Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites

Maternal chronic kidney disease (CKD) during pregnancy causes adverse fetal programming. Nitric oxide (NO) deficiency, gut microbiota dysbiosis, and dysregulated renin-angiotensin system (RAS) during pregnancy are linked to the development of hypertension in adult offspring. We examined whether maternal adenine-induced CKD can program hypertension and kidney disease in adult male offspring. We also aimed to identify potential mechanisms, including alterations of gut microbiota composition, increased trimethylamine-N-oxide (TMAO), reduced NO bioavailability, and dysregulation of the RAS. To construct a maternal CKD model, female Sprague-Dawley rats received regular chow (control group) or chow supplemented with 0.5% adenine (CKD group) for 3 weeks before pregnancy. Mother rats were sacrificed on gestational day 21 to analyze placentas and fetuses. Male offspring (n = 8/group) were sacrificed at 12 weeks of age. Adenine-fed rats developed renal dysfunction, glomerular and tubulointerstitial damage, hypertension, placental abnormalities, and reduced fetal weights. Additionally, maternal adenine-induced CKD caused hypertension and renal hypertrophy in adult male offspring. These adverse pregnancy and offspring outcomes are associated with alterations of gut microbiota composition, increased uremic toxin asymmetric and symmetric dimethylarginine (ADMA and SDMA), increased microbiota-derived uremic toxin TMAO, reduced microbiota-derived metabolite acetate and butyrate levels, and dysregulation of the intrarenal RAS. Our results indicated that adenine-induced maternal CKD could be an appropriate model for studying uremia-related adverse pregnancy and offspring outcomes. Targeting NO pathway, microbiota metabolite TMAO, and the RAS might be potential therapeutic strategies to improve maternal CKD-induced adverse pregnancy and offspring outcomes.

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The gut microbiota profile of adults with kidney disease: A systematic review of the literature

10.21203/rs.2.10470/v1 ◽

2019 ◽

Author(s):

Jordan Stanford ◽

Karen Charlton ◽

Anita Stefoska-Needham ◽

Rukayat Ibrahim ◽

Kelly Lambert

Keyword(s):

Systematic Review ◽

Kidney Disease ◽

Gut Microbiota ◽

Cochrane Library ◽

Uremic Toxin ◽

Healthy Controls ◽

Microbiota Composition ◽

Dietary Intakes ◽

Microbial Composition ◽

Gut Microbiota Composition

Abstract Background There is mounting evidence that individuals with kidney disease have an abnormal gut microbiota composition. No studies to date have summarised the evidence to categorise how the gut microbiota profile of individuals with kidney disease may differ from healthy controls. Synthesis of this evidence is important to inform future clinical trials. This systematic review aims to characterise differences of the gut microbiota composition in adults with kidney disease, as well as to describe the functional capacity of the gut microbiota and reporting of diet as a confounder in these studies. Methods Included studies were those that investigated the gut microbial community in adults with any type of kidney disease and compared this to the profile of healthy controls. Six scientific databases (CINHAL, Medline, PubMed, Scopus, Web of Science, Cochrane Library) as well as selected grey literature sources were searched up until August 2018. Quality assessment was undertaken independently by three authors. The system of evidence level criteria was employed to quantitatively evaluate the alteration of microbiota by strictly considering the number, methodological quality and consistency of the findings. Additional findings relating to altered functions of the gut microbiota, dietary intakes and dietary methodologies used were qualitatively summarised. Results Sixteen articles, reporting 15 studies met the eligibility criteria and included a total of 540 adults with kidney disease and 1117 healthy controls. Compared to healthy controls, individuals with kidney disease had increased abundances of Enterobacteriaceae, and decreased abundances of Coprococcus and Prevotella. Adults with kidney stones also had an altered microbial composition with variations to Bacteroides, Lachnospiraceae NK4A136 group, Ruminiclostridium 5 group, Dorea, Enterobacter, Christensenellaceae and its genus Christensenellaceae R7 group. Altered microbial functions in adults with kidney disease were reported, particularly in the context of metabolic pathways relating to urea and uremic toxin generation. Only three of the 16 articles accounted for diet, and of these studies only two used a valid dietary assessment method. Conclusions The gut microbiota profile of adults with kidney disease differs from healthy controls. Future study designs should include adequate reporting of important confounders such as dietary intakes to assist with interpretation of findings.

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Perinatal Resveratrol Therapy Prevents Hypertension Programmed by Maternal Chronic Kidney Disease in Adult Male Offspring: Implications of the Gut Microbiome and Their Metabolites

Biomedicines ◽

10.3390/biomedicines8120567 ◽

2020 ◽

Vol 8 (12) ◽

pp. 567

Author(s):

Chien-Ning Hsu ◽

Chih-Yao Hou ◽

Guo-Ping Chang-Chien ◽

Sufan Lin ◽

Hung-Wei Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Adult Male ◽

Gut Microbiome ◽

Critical Role ◽

Male Offspring ◽

Microbial Metabolites ◽

Α Diversity

The gut microbiota plays a critical role in kidney disease and hypertension; however, whether maternal chronic kidney disease (CKD)-induced offspring hypertension is associated with alterations of the microbiota and microbial metabolites remains elusive. Using rat as an animal model, we conducted a maternal adenine-induced CKD model to examine whether adult male offspring develop hypertension and kidney disease. As resveratrol has antioxidant and prebiotic properties, we also aimed to elucidate whether its use in pregnancy and lactation can benefit hypertension programmed by maternal CKD via mediation of the gut microbiota and oxidative stress. Female Sprague-Dawley rats received regular chow (C) or chow supplemented with 0.5% adenine (CKD) from 3 weeks before pregnancy until lactation. One group of the adenine-induced CKD pregnant rats received resveratrol (R; 50 mg/L) in drinking water during gestation and lactation. Male offspring were divided into three groups: C, CKD, and CKD+R. The microbial metabolites analyzed were short chain fatty acids (SCFAs) in feces and trimethylamine (TMA)/trimethylamine N-oxide (TMAO) in plasma. We found perinatal resveratrol therapy protected against maternal CKD-induced hypertension in adult male offspring. The overall microbial compositions and diversity of bacterial community in the three groups were different. Resveratrol therapy increased α-diversity, decreased the Firmicutes to Bacteroidetes ratio, and increased the abundance of the genera Lactobacillus and Bifidobacterium. Perinatal resveratrol therapy increased plasma TMA levels but decreased the plasma TMAO-to-TMA ratio. Although resveratrol had negligible effect on fecal concentrations of SCFAs, it increased G-protein coupled receptor-41 (GPR41) protein levels in the offspring’s kidneys. Additionally, resveratrol therapy increased plasma levels of L-arginine and the L-arginine-to-ADMA ratio (AAR), and decreased oxidative stress. Overall, the protective effects of resveratrol against programmed hypertension are related to gut microbiome remodeling, including an increased abundance of beneficial microbes, mediation of the TMA-TMAO pathway, and alterations of SCFA receptors. Our results highlighted that targeting the microbiome and their metabolites might be potential therapeutic strategies to prevent maternal CKD-induced adverse pregnancy and offspring outcomes.

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Gut microbiota composition and frailty in elderly patients with Chronic Kidney Disease

PLoS ONE ◽

10.1371/journal.pone.0228530 ◽

2020 ◽

Vol 15 (4) ◽

pp. e0228530 ◽

Cited By ~ 3

Author(s):

Elisabetta Margiotta ◽

Francesco Miragoli ◽

Maria Luisa Callegari ◽

Simone Vettoretti ◽

Lara Caldiroli ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Elderly Patients ◽

Microbiota Composition ◽

Gut Microbiota Composition

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Synbiotics Alleviate the Gut Indole Load and Dysbiosis in Chronic Kidney Disease

Cells ◽

10.3390/cells10010114 ◽

2021 ◽

Vol 10 (1) ◽

pp. 114

Author(s):

Chih-Yu Yang ◽

Ting-Wen Chen ◽

Wan-Lun Lu ◽

Shih-Shin Liang ◽

Hsien-Da Huang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Statistical Significance ◽

Additional Treatment ◽

Indoxyl Sulfate ◽

Uremic Toxin ◽

Healthy Controls ◽

Gut Dysbiosis ◽

Novel Concept

Chronic kidney disease (CKD) has long been known to cause significant digestive tract pathology. Of note, indoxyl sulfate is a gut microbe-derived uremic toxin that accumulates in CKD patients. Nevertheless, the relationship between gut microbiota, fecal indole content, and blood indoxyl sulfate level remains unknown. In our study, we established an adenine-induced CKD rat model, which recapitulates human CKD-related gut dysbiosis. Synbiotic treatment in CKD rats showed a significant reduction in both the indole-producing bacterium Clostridium and fecal indole amount. Furthermore, gut microbiota diversity was reduced in CKD rats but was restored after synbiotic treatment. Intriguingly, in our end-stage kidney disease (ESKD) patients, the abundance of indole-producing bacteria, Bacteroides, Prevotella, and Clostridium, is similar to that of healthy controls. Consistently, the fecal indole tends to be higher in the ESKD patients, but the difference did not achieve statistical significance. However, the blood level of indoxyl sulfate was significantly higher than that of healthy controls, implicating that under an equivalent indole production rate, the impaired renal excretion contributes to the accumulation of this notorious uremic toxin. On the other hand, we did identify two short-chain fatty acid-producing bacteria, Faecalibacterium and Roseburia, were reduced in ESKD patients as compared to the healthy controls. This may contribute to gut dysbiosis. We also identified that three genera Fusobacterium, Shewanella, and Erwinia, in the ESKD patients but not in the healthy controls. Building up gut symbiosis to treat CKD is a novel concept, but once proved effective, it will provide an additional treatment strategy for CKD patients.

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The Association between Gut Microbiota and Uremia of Chronic Kidney Disease

Microorganisms ◽

10.3390/microorganisms8060907 ◽

2020 ◽

Vol 8 (6) ◽

pp. 907 ◽

Cited By ~ 1

Author(s):

Ji Eun Kim ◽

Hyo-Eun Kim ◽

Ji In Park ◽

Hyunjeong Cho ◽

Min-Jung Kwak ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Kidney Function ◽

Kidney Diseases ◽

Toxin Production ◽

Positive Interactions ◽

Uremic Toxin ◽

Serum Concentrations ◽

Pyruvate Metabolism

Chronic kidney disease (CKD)-associated uremia aggravates—and is aggravated by—gut dysbiosis. However, the correlation between CKD severity and gut microbiota and/or their uremic metabolites is unclear. We enrolled 103 CKD patients with stage 1 to 5 and 46 healthy controls. We analyzed patients’ gut microbiota by MiSeq system and measured the serum concentrations of four uremic metabolites (p-cresyl sulfate, indoxyl sulfate, p-cresyl glucuronide, and trimethylamine N-oxide) by liquid chromatography–tandem mass spectrometry. Serum concentrations of the uremic metabolites increased with kidney function deterioration. Gut microbial diversity did not differ among the examined patient and control groups. In moderate or higher stage CKD groups, Oscillibacter showed positive interactions with other microbiota, and the proportions of Oscillibacter were positively correlated with those of the uremic metabolites. The gut microbiota, particularly Oscillibacter, was predicted to contribute to pyruvate metabolism which increased with CKD progression. Relative abundance of Oscillibacter was significantly associated with both serum uremic metabolite levels and kidney function. Predicted functional analysis suggested that kidney-function-associated changes in the contribution of Oscillibacter to pyruvate metabolism in CKD may greatly affect the gut environment according to kidney function, resulting in dysbiosis concomitant with uremic toxin production. The gut microbiota could be associated with uremia progression in CKD. These results may provide basis for further metagenomics analysis of kidney diseases.

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Gut Microbiota Composition and Its Metabolites in Different Stages of Chronic Kidney Disease

Journal of Clinical Medicine ◽

10.3390/jcm10173881 ◽

2021 ◽

Vol 10 (17) ◽

pp. 3881

Author(s):

Tso-Hsiao Chen ◽

Chao-Wei Liu ◽

Yi-Hsien Ho ◽

Chun-Kai Huang ◽

Ching-Sheng Hung ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Gradual Increase ◽

Klebsiella Pneumonia ◽

Cross Sectional ◽

Sequencing Platform ◽

Long Read ◽

Stage 1 ◽

Gut Microbiota Composition

A growing body of study have documented the association of gut dysbiosis or fecal metabolites with chronic kidney disease (CKD). However, it is not clear whether the phenomenon simply reflects the microenvironment changes correlated with the CKD severity or contributes to the progression of CKD. In this study, we identified the gut microbiota and metabolite in feces samples correlated with CKD severity using the Nanopore long-read sequencing platform and UPLC-coupled MS/MS approach. A cross-sectional cohort study was performed from 1 June 2020 to 31 December 2020. One hundred and fifty-six clinical participants, including 60 healthy enrollees and 96 Stage 1–5 CKD patients, were enrolled in this study. The ROC curve generated with the relative abundance of Klebsiella pneumonia or S-Adenosylhomocysteine showed a gradual increase with the CKD severity. Our results further revealed the positive correlation of increased K. pneumonia and S-Adenosylhomocysteine in gut environment, which may be of etiological importance to the deterioration of a CKD patient. In that sense, the microbiota or metabolite changes constitute potential candidates for evaluating the progression of CKD.

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Chronic intermittent hypoxia disrupts cardiorespiratory homeostasis and gut microbiota composition in adult male guinea-pigs

EBioMedicine ◽

10.1016/j.ebiom.2018.11.010 ◽

2018 ◽

Vol 38 ◽

pp. 191-205 ◽

Cited By ~ 19

Author(s):

Eric F. Lucking ◽

Karen M. O'Connor ◽

Conall R. Strain ◽

Fiona Fouhy ◽

Thomaz F.S. Bastiaanssen ◽

...

Keyword(s):

Gut Microbiota ◽

Adult Male ◽

Guinea Pigs ◽

Intermittent Hypoxia ◽

Chronic Intermittent Hypoxia ◽

Microbiota Composition ◽

Gut Microbiota Composition

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Uremic Toxin-Producing Gut Microbiota in Rats with Chronic Kidney Disease

Nephron ◽

10.1159/000450619 ◽

2016 ◽

Vol 135 (1) ◽

pp. 51-60 ◽

Cited By ~ 34

Author(s):

Mami Kikuchi ◽

Mariko Ueno ◽

Yoshiharu Itoh ◽

Wataru Suda ◽

Masahira Hattori

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Uremic Toxin

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Curcumin Supplementation (Meriva®) Modulates Inflammation, Lipid Peroxidation and Gut Microbiota Composition in Chronic Kidney Disease

Nutrients ◽

10.3390/nu14010231 ◽

2022 ◽

Vol 14 (1) ◽

pp. 231

Author(s):

Francesca Pivari ◽

Alessandra Mingione ◽

Giada Piazzini ◽

Camilla Ceccarani ◽

Emerenziana Ottaviano ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Lipid Peroxidation ◽

Kidney Disease ◽

Gut Microbiota ◽

Term Administration ◽

Inflammatory State ◽

Gut Microbiota Composition

Chronic kidney disease (CKD) subjects suffer from high risk of cardiovascular mortality, and any intervention preventing the progression of CKD may have an enormous impact on public health. In the last decade, there has been growing awareness that the gut microbiota (GM) can play a pivotal role in controlling the pathogenesis of systemic inflammatory state and CKD progression. To ameliorate the quality of life in CKD subjects, the use of dietary supplements has increased over time. Among those, curcumin has demonstrated significant in vitro anti-inflammatory properties. In this pilot study, 24 CKD patients and 20 healthy volunteers were recruited. CKD patients followed nutritional counselling and were supplemented with curcumin (Meriva®) for six months. Different parameters were evaluated at baseline and after 3–6 months: uremic toxins, metagenomic of GM, and nutritional, inflammatory, and oxidative status. Curcumin significantly reduced plasma pro-inflammatory mediators (CCL-2, IFN-γ, and IL-4) and lipid peroxidation. Regarding GM, after 6 months of curcumin supplementation, Escherichia-Shigella was significantly lower, while Lachnoclostridium was significant higher. Notably, at family level, Lactobacillaceae spp. were found significantly higher in the last 3 months of supplementation. No adverse events were observed in the supplemented group, confirming the good safety profile of curcumin phytosome after long-term administration.

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