Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation

Background:The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the sa...

Descripción completa

Detalles Bibliográficos
Autores: Olivares, Marta, Hernández Calderón, Paula, Cárdenas Brito, Sonia, Liébana García, Rebeca, Sanz Herranz, Yolanda, Benítez-Páez, Alfonso
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/362688
Acceso en línea:http://hdl.handle.net/10261/362688
Access Level:acceso abierto
Palabra clave:DPP4 enzyme
GLP-1
Gliptins
Glucose metabolism
Gut microbiome
Incretins
Obesity
Type 2 diabetes
glucose
microbiomes
intestines
obesity
diabetes
carbohydrate metabolism
id ES_21809d72f9e7dcefc1501896f1d29b96
oai_identifier_str oai:digital.csic.es:10261/362688
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation
title Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation
spellingShingle Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation
Olivares, Marta
DPP4 enzyme
GLP-1
Gliptins
Glucose metabolism
Gut microbiome
Incretins
Obesity
Type 2 diabetes
glucose
microbiomes
intestines
obesity
diabetes
carbohydrate metabolism
title_short Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation
title_full Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation
title_fullStr Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation
title_full_unstemmed Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation
title_sort Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation
dc.creator.none.fl_str_mv Olivares, Marta
Hernández Calderón, Paula
Cárdenas Brito, Sonia
Liébana García, Rebeca
Sanz Herranz, Yolanda
Benítez-Páez, Alfonso
author Olivares, Marta
author_facet Olivares, Marta
Hernández Calderón, Paula
Cárdenas Brito, Sonia
Liébana García, Rebeca
Sanz Herranz, Yolanda
Benítez-Páez, Alfonso
author_role author
author2 Hernández Calderón, Paula
Cárdenas Brito, Sonia
Liébana García, Rebeca
Sanz Herranz, Yolanda
Benítez-Páez, Alfonso
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Agencia Estatal de Investigación (España)
Ministerio de Ciencia e Innovación (España)
Instituto de Salud Carlos III
European Commission
Benítez-Páez, Alfonso [0000-0001-5707-4340]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv DPP4 enzyme
GLP-1
Gliptins
Glucose metabolism
Gut microbiome
Incretins
Obesity
Type 2 diabetes
glucose
microbiomes
intestines
obesity
diabetes
carbohydrate metabolism
topic DPP4 enzyme
GLP-1
Gliptins
Glucose metabolism
Gut microbiome
Incretins
Obesity
Type 2 diabetes
glucose
microbiomes
intestines
obesity
diabetes
carbohydrate metabolism
description Background:The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function. Results: We identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae. Conclusions: Our findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/362688
url http://hdl.handle.net/10261/362688
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/EC/FP7/613979
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-119536RB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/CEX 2021-001189-S
Genome biology
The underlying dataset has been published as supplementary material of the article in the publisher platform at https://doi.org/10.1186/s13059-024-03325-4
https://doi.org/10.1186/s13059-024-03325-4
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869404519526301696
spelling Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivationOlivares, MartaHernández Calderón, PaulaCárdenas Brito, SoniaLiébana García, RebecaSanz Herranz, YolandaBenítez-Páez, AlfonsoDPP4 enzymeGLP-1GliptinsGlucose metabolismGut microbiomeIncretinsObesityType 2 diabetesglucosemicrobiomesintestinesobesitydiabetescarbohydrate metabolismBackground:The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function. Results: We identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae. Conclusions: Our findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. The authors acknowledge the following funding bodies that provided support for this study: European Commission 7th Framework Program through the MyNewGut project (Grant agreement No. 613979) and the Spanish Ministry of Science and Innovation (MICINN) (grant PID2020-119536RB-I00) to YS; Institute of Health Carlos III (ISCIII) via CP19/00132 grant to AB-P with funds from the European Social Fund (ESF/FSE), CIPF Predoctoral Training Fellowships 2022 funded by JANSSEN-CILAG—supporting the contract of PH-C, CIPF core funding for the contract of SC-B; Early Career Grant from the Society for Endocrinology award to MO. Spanish Government MCIN/AEI for the Center of Excellence Accreditation Severo Ochoa (CEX2021-001189-S/ MCIN/AEI / https://doi.org/10.13039/501100011033).With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2021-001189-S)Peer reviewedBioMed CentralAgencia Estatal de Investigación (España)Ministerio de Ciencia e Innovación (España)Instituto de Salud Carlos IIIEuropean CommissionBenítez-Páez, Alfonso [0000-0001-5707-4340]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/362688reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/FP7/613979info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-119536RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/CEX 2021-001189-SGenome biologyThe underlying dataset has been published as supplementary material of the article in the publisher platform at https://doi.org/10.1186/s13059-024-03325-4https://doi.org/10.1186/s13059-024-03325-4Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3626882026-05-22T06:33:51Z
score 15.198674

Similares en LA Referencia