Protective Effects of Probiotic Consumption in Cardiovascular Disease in Systemic Lupus Erythematosus

The prevalence of renal and cardiovascular disease (CVD) in patients with systemic lupus erythematosus (SLE) is higher than in general populations. Recently, a causal role of gut microbiota on the development of immune responses in SLE has been described. Probiotic consumption changes the composition of gut microbiota, preventing SLE progression. The aim of this review is to explore the role of the gut microbiota in the development of renal and cardiovascular disease in SLE and how probiotics could be a therapeutic option. Despite strong evidence on the beneficial effects of probiotics in the development of autoimmunity and nephritis in SLE, only a few studies described the protective effects of Lactobacillus in important risk factors for CVD, such as endothelial dysfunction and hypertension in mice. The preventive effects of probiotics in renal and CVD in humans have not been established yet.This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (MINECO) (SAF2014-55523-R, SAF2017-84894-R) and Junta de Andalucía (Proyecto de excelencia P12-CTS-2722, and CTS 164), with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV). I.R.-V. is a predoctoral fellow of MINECO; N.d.l.V. is a predoctoral fellow of Junta de Andalucía and Fondo Social Europeo “FEDER una manera de hacer Europa”, and M.T. is a postdoctoral fellow of Instituto de Salud Carlos III (Sara Borrell Program)

Mycophenolate mediated remodeling of gut microbiota and improvement of gut-brain axis in spontaneously hypertensive rats

This work was supported by Grants from Comisi´on Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (SAF2017-84894-R), Junta de Andalucía (CTS-164) with funds from the European Union, Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain. M.T. is a postdoctoral fellow of Instituto de Salud Carlos III (Sara Borrell Program). I.R.-V. is a predoctoral fellow of MINECO. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).Microbiota has a role in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzes whether MMF improves dysbiosis in a genetic model of hypertension. Twenty weeks old male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were randomly divided into three groups: untreated WKY, untreated SHR, and SHR treated with MMF for 5 weeks. MMF treatment restored gut bacteria from the phyla Firmicutes and Bacteroidetes, and acetate- and lactate-producing bacteria to levels similar to those found in WKY, increasing butyrate-producing bacteria. MMF increased the percentage of anaerobic bacteria in the gut. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. MMF increased the lower regulatory T cells proportion in mesenteric lymph nodes and Th17 and Th1 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that MMF reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity due to reduced sympathetic drive in the gut associated to the reduced brain neuroinflammation.Comision Interministerial de Ciencia y Tecnologia, Ministerio de Economia y competitividad SAF201784894RJunta de Andalucia CTS-164European CommissionSpanish GovernmentInstituto de Salud Carlos III (CIBERCV) , SpainEuropean Union (Fondo Europeo de Desarrollo Regional, FEDER, "FEDER una manera de hacer Europa"

Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice

This work was supported by Grants from Comision Interministerial de Ciencia y Tecnologia, Ministerio de Economia y competitividad (MINECO) (SAF2017-84894-R), Ministerio de Ciencia e Innovacion (MCIN)/Agencia Estatal de Investigacion (AEI)/10.13039/501100011033 (PID2020-116347RB-I00), Junta de Andalucia (CTS 164, P20_00193) with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV). J.M. and C.G.C. are predoctoral fellows of MINECO and Junta de Andalucia, respectively. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, FEDER una manera de hacer Europa).Plasma levels of trimethylamine N-oxide (TMAO) are elevated in lupus patients. We analyzed the implication of TMAO in autoimmunity and vascular dysfunction of the murine model of systemic lupus erythematosus (SLE) induced by the activation of the Toll-like receptor (TLR)7 with imiquimod (IMQ). Female BALB/c mice were randomly divided into four groups: untreated control mice, control mice treated with the trimethylamine lyase inhibitor 3,3-dimethyl-1-butanol (DMB), IMQ mice, and IMQ mice treated with DMB. The DMB-treated groups were administered the substance in their drinking water for 8 weeks. Treatment with DMB reduced plasma levels of TMAO in mice with IMQ-induced lupus. DMB prevents the development of hypertension, reduces disease progression (plasma levels of anti-dsDNA autoantibodies, splenomegaly, and proteinuria), reduces polarization of T lymphocytes towards Th17/Th1 in secondary lymph organs, and improves endothelial function in mice with IMQ-induced lupus. The deleterious vascular effects caused by TMAO appear to be associated with an increase in vascular oxidative stress generated by increased NADPH oxidase activity, derived in part from the vascular infiltration of Th17/Th1 lymphocytes, and reduced nrf2-driven antioxidant defense. In conclusion, our findings identified the bacterialderived TMAO as a regulator of immune system, allowing for the development of autoimmunity and endothelial dysfunction in SLE mice.Comision Interministerial de Ciencia y Tecnologia, Ministerio de Economia y competitividad (MINECO) SAF2017-84894-RMinisterio de Ciencia e Innovacion (MCIN)/Agencia Estatal de Investigacion (AEI) PID2020-116347RB-I00Junta de Andalucia CTS 164 P20_00193European CommissionMinisterio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV)European Union (Fondo Europeo de Desarrollo Regional, FEDER, FEDER una manera de hacer Europa

Changes in Gut Microbiota Induced by Doxycycline Influence in Vascular Function and Development of Hypertension in DOCA-Salt Rats

Previous experiments in animals and humans show that shifts in microbiota and its metabolites are linked to hypertension. The present study investigates whether doxycycline (DOX, a broad-spectrum tetracycline antibiotic) improves dysbiosis, prevent cardiovascular pathology and attenuate hypertension in deoxycorticosterone acetate (DOCA)-salt rats, a renin-independent model of hypertension. Male Wistar rats were randomly assigned to three groups: control, DOCA-salt hypertensive rats, DOCA-salt treated with DOX for 4 weeks. DOX decreased systolic blood pressure, improving endothelial dysfunction and reducing aortic oxidative stress and inflammation. DOX decreased lactate-producing bacterial population and plasma lactate levels, improved gut barrier integrity, normalized endotoxemia, plasma noradrenaline levels and restored the Treg content in aorta. These data demonstrate that DOX through direct effects on gut microbiota and its non-microbial effects (anti-inflammatory and immunomodulatory) reduces endothelial dysfunction and the increase in blood pressure in this low-renin form of hypertension.Grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (SAF2017-84894-R)Ministerio de Ciencia e Innovación (PID2020-116347RB-I00)Junta de Andalucía (CTS-164, P20_00193)European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV; Ciberes)Instituto de Salud Carlos III (Sara Borrell Program)European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”

Gut Microbiota Has a Crucial Role in the Development of Hypertension and Vascular Dysfunction in Toll-like Receptor 7-Driven Lupus Autoimmunity

Our group has investigated the involvement of gut microbiota in hypertension in a murine model of systemic lupus erythematosus induced by Toll-like receptor (TLR)-7 activation. Female BALB/c mice were randomly assigned to four experimental groups: an untreated control (CTR), a group treated with the TLR7 agonist imiquimod (IMQ), IMQ-treated with vancomycin, and IMQtreated with a cocktail of broad-spectrum antibiotics. We carried out faecal microbiota transplant (FMT) from donor CTR or IMQ mice to recipient IMQ or CTR animals, respectively. Vancomycin inhibited the increase in blood pressure; improved kidney injury, endothelial function, and oxidative stress; and reduced T helper (Th)17 infiltration in aortas from IMQ-treated mice. The rise in blood pressure and vascular complications present in IMQ mice were also observed in the CTR mice recipients of IMQ microbiota. Reduced relative populations of Sutterella and Anaerovibrio were associated with high blood pressure in our animals, which were increased after stool transplantation of healthy microbiota to IMQ mice. The reduced endothelium-dependent vasodilator responses to acetylcholine induced by IMQ microbiota were normalized after interleukin-17 neutralization. In conclusion, gut microbiota plays a role in the TLR7-driven increase in Th17 cell, endothelial dysfunction, vascular inflammation, and hypertension. The vascular changes induced by IMQ microbiota were initiated by Th17 infiltrating the vasculature.Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (MINECO) (SAF2017-84894-R, PID2020-116347RBI00)Junta de Andalucía (CTS 164, P20_00193) with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV)Instituto de Salud Carlos III (Sara Borrell Program)MINECOEuropean Union (Fondo Europeo de Desarrollo Regional, FEDER

Targeting the gut microbiota with dietary fibers: a novel approach to prevent the development cardiovascular complications linked to systemic lupus erythematosus in a preclinical study.

This study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistant-starch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gut-immune system-vascular wall axis in SLE.This work was supported by Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RBI00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033) co-funded by the European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV). IR-V is postdoctoral funded by MINECO (FJC2021-048099-I). JM is a predoctoral fellow of MINECO (FPU18/02561), and CG-C and SM are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).S

Critical Role of the Interaction Gut Microbiota – Sympathetic Nervous System in the Regulation of Blood Pressure

Association between gut dysbiosis and neurogenic diseases, such as hypertension, has been described. The aim of this study was to investigate whether changes in the gut microbiota alter gut-brain interactions inducing changes in blood pressure (BP). Recipient normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were orally gavaged with donor fecal contents from SHR and WKY. We divided the animals into four groups: WKY transplanted with WKY microbiota (W-W), SHR with SHR (S-S), WKY with SHR (W-S) and SHR with WKY (S-W). Basal systolic BP (SBP) and diastolic BP (DBP) were reduced with no change in heart rate as a result of fecal microbiota transplantation (FMT) from WKY rats to SHR. Similarly, FMT from SHR to WKY increased basal SBP and DBP. Increases in both NADPH oxidase-driven reactive oxygen species production and proinflammatory cytokines in brain paraventricular nucleus linked to higher BP drop with pentolinium and plasmatic noradrenaline (NA) levels were found in the S-S group as compared to the W-W group. These parameters were reduced by FMT from WKY to SHR. Increased levels of pro-inflammatory cytokines, tyrosine hydroxylase mRNA levels and NA content in the proximal colon, whereas reduced mRNA levels of gap junction proteins, were found in the S-S group as compared to the W-W group. These changes were inhibited by FMT from WKY to SHR. According to our correlation analyses, the abundance of Blautia and Odoribacter showed a negative correlation with high SBP. In conclusion, in SHR gut microbiota is an important factor involved in BP control, at least in part, as consequence of its effect on neuroinflammation and the sympathetic nervous system activity.This work was funded by grants from Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y Competitividad (MINECO) (SAF2017-8489-R, AGL2015-67995- C3-3-R, and SAF2014-55523-R), Junta de Andalucía (Proyecto de Excelencia P12-CTS-2722 and CTS-164) with support from the European Union, and Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (CIBER-CV, CIBER-EHD), Spain. MS is a postdoctoral fellow of Junta de Andalucía. MR is postdoctoral fellow of University of Granada. IR-V is a predoctoral fellow of MINECO. The cost of this publication was paid in part with FEDER funds

Protective effect of microbiota-derived short chain fatty acids on vascular dysfunction in mice with systemic lupus erythematosus induced by toll like receptor 7 activation

https://pubmed.ncbi.nlm.nih.gov/37972724/https://www.sciencedirect.com/science/article/pii/S1043661823003535?via%3DihubOur objective was to investigate whether short-chain fatty acids (SCFAs), specifically acetate and butyrate, could prevent vascular dysfunction and elevated blood pressure (BP) in mice with systemic lupus erythematosus (SLE) induced by TLR7 activation using imiquimod (IMQ). Treatment with both SCFAs and dietary fibers rich in resistant starch (RS) or inulin-type fructans (ITF) effectively prevented the development of hypertension and cardiac hypertrophy. Additionally, these treatments improved aortic relaxation induced by acetylcholine and mitigated vascular oxidative stress. Acetate and butyrate treatments also contributed to the maintenance of colonic integrity, reduced endotoxemia, and decreased the proportion of helper T (Th)17 cells in mesenteric lymph nodes (MLNs), blood, and aorta in TLR7-induced SLE mice. The observed changes in MLNs were correlated with increased levels of GPR43 mRNA in mice treated with acetate and increased GPR41 levels along with decreased histone deacetylase (HDAC)- 3 levels in mice treated with butyrate. Notably, the effects attributed to acetate, but not butyrate, were nullified when co-administered with the GPR43 antagonist GLPG-0974. T cell priming and differentiation into Th17 cells in MLNs, as well as increased Th17 cell infiltration, were linked to aortic endothelial dysfunction and hypertension subsequent to the transfer of faecal microbiota from IMQ-treated mice to germ-free (GF) mice. These effects were counteracted in GF mice through treatment with either acetate or butyrate. To conclude, these findings underscore the potential of SCFA consumption in averting hypertension by restoring balance to the interplay between the gut, immune system, and vascular wall in SLE induced by TLR7 activation.This work was supported by Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RB-I00 funded by MCIN/AEI/ 10.13039/501100011033) co-funded by the European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193, and A-CTS-318-UGR20) with funds from the European Union, and by the Instituto de Salud Carlos III (PI22/01046, CIBER-CV). IR-V is postdoctoral funded by MINECO (FJC2021-048099-I). J.M. is a predoctoral fellow of MINECO (FPU18/02561), and C.G.-C. and S.M. are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”). The authors thank N. Rodríguez and V. Plaza for technical assistance

Eligibility criteria for Menopausal Hormone Therapy (MHT): a position statement from a consortium of scientific societies for the use of MHT in women with medical conditions. MHT Eligibility Criteria Group

This project aims to develop eligibility criteria for menopausal hormone therapy (MHT). The tool should be similar to those already established for contraception A consortium of scientific societies coordinated by the Spanish Menopause Society met to formulate recommendations for the use of MHT by women with medical conditions based on the best available evidence. The project was developed in two phases. As a first step, we conducted 14 systematic reviews and 32 metanalyses on the safety of MHT (in nine areas: age, time of menopause onset, treatment duration, women with thrombotic risk, women with a personal history of cardiovascular disease, women with metabolic syndrome, women with gastrointestinal diseases, survivors of breast cancer or of other cancers, and women who smoke) and on the most relevant pharmacological interactions with MHT. These systematic reviews and metanalyses helped inform a structured process in which a panel of experts defined the eligibility criteria according to a specific framework, which facilitated the discussion and development process. To unify the proposal, the following eligibility criteria have been defined in accordance with the WHO international nomenclature for the different alternatives for MHT (category 1, no restriction on the use of MHT; category 2, the benefits outweigh the risks; category 3, the risks generally outweigh the benefits; category 4, MHT should not be used). Quality was classified as high, moderate, low or very low, based on several factors (including risk of bias, inaccuracy, inconsistency, lack of directionality and publication bias). When no direct evidence was identified, but plausibility, clinical experience or indirect evidence were available, "Expert opinion" was categorized. For the first time, a set of eligibility criteria, based on clinical evidence and developed according to the most rigorous methodological tools, has been defined. This will provide health professionals with a powerful decision-making tool that can be used to manage menopausal symptoms

Microbiota y complicaciones cardiovasculares asociadas al lupus eritematoso sistémico

El lupus eritematoso sistémico (LES) es una patología inflamatoria crónica y multisistémica caracterizada por el anormal funcionamiento de linfocitos B, los cuales producen autoanticuerpos que, al formar inmunocomplejos que se depositan en el sistema vascular, causan daños en diversos órganos, como la piel, los riñones o el propio sistema vascular, produciendo una serie de complicaciones. Por ello, las complicaciones cardiovasculares asociadas al lupus son la principal causa de mortalidad en esta enfermedad, y la mayoría de los pacientes las presentan, aunque puede que de forma subclínica, incluyendo la disfunción endotelial. Según los conocimientos con los que se contaba hasta ahora, el desarrollo de estas complicaciones vasculares va asociado a un ciclo capaz de autoperpetuarse que involucra la inflamación, la respuesta celular inmune y el estrés oxidativo. Los objetivos desarrollados en la tesis fueron los siguientes: I) Analizar el papel de la microbiota intestinal en el desarrollo y mantenimiento del LES en un modelo genético murino de la enfermedad (NZBW/F1), centrándonos en las alteraciones renales y vasculares. II) Establecer el posible papel protector como suplemento dietético del microorganismo Lactobacillus fermentum CECT5716 (LC40) sobre las complicaciones vasculares y renales del LES. III) Caracterizar las posibles complicaciones cardiovasculares en un modelo inducible de LES mediante administración de un agonista de TLR-7. IV) Determinar si Lactobacillus fermentum CECT5716 (LC40) y/o Bifidobacterium breve CECT7263 (BFM) pueden prevenir disbiosis intestinal la disfunción endotelial y la hipertensión en nuestro modelo inducible.Tesis Univ. Granada