Melatonin Prevents Chronic Kidney Disease-Induced Hypertension in Young Rat Treated with Adenine: Implications of Gut Microbiota-Derived Metabolites

Melatonin, a signaling hormone with pleiotropic biofunctions, has shown health benefits. Trimethylamine-N-oxide (TMAO) and asymmetric dimethylarginine (ADMA) are uremic toxins involved in the development of hypertension. TMAO originates from trimethylamine (TMA), a gut microbial product. ADMA is an endogenous nitric oxide (NO) synthase inhibitor. We examined whether melatonin therapy could prevent hypertension and kidney disease by mediating gut microbiota-derived metabolites and the NO pathway using an adenine-induced chronic kidney disease (CKD) young rat model. Six-week-old young Sprague Dawley rats of both sexes were fed a regular diet (C group), a diet supplemented with 0.5% adenine (CKD group), or adenine plus 0.01% melatonin in their drinking water (CKD + M group) for three weeks (N = 8/group). Adenine-fed rats developed renal dysfunction, hypertension, renal hypertrophy and increased uremic toxin levels of TMAO and ADMA. Melatonin therapy prevented hypertension in both sexes and attenuated kidney injury in males. Melatonin reversed the changes to the plasma TMAO-to-TMA ratio induced by CKD in both sexes. Besides, the protective effects of melatonin were associated with restoration of gut microbiota alterations, including increased α-diversity, and enhancement of the abundance of the phylum Proteobacteria and the genus Roseburia in male rats. Melatonin therapy also partially prevented the increases in ADMA in male CKD rats. Melatonin sex-specifically protected young rats against hypertension and kidney injury induced by CKD. The results of this study contribute toward a greater understanding of the interaction between melatonin, gut microbiota-derived metabolites, and the NO pathway that is behind CKD, which will help to prevent CKD-related disorders in children.

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Significance of the Gut Microbiota in Acute Kidney Injury

Toxins ◽

10.3390/toxins13060369 ◽

2021 ◽

Vol 13 (6) ◽

pp. 369

Author(s):

Taku Kobayashi ◽

Yasunori Iwata ◽

Yusuke Nakade ◽

Takashi Wada

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Kidney Disease ◽

Gut Microbiota ◽

Kidney Injury ◽

Protective Effects ◽

Diseased Condition ◽

New Treatments ◽

Established Treatment

Recent studies have revealed that the gut microbiota plays a crucial role in maintaining a healthy, as well as diseased condition. Various organs and systems, including the kidney, are affected by the gut microbiota. While the impacts of the gut microbiota have been reported mainly on chronic kidney disease, acute kidney injury (AKI) is also affected by the intestinal environment. In this review, we discussed the pathogenesis of AKI, highlighting the relation to the gut microbiota. Since there is no established treatment for AKI, new treatments for AKI are highly desired. Some kinds of gut bacteria and their metabolites reportedly have protective effects against AKI. Current studies provide new insights into the role of the gut microbiota in the pathogenesis of AKI.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21197237 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7237 ◽

Cited By ~ 2

Author(s):

Chien-Ning Hsu ◽

Hung-Wei Yang ◽

Chih-Yao Hou ◽

Guo-Ping Chang-Chien ◽

Sufan Lin ◽

...

Keyword(s):

Nitric Oxide ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Adult Male ◽

Male Offspring ◽

Uremic Toxin ◽

Microbiota Composition ◽

Adverse Pregnancy ◽

Gut Microbiota Composition

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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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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A Link between Chronic Kidney Disease and Gut Microbiota in Immunological and Nutritional Aspects

Nutrients ◽

10.3390/nu13103637 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3637

Author(s):

Paulina Mertowska ◽

Sebastian Mertowski ◽

Julia Wojnicka ◽

Izabela Korona-Głowniak ◽

Ewelina Grywalska ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Immune System ◽

Kidney Disease ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Kidney Diseases ◽

Disease Onset ◽

Kidney Injury ◽

Dietary Factors

Chronic kidney disease (CKD) is generally progressive and irreversible, structural or functional renal impairment for 3 or more months affecting multiple metabolic pathways. Recently, the composition, dynamics, and stability of a patient’s microbiota has been noted to play a significant role during disease onset or progression. Increasing urea concentration during CKD can lead to an acceleration of the process of kidney injury leading to alterations in the intestinal microbiota that can increase the production of gut-derived toxins and alter the intestinal epithelial barrier. A detailed analysis of the relationship between the role of intestinal microbiota and the development of inflammation within the symbiotic and dysbiotic intestinal microbiota showed significant changes in kidney dysfunction. Several recent studies have determined that dietary factors can significantly influence the activation of immune cells and their mediators. Moreover, dietary changes can profoundly affect the balance of gut microbiota. The aim of this review is to present the importance and factors influencing the differentiation of the human microbiota in the progression of kidney diseases, such as CKD, IgA nephropathy, idiopatic nephropathy, and diabetic kidney disease, with particular emphasis on the role of the immune system. Moreover, the effects of nutrients, bioactive compounds on the immune system in development of chronic kidney disease were reviewed.

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Does Low-Protein Diet Influence the Uremic Toxin Serum Levels From the Gut Microbiota in Nondialysis Chronic Kidney Disease Patients?

Journal of Renal Nutrition ◽

10.1053/j.jrn.2017.11.007 ◽

2018 ◽

Vol 28 (3) ◽

pp. 208-214 ◽

Cited By ~ 28

Author(s):

Ana Paula Black ◽

Juliana S. Anjos ◽

Ludmila Cardozo ◽

Flávia L. Carmo ◽

Carla J. Dolenga ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Serum Levels ◽

Protein Diet ◽

Low Protein Diet ◽

Uremic Toxin ◽

Low Protein

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Gut-Derived Protein-Bound Uremic Toxins

Toxins ◽

10.3390/toxins12090590 ◽

2020 ◽

Vol 12 (9) ◽

pp. 590 ◽

Cited By ~ 1

Author(s):

Amanda L. Graboski ◽

Matthew R. Redinbo

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Filtration Rate ◽

Therapeutic Strategies ◽

Uremic Toxins ◽

Uremic Toxin ◽

Risk Of Death ◽

Gut Dysbiosis ◽

Causes Of Mortality

Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.

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Dietary Fermented Soy Extract and Active Lactic Acid Alleviate Chronic Kidney Disease in Mice via Inhibition of Inflammation and Modulation of Gut Microbiota (FS15-07-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.fs15-07-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Lixia He

Keyword(s):

Chronic Kidney Disease ◽

Lactic Acid ◽

Kidney Disease ◽

Gut Microbiota ◽

Kidney Injury ◽

Serum Levels ◽

Negative Control ◽

Mrna Levels ◽

Blood Cytokines ◽

Model Control

Abstract Objectives Chronic kidney disease (CKD) is a global epidemic and posing serious health problems with an increasing prevalence worldwide. Effective preventive strategies are urgently needed. This study was conducted to investigate the effect of a fermented soybean product (ImmunBalance, IMB) and active lactic acid (ALA) on adenine-induced CKD in mice. Methods Female C57BL/6 mice were randomly assigned into one of the following experimental groups: negative control (NC), model control (MC), models with oral gavage of IMB at 250 (IMB-L) or 1000 mg/kg BW (IMB-H), ALA at 1000 (ALA-L) or 2000 mg/kg BW (ALA-H). The CKD model was established by ip. injection of adenine daily for 4 weeks, and treatments started the same day as adenine injection till for 8 weeks. The kidney histopathology was evaluated by H&E staining. Blood cytokines and kidney injury biomarkers were measured by Multiplex sandwich immunoassays. Expression of cytokines and stem cells-related genes in kidney was analyzed by quantitative real-time PCR. The levels of major phyla of gut microbiota were quantified by quantitative PCR. Results The CKD mice showed obvious tubular dilation, tubulointerstitium degeneration or atrophy, interstitial chronic and acute inflammation. The administration of IMB and ALA significantly improved histopathological damages. Both of IMB and ALA decreased serum levels of cytokines and kidney toxicity biomarkers MCP-1, IL-6, IP-10, TIMP-1, Cystatin C and Clusterin, and the mRNA levels of inflammatory biomarkers IL-6, IL-1β, TGF-β1, TLR-4, F4/80 and TNF-α in kidney samples. CKD increased gene expression levels of stem cell biomarkers in kidney, which were reduced by IMB or ALA treatment. CKD reduced gut Clostridium leptumb level that was significantly increased by IMB or ALA treatment. Conclusions Our results suggest that dietary supplementation of IMB or ALA may significantly delay the development and progression of CKD. Funding Sources Nichimo Biotics Co., Ltd and Lifetrade Co. Ltd, Japan.

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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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