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Serotonin Transporter (SERT) Expression Modulates the Composition of the Western-Diet-Induced Microbiota in Aged Female Mice

Background. The serotonin transporter (SERT), highly expressed in the gut and brain, is implicated in metabolic processes. A genetic variant of the upstream regulatory region of the SLC6A4 gene encoding SERT, the so-called short (s) allele, in comparison with the long (l) allele, results in the decr...

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Autores principales: Bloemendaal, Mirjam, Veniaminova, Ekaterina, Anthony, Daniel C., Gorlova, Anna, Vlaming, Priscilla, Khairetdinova, Adel, Cespuglio, Raymond, Lesch, Klaus Peter, Arias Vasquez, Alejandro, Strekalova, Tatyana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10346692/
https://www.ncbi.nlm.nih.gov/pubmed/37447374
http://dx.doi.org/10.3390/nu15133048
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author Bloemendaal, Mirjam
Veniaminova, Ekaterina
Anthony, Daniel C.
Gorlova, Anna
Vlaming, Priscilla
Khairetdinova, Adel
Cespuglio, Raymond
Lesch, Klaus Peter
Arias Vasquez, Alejandro
Strekalova, Tatyana
author_facet Bloemendaal, Mirjam
Veniaminova, Ekaterina
Anthony, Daniel C.
Gorlova, Anna
Vlaming, Priscilla
Khairetdinova, Adel
Cespuglio, Raymond
Lesch, Klaus Peter
Arias Vasquez, Alejandro
Strekalova, Tatyana
author_sort Bloemendaal, Mirjam
collection PubMed
description Background. The serotonin transporter (SERT), highly expressed in the gut and brain, is implicated in metabolic processes. A genetic variant of the upstream regulatory region of the SLC6A4 gene encoding SERT, the so-called short (s) allele, in comparison with the long (l) allele, results in the decreased function of this transporter, altered serotonergic regulation, an increased risk of psychiatric pathology and type-2 diabetes and obesity, especially in older women. Aged female mice with the complete (Sert(−/−): KO) or partial (Sert(+/−): HET) loss of SERT exhibit more pronounced negative effects following their exposure to a Western diet in comparison to wild-type (Sert(+/+): WT) animals. Aims. We hypothesized that these effects might be mediated by an altered gut microbiota, which has been shown to influence serotonin metabolism. We performed V4 16S rRNA sequencing of the gut microbiota in 12-month-old WT, KO and HET female mice that were housed on a control or Western diet for three weeks. Results. The relative abundance of 11 genera was increased, and the abundance of 6 genera was decreased in the Western-diet-housed mice compared to the controls. There were correlations between the abundance of Streptococcus and Ruminococcaceae_UCG-014 and the expression of the pro-inflammatory marker Toll-like-Receptor 4 (Tlr4) in the dorsal raphe, as well as the expression of the mitochondrial activity marker perixome-proliferator-activated-receptor-cofactor-1b (Ppargc1b) in the prefrontal cortex. Although there was no significant impact of genotype on the microbiota in animals fed with the Control diet, there were significant interactions between diet and genotype. Following FDR correction, the Western diet increased the relative abundance of Intestinimonas and Atopostipes in the KO animals, which was not observed in the other groups. Erysipelatoclostridium abundance was increased by the Western diet in the WT group but not in HET or KO animals. Conclusions. The enhanced effects of a challenge with a Western diet in SERT-deficient mice include the altered representation of several gut genera, such as Intestinimonas, Atopostipes and Erysipelatoclostridium, which are also implicated in serotonergic and lipid metabolism. The manipulation of these genera may prove useful in individuals with the short SERT allele.
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spelling pubmed-103466922023-07-15 Serotonin Transporter (SERT) Expression Modulates the Composition of the Western-Diet-Induced Microbiota in Aged Female Mice Bloemendaal, Mirjam Veniaminova, Ekaterina Anthony, Daniel C. Gorlova, Anna Vlaming, Priscilla Khairetdinova, Adel Cespuglio, Raymond Lesch, Klaus Peter Arias Vasquez, Alejandro Strekalova, Tatyana Nutrients Article Background. The serotonin transporter (SERT), highly expressed in the gut and brain, is implicated in metabolic processes. A genetic variant of the upstream regulatory region of the SLC6A4 gene encoding SERT, the so-called short (s) allele, in comparison with the long (l) allele, results in the decreased function of this transporter, altered serotonergic regulation, an increased risk of psychiatric pathology and type-2 diabetes and obesity, especially in older women. Aged female mice with the complete (Sert(−/−): KO) or partial (Sert(+/−): HET) loss of SERT exhibit more pronounced negative effects following their exposure to a Western diet in comparison to wild-type (Sert(+/+): WT) animals. Aims. We hypothesized that these effects might be mediated by an altered gut microbiota, which has been shown to influence serotonin metabolism. We performed V4 16S rRNA sequencing of the gut microbiota in 12-month-old WT, KO and HET female mice that were housed on a control or Western diet for three weeks. Results. The relative abundance of 11 genera was increased, and the abundance of 6 genera was decreased in the Western-diet-housed mice compared to the controls. There were correlations between the abundance of Streptococcus and Ruminococcaceae_UCG-014 and the expression of the pro-inflammatory marker Toll-like-Receptor 4 (Tlr4) in the dorsal raphe, as well as the expression of the mitochondrial activity marker perixome-proliferator-activated-receptor-cofactor-1b (Ppargc1b) in the prefrontal cortex. Although there was no significant impact of genotype on the microbiota in animals fed with the Control diet, there were significant interactions between diet and genotype. Following FDR correction, the Western diet increased the relative abundance of Intestinimonas and Atopostipes in the KO animals, which was not observed in the other groups. Erysipelatoclostridium abundance was increased by the Western diet in the WT group but not in HET or KO animals. Conclusions. The enhanced effects of a challenge with a Western diet in SERT-deficient mice include the altered representation of several gut genera, such as Intestinimonas, Atopostipes and Erysipelatoclostridium, which are also implicated in serotonergic and lipid metabolism. The manipulation of these genera may prove useful in individuals with the short SERT allele. MDPI 2023-07-06 /pmc/articles/PMC10346692/ /pubmed/37447374 http://dx.doi.org/10.3390/nu15133048 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bloemendaal, Mirjam
Veniaminova, Ekaterina
Anthony, Daniel C.
Gorlova, Anna
Vlaming, Priscilla
Khairetdinova, Adel
Cespuglio, Raymond
Lesch, Klaus Peter
Arias Vasquez, Alejandro
Strekalova, Tatyana
Serotonin Transporter (SERT) Expression Modulates the Composition of the Western-Diet-Induced Microbiota in Aged Female Mice
title Serotonin Transporter (SERT) Expression Modulates the Composition of the Western-Diet-Induced Microbiota in Aged Female Mice
title_full Serotonin Transporter (SERT) Expression Modulates the Composition of the Western-Diet-Induced Microbiota in Aged Female Mice
title_fullStr Serotonin Transporter (SERT) Expression Modulates the Composition of the Western-Diet-Induced Microbiota in Aged Female Mice
title_full_unstemmed Serotonin Transporter (SERT) Expression Modulates the Composition of the Western-Diet-Induced Microbiota in Aged Female Mice
title_short Serotonin Transporter (SERT) Expression Modulates the Composition of the Western-Diet-Induced Microbiota in Aged Female Mice
title_sort serotonin transporter (sert) expression modulates the composition of the western-diet-induced microbiota in aged female mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10346692/
https://www.ncbi.nlm.nih.gov/pubmed/37447374
http://dx.doi.org/10.3390/nu15133048
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