genetic analyses indicate that these divergent phenotypes emerge gradually over generations and can recur in an independently generated pllp allele upon inbreeding and natural selection. Overall, our study illustrates that genome-wide transcriptional changes are associated with stable improvements in intestinal function and organismal survival in response to protein malnutrition. Author summary: In this study, we investigated how zebrafish adapt to protein malnutrition when the function of specialized intestinal protein-absorbing enterocytes, also found in newborn mammals, is impaired. We observed that fish carrying a mutation that severely disrupts intestinal protein absorption gradually recovered their ability to survive over multiple generations of inbreeding, even though the underlying mutation remained intact. By comparing gene activity in these adapted fish with that of newly generated mutants, we found that the adapted state is associated with changes in two systems: enterocytes show increased protein uptake and degradation that even surpass those of wild type fish, while the immune system was simultaneously recalibrated to dampen inflammation. We further show that this trajectory can be recapitulated in a second, independently generated mutant line that underwent a strikingly similar recovery trajectory over successive generations. Together, our findings reveal that animals can overcome a severe, heritable nutritional deficit through a gradual, genome-wide transcriptional response that fundamentally reshapes intestinal function across generations.", "abstract_shown": true, "affiliations": [ "Department of Cell Biology, Duke University, Durham, North Carolina, United States of America", "Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, United States of America", "UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America", "Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 5, "authors": [ { "affs": [ 0 ], "name": "Siyao Wang" }, { "affs": [ 1 ], "name": "Laura Childers" }, { "affs": [ 2 ], "name": "Fernando Martinez III" }, { "affs": [ 3 ], "name": "Michel Bagnat" }, { "name": "Jieun Park" } ], "bibtex": "https://research.draconitic.com/paper/4pn8abhjnacaj.bib", "cited_by": 0, "doi": "10.1371/journal.pgen.1012071", "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012071", "id": "4pn8abhjnacaj", "issns": [ "1553-7404" ], "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012071", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1104|Aquaculture Nutrition and Growth" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Guide RNA" ], [ "plos", "/Biology and life sciences/Developmental biology/Life cycles/Larvae" ], [ "plos", "/Biology and life sciences/Ecology/Community ecology/Trophic interactions" ], [ "plos", "/Biology and life sciences/Evolutionary biology/Population genetics/Gene pool" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression" ], [ "plos", "/Biology and life sciences/Genetics/Population genetics/Gene pool" ], [ "plos", "/Biology and life sciences/Immunology/Immune response" ], [ "plos", "/Biology and life sciences/Nutrition/Diet" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota/Animals/Vertebrates/Fish/Osteichthyes/Zebrafish" ], [ "plos", "/Biology and life sciences/Population biology/Population genetics/Gene pool" ], [ "plos", "/Biology and life sciences/Zoology/Animals/Vertebrates/Fish/Osteichthyes/Zebrafish" ], [ "plos", "/Ecology and environmental sciences/Ecology/Community ecology/Trophic interactions" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response" ], [ "plos", "/Medicine and health sciences/Nutrition/Diet" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Animal models/Zebrafish" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Zebrafish" ], [ "plos", "/Research and analysis methods/Model organisms/Zebrafish" ] ], "openalex": "W7214589718", "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012071&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-28", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/4pn8abhjnacaj.ris", "sources": [ { "first_seen": "2026-10-30T12:17:37Z", "native_id": "10.1371/journal.pgen.1012071", "source": "plos", "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012071" } ], "subjects": [ { "field": "biology", "origin": "plos:ecology", "subfield": "ecology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:nutrition", "subfield": "nutrition" } ], "title": "Genome wide transcriptional changes underlie gradual and recurrent adaptation to protein malnutrition in zebrafish", "title_text": "Genome wide transcriptional changes underlie gradual and recurrent adaptation to protein malnutrition in zebrafish", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:37Z", "url": "https://research.draconitic.com/paper/4pn8abhjnacaj", "venue": "PLOS Genetics", "versions": [] }