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Cited by 753Gut microbiota and healthChronic Kidney Disease and DiabetesBlood Pressure and Hypertension Studies

The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease

Open access
Yang, Tao, Richards, Elaine M., Pepine, Carl J., Raizada, Mohan K.·2018·Nature Reviews Nephrology
DOI 10.1038/s41581-018-0018-2PMC PMC6385605
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Abstract

Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host-microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain-gut-kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain-gut-kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain-gut-kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review proposes a brain–gut–kidney axis in which gut dysbiosis, microbial metabolites, immune activation, and sympathetic nervous system signaling interact to promote hypertension and chronic kidney disease (CKD). It synthesizes animal and human evidence and argues that targeting the gut microbiota, diet, probiotics, antibiotics, or metabolites may offer therapeutic strategies.

Key findings

  • The authors propose a triangular brain–gut–kidney hypothesis: environmental/dietary stimuli act on autonomic brain regions, increasing sympathetic drive to the gut and bone marrow; this promotes gut dysbiosis, barrier dysfunction, low-grade inflammation, and altered microbial metabolites, culminating in hypertension and CKD.
  • Gut dysbiosis is linked to hypertension and CKD. Faecal microbiota transplantation from patients with hypertension to germ-free mice or from hypertensive stroke-prone SHRs to normotensive WKY rats increased blood pressure; in salt-sensitive mice, *Lactobacillus murinus* lowered systolic and diastolic blood pressure by ~5 mmHg each.
  • CKD and ESRD are associated with microbial changes, including decreased *Lactobacillus* and increased Enterobacteriaceae; ESRD faecal microbiota differed from healthy controls across 190 operational taxonomic units, and a switch from *Prevotella*-dominant enterotype 2 to *Bacteroides*-dominant enterotype 1 was reported in Chinese patients with ESRD. In 30 patients with ESRD not on dialysis, bacterial DNA was detected in blood of 6 (20%), with higher C-reactive protein and IL-6.
  • Therapeutic modulation showed variable benefits: high-fibre diet reduced SBP and DBP by ~20 mmHg in DOCA-salt hypertensive mice; meta-analysis found high versus low fibre reduced DBP by 1.65 mmHg, with larger reductions in hypertension (SBP 5.95 mmHg, DBP 4.2 mmHg); probiotic meta-analysis reduced SBP by 3.65 mmHg and DBP by 2.38 mmHg in populations with baseline BP ≥135/85 mmHg.

Methods

  • Narrative review synthesizing mechanistic, animal-model, human observational, clinical trial, and meta-analysis evidence on the gut microbiota, brain, gut, and kidney in hypertension and CKD.
  • The paper does not report a systematic search strategy, inclusion criteria, or formal quality appraisal; its main analysis is a conceptual synthesis proposing and supporting the brain–gut–kidney axis hypothesis.
  • Evidence cited includes germ-free and conventional animal models, faecal microbiota transplantation experiments, human CKD/ESRD microbiota studies, and trials of dietary fibre, probiotics, antibiotics, and metabolite modulation.

Limitations

  • The paper states that many mechanisms remain unclear: whether sympathetic activation to the bone marrow and gut is increased in CKD, whether changes in kidney function are associated with increased gut permeability, and whether hypertension and CKD are associated with specific gut microbial profiles and metabolomes remain to be addressed.
  • The authors state that no studies of faecal microbiota transplantation or sterile faecal filtrate transfer for treating patients with hypertension or CKD had been published to date, and they call for large-scale, well-controlled translational and preclinical studies.
  • Evident from the text: this is a narrative review without systematic methods, and much of the evidence is preclinical or associative; some cited experiments also lack key measurements, such as glomerular filtration rate in mice receiving CKD patient faecal transplants, limiting causal conclusions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41581-018-0018-2

Cites

242 of 242 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 181 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    Increasing evidence indicates an important role of the gut microbiota in the development of hypertension and CKD.

    “Increasing evidence indicates an important role of the gut microbiota in the development of hypertension and CKD.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Blood-pressure lowering is an important and widely used approach to slow CKD progression.

    “Thus, blood-pressure lowering is an important and widely used approach to slow CKD progression.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The gut microbiota constantly communicates with vital organ systems of the host, such as the brain, bone marrow, vasculature, kidney, immune system and autonomic nervous system (ANS).

    “The gut microbiota constantly communicates with vital organ systems of the host, such as the brain6, bone marrow7, vasculature8, kidney9, immune system10 and autonomic nervous system (ANS)11,12.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Dinan, T. G. & Cryan, J. F. Gut-brain axis in 2016: Brain-gut-microbiota axis — mood, metabolism and behaviour. Nat. Rev. Gastroenterol. Hepatol. 14, 69–70 (2017). source

      Not checked in the free run.

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      Not checked in the free run.

    • cites [8] Karbach, S. H. et al. Gut microbiota promote angiotensin II-induced arterial hypertension and vascular dysfunction. J. Am. Heart Assoc. 5, e003698 (2016). source

      Not checked in the free run.

  • Premisecitation

    Bone-marrow-derived immune cells are activated by the gut microbiota, leading to low-grade inflammation that affects the brain, ANS and the kidney via the circulation.

    “Bone-marrow-derived immune cells are activated by the gut microbiota, leading to low-grade inflammation that affects the brain, ANS and the kidney via the circulation13–15.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Akchurin, O. M. & Kaskel, F. Update on inflammation in chronic kidney disease. Blood Purif. 39, 84–92 (2015). source

      Not checked in the free run.

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      Not checked in the free run.

    • cites [15] Santisteban, M. M. et al. Involvement of bone marrow cells and neuroinflammation in hypertension. Circ. Res. 117, 178–191 (2015). source

      Not checked in the free run.

  • Interpretationreasoning

    Enteroendocrine cell-derived hormones and gut-microbiota-derived metabolites exert profound effects on gut homeostasis.

    “Therefore, enteroendocrine cell-derived hormones and gutmicrobiota-derived metabolites exert profound effects on gut homeostasis.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 40
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisecitation

    Long-term hypertension leads to high intraglomerular pressure, which subsequently impairs glomerular filtration.

    “Long-term hypertension leads to high intraglomerular pressure, which subsequently impairs glomerular filtration3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Taler, S. J. et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am. J. Kidney Dis. 62, 201–213 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hypertension is an important risk factor for CKD, and approximately 85-90% of patients with stage 3-5 CKD have hypertension.

    “Hypertension is an important risk factor for CKD, and approximately 85–90% of patients with stage 3–5 CKD have hypertension2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Rao, M. V., Qiu, Y., Wang, C. & Bakris, G. Hypertension and CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES), 1999–2004. Am. J. Kidney Dis. 51, S30–S37 (2008). source

      Not checked in the free run.

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    Premisecitation

    No cure or strategy for prevention of CKD exists, and timely treatment is extremely challenging owing to a lack of symptoms in the early stages of the disease.

    “No cure or strategy for prevention of CKD exists, and timely treatment is extremely challenging owing to a lack of symptoms in the early stages of the disease5.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Andrassy, K. M. Comments on ‘KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease’. Kidney Int. 84, 622–623 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with medium fermented by the probiotic bacteria Bifidobacterium longum reduced anxiety and decreased the excitability of the ileal myenteric plexus neurons in mice with infectious colitis.

    “In addition, treatment with medium fermented by the probiotic bacteria Bifidobacterium longum reduced anxiety and decreased the excitability of the ileal myenteric plexus neurons in mice with infectious colitis11, indicating communication of probiotics with the CNS via the ENS and the vagal nerve.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Bercik, P. et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol. Motil. 23, 1132–1139 (2011). source

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    Premisecitation

    Immune and gut microbiota-derived products affect renal function and have important effects on CKD.

    “In addition, immune and gut microbiota-derived products affect renal function and have important effects on CKD17.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Cigarran Guldris, S., González Parra, E. & Cases Amenós, A. Gut microbiota in chronic kidney disease. Nefrologia 37, 9–19 (2017). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Activation of the vagal afferent SCFA-sensing pathway has been implicated in glucose homeostasis.

    “Vagal afferents express receptors that sense SCFAs55, and activation of this pathway has been implicated in glucose homeostasis56.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Zadeh-Tahmasebi, M. et al. Activation of short and long chain fatty acid sensing machinery in the ileum lowers glucose production in vivo. J. Biol. Chem. 291, 8816–8824 (2016). source

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    Premisecitation

    Treg cells are induced by a variety of bacterial groups and by the SCFA butyrate.

    “Treg cells are induced by a variety of bacterial groups67,68 and by the SCFA butyrate47, which is produced by bacterial fermentation.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [67] Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011). source

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    • cites [68] Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010). source

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    • cites [47] Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Beneficial effects of treatment with probiotics (Lactobacillus rhamnosus and B. longum) on stress and anxiety are vagus-nerve-dependent.

    “A series of beneficial effects of treatment with probiotics (Lactobacillus rhamnosus and B. longum) on stress and anxiety have been demonstrated to be vagus-nerve-dependent11,12.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Bercik, P. et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol. Motil. 23, 1132–1139 (2011). source

      Not checked in the free run.

    • cites [12] Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055 (2011). source

      Not checked in the free run.

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    Premisecitation

    The gut microbiota has a critical role not only in determining local immune outcomes but also in maintaining systemic physiology.

    “The gut microbiota therefore has a critical role not only in determining local immune outcomes but also in maintaining systemic physiology57.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation

    SCFAs have multiple roles in the maintenance of intestinal homeostasis, including control of the balance between proliferation and apoptosis of intestinal epithelial cells, induction of the secretion of endogenous antimicrobial peptides, differentiation of Treg cells, modulation of cytokine production and maintenance of gut barrier function.

    “SCFAs also have multiple roles in the maintenance of intestinal homeostasis, including control of the balance between proliferation and apoptosis of intestinal epithelial cells44, induction of the secretion of endogenous antimicrobial peptides from intestinal epithelial cells45,46 and of the differentiation of regulatory T (Treg) cells47, modulation of cytokine production37 and maintenance of gut”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [44] Donohoe, D. R. et al. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol. Cell 48, 612–626 (2012). source

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    • cites [45] Raqib, R. et al. Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc. Natl Acad. Sci. USA 103, 9178–9183 (2006). source

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    • cites [46] Zeng, X. et al. Induction of porcine host defense peptide gene expression by short-chain fatty acids and their analogs. PLoS ONE 8, e72922 (2013). source

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    Premisecitation

    Germ-free animals exhibit multiple immune abnormalities, including reduced TH17 cells, B cells, IgA, plasma cells, imbalanced TH1/TH2 responses, and impaired Treg cell function.

    “Germ-free animals have a substantial reduction in the levels of T helper 17 (TH17) cells61, B cells, immunoglobulin A (IgA) and plasma cells62–63, an imbalance of TH1 and TH2 responses64 and impaired Treg cell function65.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [61] Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008). source

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    • cites [62] Bunker, J. J. et al. Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358, eaan6619 (2017). source

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    Premisecitation

    A lack of gut microbiota leads to deficient development of the GALT and abnormal systemic and central immunity.

    “A lack of gut microbiota leads to deficient development of the GALT58 and abnormal systemic59 and central immunity60.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [58] Eberl, G. & Lochner, M. The development of intestinal lymphoid tissues at the interface of self and microbiota. Mucosal Immunol. 2, 478–485 (2009). source

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    • cites [59] Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 4, 478–485 (2004). source

      Not checked in the free run.

    • cites [60] Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015). source

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  • May combine two claims.

    Premisecitation

    Transferring dysbiotic faecal samples from patients with hypertension to germ-free mice or faeces from hypertensive stroke-prone SHRs to normotensive WKY rats increased blood pressure in the recipients.

    “Further evidence for a causative role of gut dysbiosis in the genesis of hypertension came from faecal microbiota transplantation (FMT) experiments in which transferring dysbiotic faecal samples from patients with hypertension to germ-free mice90 or faeces from hypertensive stroke-prone SHRs to normotensive WKY rats92 increased blood pressure in the recipients.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [90] Li, J. et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 5, 14 (2017). source

      Not checked in the free run.

    • cites [92] Wilck, N. et al. Salt-responsive gut commensal modulates T. Nature 551, 585–589 (2017). source

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  • May combine two claims.

    Interpretationreasoning

    SCFAs regulate immune responses and attenuate kidney pathology.

    “These findings indicate that SCFAs regulate immune responses and attenuate kidney pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The gut microbiota modulates not only the activation of intestinal immune cells but also the profile of immune progenitor cells in the bone marrow.

    “Therefore, the gut microbiota modulates not only the activation of intestinal immune cells but also the profile of immune progenitor cells in the bone marrow.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Overgrown bacteria translocate from the gut to the blood, where they contribute to increased levels of low-grade inflammation and thus exacerbate CKD pathology.

    “These findings suggest that overgrown bacteria trans-locate from the gut to the blood, where they contribute to increased levels of low-grade inflammation and thus exacerbate CKD pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Adrenergic receptors are expressed on immune cells residing in immune organs, indicating that sympathetic catecholamines regulate the immune system.

    “Expression of adrenergic receptors on immune cells residing in immune organs indicates regulatory effects of sympathetic catecholamines on the immune system154,167.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [154] Yang, T. et al. Shifts in the gut microbiota composition due to depleted bone marrow beta adrenergic signaling are associated with suppressed inflammatory transcriptional networks in the mouse colon. Front. Physiol. 8, 220 (2017).

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    • cites [167] Pongratz, G. & Straub, R. H. The sympathetic nervous response in inflammation. Arthritis Res. Ther. 16, 504 (2014). source

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  • May combine two claims.

    Premisecitation

    Gut dysbiosis has been reported in animal models and in patients with hypertension.

    “Gut dysbiosis has been reported in animal models87–89 and in patients with hypertension87,90 (Table 1).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [87] Yang, T. et al. Gut dysbiosis is linked to hypertension. Hypertension 65, 1331–1340 (2015). This study demonstrates a clear association between gut dysbiosis and hypertension in rats and a small cohort of human patients with hypertension. source

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    • cites [88] Mell, B. et al. Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol. Genom. 47, 187–197 (2015). source

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    • cites [89] Durgan, D. J. et al. Role of the gut microbiome in obstructive sleep apnea-induced hypertension. Hypertension 67, 469–474 (2016). source

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    • cites [90] Li, J. et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 5, 14 (2017). source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Emerging evidence indicates that the gut microbiota has an essential role in hypertension development.

    “In addition, emerging evidence indicates that the gut microbiota has an essential role in hypertension development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the kd/kd mouse model of collapsing glomerulopathy, germ-free conditions postponed the onset of renal mitochondrial ultrastructural defects, indicating a contribution of the gut microbiota to the pathogenesis of this kidney disease.

    “In the kd/kd mouse model of collapsing glomerulopathy, germ-free conditions postponed the onset of renal mitochondrial ultrastructural defects79, indicating a contribution of the gut microbiota to the pathogenesis of this kidney disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Hallman, T. M. et al. The mitochondrial and kidney disease phenotypes of kd/kd mice under germfree conditions. J. Autoimmun 26, 1–6 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The immune pathway of the brain-kidney axis involves input from the CNS and/or sympathetic nervous system to the bone marrow and effects of inflammatory cells released from the bone marrow on the kidney.

    “Therefore, the immune pathway of the brain-kidney axis involves input from the CNS and/or SNS to the bone marrow and the effects of inflammatory cells released from the bone marrow on the kidney.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Santisteban, M. M. et al. Involvement of bone marrow cells and neuroinflammation in hypertension. Circ. Res. 117, 178–191 (2015). source

      Not checked in the free run.

    • cites [156] Zubcevic, J. et al. Altered inflammatory response is associated with an impaired autonomic input to the bone marrow in the spontaneously hypertensive rat. Hypertension 63, 542–550 (2014). source

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    • cites [189] van Koppen, A. et al. Healthy bone marrow cells reduce progression of kidney failure better than CKD bone marrow cells in rats with established chronic kidney disease. Cell Transplant 21, 2299–2312 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In chronic kidney disease, indoxyl sulfate increases neuroinflammation, which may facilitate neurodegeneration observed in some patients.

    “In CKD, indoxyl sulfate increases neuroinflammation, which may facilitate the neurodegeneration that has been observed in some patients175.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Adesso, S. et al. Indoxyl sulfate affects glial function increasing oxidative stress and neuroinflammation in chronic kidney disease: interaction between astrocytes and microglia. Front. Pharmacol. 8, 370 (2017). source

      Not checked in the free run.

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    Premisecitation

    Other studies found no statistically significant correlation between eGFR and cognitive impairment but reported that albuminuria and rate of eGFR decline are associated with cognitive decline.

    “Other studies failed to identify statistically significant correlations between eGFR and cognitive impairment but reported that albuminuria and the rate of eGFR decline were associated with cognitive decline179–181.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [179] Jassal, S. K., Kritz-Silverstein, D. & Barrett-Connor, E. A prospective study of albuminuria and cognitive function in older adults: the Rancho Bernardo study. Am. J. Epidemiol. 171, 277–286 (2010). source

      Not checked in the free run.

    • cites [180] Helmer, C. et al. Chronic kidney disease, cognitive decline, and incident dementia: the 3C Study. Neurology 77, 2043–2051 (2011). source

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    • cites [181] Kurella Tamura, M. et al. Albuminuria, kidney function, and the incidence of cognitive impairment among adults in the United States. Am. J. Kidney Dis. 58, 756–763 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Quinolinic acid is an excitotoxin with high affinity for glutamate N-methyl-d-aspartate (NMDA) receptors.

    “which is an excitotoxin with high affinity for glutamate N-methyl-d-aspartate (NMDA) receptors186.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] Davis, I. & Liu, A. What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics? Expert Rev. Neurother 15, 719–721 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple central neural sites, including the paraventricular nucleus of hypothalamus, nucleus of the solitary tract and rostral ventrolateral medulla, regulate sympathetic outflow and communicate with each other to determine tonicity of sympathetic outflow.

    “Multiple central neural sites have been implicated in the regulation of sympathetic outflow, including the paraventricular nucleus of hypothalamus (PVN), NTS and rostral ventrolateral medulla (RVLM). These regions communicate with each other and integrate diverse inputs to determine the tonicity of sympathetic outflow171.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Fisher, J. P., Young, C. N. & Fadel, P. J. Central sympathetic overactivity: maladies and mechanisms. Auton. Neurosci. 148, 5–15 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same meta-analysis, blood pressure reductions were more pronounced when restricted to trials in patients with hypertension (SBP 5.95 mmHg, DBP 4.2 mmHg) or to trials with long interventions (≥8 weeks; SBP 3.12 mmHg, DBP 2.57 mmHg).

    “Importantly, more pronounced blood pressure reductions were found when the analysis was restricted to trials conducted in patients with hyper-tension (SBP 5.95 mmHg, DBP 4.2 mmHg) or to trials with long interventions (≥8 weeks; SBP 3.12 mmHg, DBP 2.57 mmHg).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Whelton, S. P. et al. Effect of dietary fiber intake on blood pressure: a meta-analysis of randomized, controlled clinical trials. J. Hypertens. 23, 475–481 (2005). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The gut microbiome induces host epigenetic changes that might contribute to the development of cancer.

    “The gut microbiome has been shown to induce host epigenetic changes that might contribute to the development of cancer193,194”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [193] Paul, B. et al. Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clin. Epigenet. 7, 112 (2015). source

      Not checked in the free run.

    • cites [194] Yang, T., Owen, J. L., Lightfoot, Y. L., Kladde, M. P. & Mohamadzadeh, M. Microbiota impact on the epigenetic regulation of colorectal cancer. Trends Mol. Med. 19, 714–725 (2013). source

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  • May combine two claims.

    Interpretationcitation

    The resulting imbalance in the plasma metabolome adversely affects various cardio-renal tissues; for example, accumulation of uraemic toxins or a lack of short-chain fatty acids leads to activation of systemic and tissue inflammation.

    “The resulting imbalance in the plasma metabolome adversely affects various cardio-renal tissues; for example, accumulation of uraemic toxins or a lack of SCFAs leads to activation of systemic and tissue inflammation147,203.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [147] Ito, S. & Yoshida, M. Protein-bound uremic toxins: new culprits of cardiovascular events in chronic kidney disease patients. Toxins 6, 665–678 (2014). source

      Not checked in the free run.

    • cites [203] Kim, S. et al. Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure. Clin. Sci. 132, 701–718 (2018). source

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  • May combine two claims.

    Premisecitation

    In mice, perinatal exposure to a high-fat, high-sucrose diet epigenetically primes the central renin-angiotensin system, leading to hypertension, potentially owing to limited plasticity of the autonomic system.

    “For example, in mice, perinatal exposure to a high-fat, high-sucrose diet epi-genetically primed the central renin-angiotensin system leading to hypertension, potentially owing to limited plasticity of the autonomic system202.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Mukerjee, S. et al. Perinatal exposure to Western diet programs autonomic dysfunction in the male offspring. Cell. Mol. Neurobiol. 38, 233–242 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sympathetic drive to the bone marrow shifts the balance of physiological inflammation towards overactivation, perpetuates low-grade systemic inflammation, and results in reduced production of pluripotent stem cells from the bone marrow for vascular, intestinal and renal repair.

    “Sympathetic drive to the bone marrow shifts the balance of physiological inflammation towards overactivation, which perpetuates low-grade systemic inflammation and results in a reduction in the production of pluripotent stem cells from the bone marrow for vascular, intestinal and renal repair.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A meta-analysis of 25 randomized placebo-controlled trials reported that high versus low dietary fibre intake is associated with a modest but statistically significant reduction in diastolic blood pressure (1.65 mmHg) but not systolic blood pressure.

    “Moreover, a meta-analysis of 25 randomized placebo-controlled trials reported that high versus low dietary fibre intake was associated with a modest but statistically significant reduction in DBP (1.65 mmHg) but not in SBP97.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Whelton, S. P. et al. Effect of dietary fiber intake on blood pressure: a meta-analysis of randomized, controlled clinical trials. J. Hypertens. 23, 475–481 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Activation of the sympathetic nervous system initiates a sequence of events in the gut that leads to increased gut wall permeability, dysbiosis, migration of pro-inflammatory cells from the bone marrow, and release of microbial products and metabolites into the blood.

    “Activation of the SNS initiates a sequence of events in the gut that leads to increased gut wall permeability, dysbiosis, migration of pro-inflammatory cells from the bone marrow and the release of microbial products and metabolites into the blood.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Intracerebroventricular administration of minocycline suppresses microglial and sympathetic activation and lowers blood pressure in animal models of hypertension.

    “Consistent with this postulate, intracerebroventricular administration of minocycline suppresses microglial and sympathetic activation and lowers blood pressure in animal models of hypertension205.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] Shi, P. et al. Brain microglial cytokines in neurogenic hypertension. Hypertension 56, 297–303 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Environmental, dietary and other pro-hypertensive and/or CKD-relevant stimuli are perceived at autonomic brain regions, where they are integrated into signals that lead to increased sympathetic nervous drive to the gut and bone marrow.

    “Environmental, dietary and other pro-hypertensive and/or CKD-relevant stimuli are perceived at the autonomic brain regions, where they are integrated into signals that lead to increased sympathetic nervous drive to the gut and bone marrow.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Modulation of the gut microbiota reduces systemic inflammation and sympathetic nervous system activity, both of which contribute to hypertension and chronic kidney disease.

    “Modulation of the gut microbiota reduces systemic inflammation and SNS activity, both of which contribute to hypertension and CKD80,162,208.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [80] Yang, T. & Zubcevic, J. Gut-brain axis in regulation of blood pressure. Front. Physiol. 8, 845 (2017). source

      Not checked in the free run.

    • cites [162] Kaur, J., Young, B. E. & Fadel, P. J. Sympathetic overactivity in chronic kidney disease: consequences and mechanisms. Int. J. Mol. Sci. 18, 1682 (2017). source

      Not checked in the free run.

    • cites [208] Clark, A. & Mach, N. Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes. J. Int. Soc. Sports Nutr. 13, 43 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 157 patients in China, a fibre intake of ≥25 g per day compared with <25 g per day is associated with a smaller reduction in eGFR and lower levels of serum C-reactive protein, indoxyl sulfate, cholesterol and IL-6 during 18 months of follow-up.

    “Similarly, a study that investigated the association of dietary fibre intake with CKD-related parameters in 157 patients in China reported that a fibre intake of ≥25 g per day compared with <25 g per day was associated with a smaller reduction in eGFR and lower levels of serum C-reactive protein, indoxyl sulfate, cholesterol and IL-6 during 18 months offollow-up213.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [213] Lu, L. et al. Dietary fiber intake is associated with chronic kidney disease (CKD) progression and cardiovascular risk, but not protein nutritional status, in adults with CKD. Asia Pac. J. Clin. Nutr. 26, 598–605 (2017).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The gut microbiota has a critical role in a variety of diseases, including hypertension and chronic kidney disease.

    “The gut microbiota has a critical role in a variety of diseases, including hypertension and CKD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Metabolomics studies of hypertension are limited, but changes in lipid and fatty acid profiles have been reported.

    “To date, metabolomics studies of hypertension are limited, but changes in lipid and fatty acid profiles have been reported229.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Nikolic, S. B., Sharman, J. E., Adams, M. J. & Edwards, L. M. Metabolomics in hypertension. J. Hypertens. 32, 1159–1169 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Faecal microbiota transplantation and transplantation of sterile faecal filtrate have been utilized for treatment of Clostridium difficile infection, which is a common complication in patients with chronic kidney disease, particularly those undergoing haemodialysis.

    “However, FMT and FFT have been utilized for the treatment of Clostridium difficile infection, which is a common complication in patients with CKD, particularly in those undergoing haemodialysis224–226.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [224] Thongprayoon, C., Cheungpasitporn, W., Phatharacharukul, P., Mahaparn, P. & Bruminhent, J. High mortality risk in chronic kidney disease and end stage kidney disease patients with Clostridium difficile infection: a systematic review and meta-analysis. J. Nat. Sci. 1, e85 (2015).

      Not checked in the free run.

    • cites [225] Youngster, I. et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 312, 1772–1778 (2014). source

      Not checked in the free run.

    • cites [226] Ott, S. J. et al. Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile Infection. Gastroenterology 152, 799–811.e7 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Probiotics containing multiple rather than single species, a longer duration of intervention (≥8 weeks), and higher daily doses (≥10^11 colony-forming units) are associated with more effective blood-pressure lowering.

    “Probiotics that contained multiple rather than single species of bacteria, a longer duration of the intervention (≥8 weeks) and higher daily doses (≥1011 colony-forming units) were associated with more effective blood-pressure lowering in this study.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Khalesi, S., Sun, J., Buys, N. & Jayasinghe, R. Effect of probiotics on blood pressure: a systematic review and meta-analysis of randomized, controlled trials. Hypertension 64, 897–903 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with uraemia undergoing haemodialysis, oral administration of a preparation of antibiotic-resistant lactic acid bacteria (Lebenin) restores the composition of the gut microbiota to normal and inhibits accumulation of uraemic toxins in the blood.

    “In patients with uraemia undergoing haemodialysis, oral administration of a preparation of antibiotic-resistant lactic acid bacteria (known as Lebenin) restored the composition of the gut microbiota to normal and inhibited the accumulation of uraemic toxins in the blood218.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [218] Hida, M. et al. Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis. Nephron 74, 349–355 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Haemodialysis removes most uraemic toxins with the exception of protein-bound uraemic toxins such as indoxyl sulfate and p-cresyl sulfate, which bind serum albumin.

    “Haemodialysis removes most uraemic toxins with the exception of protein-bound uraemic toxins such as indoxyl sulfate and p-cresyl sulfate, which bind serum albumin227.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [227] Itoh, Y., Ezawa, A., Kikuchi, K., Tsuruta, Y. & Niwa, T. Protein-bound uremic toxins in hemodialysis patients measured by liquid chromatography/tandem mass spectrometry and their effects on endothelial ROS production. Anal. Bioanal. Chem. 403, 1841–1850 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AST-120 has been approved as a treatment to delay initiation of haemodialysis in patients with chronic kidney disease in Japan but not in Europe or the United States, owing to a lack of proof of an unequivocal therapeutic benefit in large randomized clinical trials with hard renal and cardiovascular end points.

    “AST-120 has been approved as a treatment to delay the initiation of haemodialysis in patients with CKD in Japan but not in Europe or the United States, owing to a lack of proof of an unequivocal therapeutic benefit in large randomized clinical trials with hard renal and cardiovascular end points228.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Yamaguchi, J., Tanaka, T. & Inagi, R. Effect of AST-120 in chronic kidney disease treatment: still a controversy? Nephron 135, 201–206 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rats with angiotensin-II-induced hypertension, minocycline administration changes the gut microbiota and lowers blood pressure.

    “For example, in rats with angiotensin-II-induced hypertension, minocycline administration changed the gut micro-biota and lowered blood pressure87.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Yang, T. et al. Gut dysbiosis is linked to hypertension. Hypertension 65, 1331–1340 (2015). This study demonstrates a clear association between gut dysbiosis and hypertension in rats and a small cohort of human patients with hypertension. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    High fibre intake seems to retard loss of GFR and is negatively associated with cardiovascular risk.

    “Thus, high fibre intake seems to retard loss of GFR and is negatively associated with cardiovascular risk.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [212] Chiavaroli, L., Mirrahimi, A., Sievenpiper, J. L., Jenkins, D. J. & Darling, P. B. Dietary fiber effects in chronic kidney disease: a systematic review and meta-analysis of controlled feeding trials. Eur. J. Clin. Nutr. 69, 761–768 (2015). source

      Not checked in the free run.

    • cites [213] Lu, L. et al. Dietary fiber intake is associated with chronic kidney disease (CKD) progression and cardiovascular risk, but not protein nutritional status, in adults with CKD. Asia Pac. J. Clin. Nutr. 26, 598–605 (2017).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut epithelium is dynamic, has high regenerative capacity, and is epigenetically modified by the gut microbiota and their metabolites.

    “The gut epithelium is dynamic, has high regenerative capacity and is epigenetically modified by the gut microbiota and their metabolites194.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [194] Yang, T., Owen, J. L., Lightfoot, Y. L., Kladde, M. P. & Mohamadzadeh, M. Microbiota impact on the epigenetic regulation of colorectal cancer. Trends Mol. Med. 19, 714–725 (2013). source

      Not checked in the free run.

46 of 46

  • The paper relies on this without support.

    With the exception of dialysis and kidney transplantation, effective treatments for end-stage renal disease (ESRD) are lacking.

    “Moreover, with the exception of dialysis and kidney transplantation, effective treatments for end-stage renal disease (ESRD) are lacking.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Short-chain fatty acids are thought to affect the function of the immune system, epithelial cells, blood vessels, and nervous system and may underlie the reductions in hypertension risk associated with fibre-rich diets.

    “These SCFAs are thought to affect the function of the immune system, epithelial cells, blood vessels and nervous system and may underlie the reductions in hypertension risk that are associated with fibre-rich diets103,106.”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [103]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Bone-marrow sympathetic activation in CKD is both asserted and described as unresolved

    Minor

    The paper states that abnormal sympathetic drive to the bone marrow in CKD shifts immune cells toward a pro-inflammatory state, but its conclusion says whether that activation is increased in CKD remains to be addressed.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Kim, S. et al. Hypertensive patients exhibit gut microbial dysbiosis and an increase in TH17 cells [abstract]. J. Hypertension 33 (Suppl. 1), 6B.07 (2015).

Cited by

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Related

Authors
Yang, T., Richards, E. M., Pepine, C. J., & Raizada, M. K.
Affiliations
University of Florida (US)
Corresponding author
Raizada, Mohan K.
ORCID
Venue
Nature Reviews Nephrology
Publisher
Springer Science and Business Media LLC
Published
2018-05-14
Volume
14
Issue
7
Pages
442-456
ISSN
  • 1745-8323 (ISSN-L)
  • 1759-5061
  • 1759-507X
DOI
10.1038/s41581-018-0018-2
PMC
PMC6385605
OpenAlex
W2799300982
Cited by
753
References
242
Citations by year
2026: 83 · 2025: 115 · 2024: 140 · 2023: 119 · 2022: 109 · 2021: 82 · 2020: 65 · 2019: 33 · 2018: 6
FWCI
4.55
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Nephrology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL033610, R01HL102033, R01HL132448)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords
gut microbiota, hypertension, chronic kidney disease, gut dysbiosis, host-microbiota crosstalk, immune dysregulation, metabolic disorders, sympathetic activation, microbial metabolites, pathogenesis, therapeutic target
MeSH terms
Gastrointestinal Microbiome, Animals, Brain, Fatty Acids, Volatile, Humans, Hypertension, Kidney, Sympathetic Nervous System, Enteroendocrine Cells, Gastrointestinal Tract, Epigenesis, Genetic, Renal Insufficiency, Chronic

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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