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Neuropeptides neurotensin and substance P accelerate diabetic wound healing by modulating immunity and the skin microbiome

2026-02-17Artigo científico Acesso aberto
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datacite.subject.fosCiências Médicas::Ciências da Saúde
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorMaranha, Ana
dc.contributor.authorLeal, Ermelindo C.
dc.contributor.authorAlarico, Susana
dc.contributor.authorTiago, Igor
dc.contributor.authorPereira, Sónia G.
dc.contributor.authorEmpadinhas, Nuno
dc.contributor.authorCarvalho, Eugénia
dc.date.accessioned2026-09-10T13:52:11Z
dc.date.available2026-09-10T13:52:11Z
dc.date.issued2026-02-17
dc.descriptionArticle nr 9456
dc.description.abstractDiabetic foot ulcers (DFUs) are a common and debilitating complication of diabetes mellitus, typified by impaired healing, persistent inflammation, and skin microbiota dysbiosis. Although some neuropeptides are immunomodulatory, their effects on skin microbiota and wound resolution remain largely unexplored. We examined the therapeutic potential of the neuropeptides neurotensin (NT) and substance P (SP) in reshaping inflammatory and microbial dynamics and accelerating wound closure in a healthy and streptozotocin-induced diabetic mice model. Full-thickness cutaneous wounds were induced on both groups, followed by daily topical applications of saline (CT), NT, or SP. Wound closure was monitored and changes in skin bacterial communities characterized using next-generation sequencing. Wound tissue samples were collected for immunohistochemical analysis. Topical application of NT or SP significantly accelerated wound healing, with the most pronounced effects in diabetic animals. Both neuropeptides reduced the number of pro-inflammatory cells, lowering M1 macrophages in diabetic wounds from 16.4 ± 4 to 12.1 ± 3 with NT and 10.9 ± 3 with SP, while increasing M2 macrophages from 11.6 ± 4 to 18.1 ± 4 (NT) and 21.6 ± 5 (SP). SP exerted the most pronounced immunomodulatory effect, normalizing the M1/M2 ratio and reducing the number of CD3⁺ T cells (12.4 ± 3) and neutrophils (12.1 ± 3) to levels comparable to non-diabetic skin. Concurrently, SP treatment induced substantial microbiota remodeling in diabetic wounds, reducing Staphylococcus by circa 34%, Aerococcaceae_unclassified by 6.8%, Aerococcus by 1.5% and nearly eliminating Weissella. These reductions were accompanied by an over twofold increase in commensal genera (Lactobacillus, Micrococcaceae_unclassified, Actinobacteria_unclassified), shifting the microbial community toward a more non-diabetic profile. Our findings suggest that NT and especially SP, enhance diabetic wound healing through dual local immunomodulation and microbiota restructuring.eng
dc.description.sponsorshipThis research was funded by Fundação para a Ciência e a Tecnologia (FCT), under projects UIDB/04539/2020, UIDP/04539/2020 and LA/P/0058/2020. FCT support to A. Maranha through a Junior Investigator contract under project PTDC/BIA-MIC/0122/2021 and 2022.06809.PTDC (htpps://https://doi.org/10.54499/2022.06809.PTDC), to S. Alarico through contract https://doi.org/10.54499/DL57/2016/CP1448/CT0017, to E.C. Leal through contract DL57/2016/CP1448/CT0024 and grant 2023.13851.PEX, and to SGP through contract CEECINST/00051/2018 (htpps://https://doi.org/10.54499/CEECINST/0051/2018/CP1566/CT004) and UIDB/05704/2020 (htpps://https://doi.org/10.54499/UIDB/05704/2020) funding is also acknowledged. We also acknowledge INFARMED, Fundo para a Investigação em Saúde, FIS-FIS-2015-01_DIA_20150630-144, for financial support.
dc.identifier.citationMaranha, A., Leal, E.C., Alarico, S. et al. Neuropeptides neurotensin and substance P accelerate diabetic wound healing by modulating immunity and the skin microbiome. Sci Rep 16, 9456 (2026). https://doi.org/10.1038/s41598-025-30723-w
dc.identifier.doi10.1038/s41598-025-30723-w
dc.identifier.eissn2045-2322
dc.identifier.urihttp://hdl.handle.net/10400.8/16852
dc.language.isoeng
dc.peerreviewedyes
dc.publisherSpringer Nature
dc.relationCenter for Innovative Biomedicine and Biotechnology
dc.relationCenter for Innovative Biomedicine and Biotechnology
dc.relationCenter for Innovative Biomedicine and Biotechnology - Associate Laboratory
dc.relationNontuberculous mycobacteria from drinking water: beyond the lung disease epidemic
dc.relationExploring bacterial interactions to find novel molecules to combat the antimicrobial resistance catastrophe
dc.relationInhibition of protein tyrosine phosphatase 1b to promote wound healing in diabetes
dc.relationMicrobiology Advancing Health: Microbiome-Autoimmunity Interplay and the Artificial Intelligence of Infection Prevention and Control
dc.relationCenter for Innovative Care and Health Technology
dc.relation"DL57/2016/CP1448/CT0017"
dc.relation.hasversionhttps://www.nature.com/articles/s41598-025-30723-w
dc.relation.ispartofScientific Reports
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectNeuropeptides
dc.subjectSubstance P
dc.subjectNeurotensin
dc.subjectSkin microbiota
dc.subjectDiabetic wound healing
dc.subjectInflammation
dc.subjectDysbiosis
dc.titleNeuropeptides neurotensin and substance P accelerate diabetic wound healing by modulating immunity and the skin microbiomeeng
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberUIDB/04539/2020
oaire.awardNumberUIDP/04539/2020
oaire.awardNumberLA/P/0058/2020
oaire.awardNumberPTDC/BIA-MIC/0122/2021
oaire.awardNumber2022.06809.PTDC
oaire.awardNumber2023.13851.PEX
oaire.awardNumberCEECINST/00051/2018/CP1566/CT0004
oaire.awardNumberUIDB/05704/2020
oaire.awardTitleCenter for Innovative Biomedicine and Biotechnology
oaire.awardTitleCenter for Innovative Biomedicine and Biotechnology
oaire.awardTitleCenter for Innovative Biomedicine and Biotechnology - Associate Laboratory
oaire.awardTitleNontuberculous mycobacteria from drinking water: beyond the lung disease epidemic
oaire.awardTitleExploring bacterial interactions to find novel molecules to combat the antimicrobial resistance catastrophe
oaire.awardTitleInhibition of protein tyrosine phosphatase 1b to promote wound healing in diabetes
oaire.awardTitleMicrobiology Advancing Health: Microbiome-Autoimmunity Interplay and the Artificial Intelligence of Infection Prevention and Control
oaire.awardTitleCenter for Innovative Care and Health Technology
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04539%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04539%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/LA%2FP%2F0058%2F2020/PT
oaire.awardURIhttp://hdl.handle.net/10400.8/16846
oaire.awardURIhttp://hdl.handle.net/10400.8/16848
oaire.awardURIhttp://hdl.handle.net/10400.8/16847
oaire.awardURIhttp://hdl.handle.net/10400.8/16607
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F05704%2F2020/PT
oaire.citation.endPage14
oaire.citation.issue1
oaire.citation.startPage1
oaire.citation.titleScientific Reports
oaire.citation.volume16
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamConcurso de Projetos IC&DT em Todos os Domínios Científicos
oaire.fundingStreamConcurso de Projetos de I&D em Todos os Domínios Científicos - 2022 - PEX
oaire.fundingStreamConcurso de Projetos Exploratórios em Todos os Domínios Científicos 2023
oaire.fundingStreamCEEC INST 2018
oaire.fundingStream6817 - DCRRNI ID
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameGonçalves Pereira
person.givenNameSónia
person.identifier461252
person.identifier.ciencia-idEB1F-4DB2-B0C9
person.identifier.orcid0000-0001-8197-1850
person.identifier.ridM-7588-2017
person.identifier.scopus-author-id7202024712
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
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