34 research outputs found
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"
Mineralocorticoid receptor blockade improved gut microbiota dysbiosis by reducing gut sympathetic tone in spontaneously hypertensive rats.
Microbiota has a crucial role in the host blood pressure (BP) regulation. The present study analyzes whether the mineralocorticoid receptor antagonist spironolactone ameliorates the dysbiosic state in a genetic model of neurogenic hypertension. Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were randomly allocated into three groups: untreated WKY, untreated SHR, and SHR treated with spironolactone for 5 weeks. Spironolactone restored the Firmicutes/Bacteroidetes proportion, and acetate-producing bacteria populations to WKY levels. Spironolactone reduced the percentage of intestinal aerobic bacteria. The amelioration of gut dysbiosis was linked to a reduction in the gut pathology, an enhanced colonic integrity, a reduced gut permeability and an attenuated sympathetic drive in the gut. Spironolactone was unable to reduce neuroinflammation and oxidative stress in the paraventricular nuclei in the hypothalamus. Spironolactone reduced the higher Th17 cells proportion in mesenteric lymph nodes and Th17 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that spironolactone reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity and pathology due to reduced sympathetic drive in the gut.This work was supported by Grants from Comision ´ Interministerial
de Ciencia y Tecnología, Ministerio de Economía y competitividad
(PID2020-116347RB-I00), and Junta de Andalucía (CTS 164,
P20_00193, A-CTS-318-UGR20) with funds from the European Union,
and by the Ministerio de Economia y Competitividad, Instituto de Salud
Carlos III (CIBER-CV), Spain. M.T. and I.R.-V. are postdoctoral fellow of
Instituto de Salud Carlos III (Juan de la Cierva Incorporacion ´ Program,
and Juan de la Cierva Formacion ´ Program, respectively). J.M. is a predoctoral fellow of MINECO, 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”).S
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”
Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity.
Conventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear. Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells. These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.We are grateful to the Immunology, Ophthalmology, and ENT Department at the UCM for
providing useful discussion and to Gillian Dunphy and Antonia Tomás for critically reading the manuscript. We thank the CNIC and UCM facilities. Funding: Work in the S.I. laboratory
is funded by the Spanish Ministerio de Ciencia, Innovación (MICINN), Agencia Estatal de
Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER), RTI2018-094484-BI00, and RYC-2016-19463. EHG is the recipient of an FPI fellowship (PRE2019-087509) from
the Spanish Ministry of Science and Innovation. Work in the DS laboratory is funded by
the CNIC; the European Research Council (ERC-2016-Consolidator Grant 725091); the
MICINN, AEI and FEDER (PID2019-108157RB); Comunidad de Madrid (B2017/BMD-3733
Immunothercan-CM); Atresmedia (Constantes y Vitales prize); and Fundació La Marató de
TV3 (201723). Work in the G.S. laboratory receives funding from the European Union’s
Seventh Framework Programme (FP7/2007-2013) under grant agreement n° ERC 260464,
EFSD/Lilly European Diabetes Research Programme GS, 2017 Leonardo Grant for
Researchers and Cultural Creators, BBVA Foundation (Investigadores-BBVA-2017)
IN[17]_BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R, EUIN2017-85875, Comunidad
de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733 and Fundación
AECC. IN receives funding from EFSD/Lilly (2019), EFSD Rising star (2019), and JdC—
Incorporation (IJC2018-035390-I). The CNIC is supported by the Instituto de Salud Carlos III
(ISCIII), the MICINN, and the Pro CNIC Foundation.S
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
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 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, 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”).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 resistantstarch
(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 gutimmune
system-vascular wall axis in SLE.Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RB- I00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033)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)MINECO (FJC2021-048099-I)MINECO (FPU18/02561)Junta de AndalucíaEuropean Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”
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