The DOI matches its Crossref record; 242 of the 242 references it cites were found in a registry or an index; 6 of the 181 sources its claims cite were checked for support.
The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
107 Not checked yet · 24 Own interpretation · 2 Supported so far · 1 Partly supported · accuracy not yet measured
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“As gut dysbiosis and altered gut pathology are associated with hypertension, and hypertension is an important factor that contributes to the development of CKD, the finding that changes in the composition of the gut microbiota (TABLE 1) are associated with CKD and ESRD is not surprising101,102.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The gut microbiota in CKD
What the sources say
- Not checked yetcites [101] Vaziri, N. D. et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 83, 308–315 (2013). This is a comprehensive study demonstrating that the gut microbiota is linked to CKD in rats and humans. Uraemia significantly altered gut microbial composition. source
- Supportedcites [102] Felizardo, R. J., Castoldi, A., Andrade-Oliveira, V. & Câmara, N. O. The microbiota and chronic kidney diseases: a double-edged sword. Clin. Transl Immunol. 5, e86 (2016). source
The “Gut microbiota and CKDs” section reports significant differences in gut bacterial composition between patients with ESRD and healthy people, as well as in an experimental CKD model. This supports the claimed association with CKD and ESRD; no page number is provided in the supplied passages. (LLM, conf=0.94)
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In the paper
“As TLR3 is abundantly expressed in the brain187, abnormal activation of NMDA receptor signalling by quinolinic acid might be at least partially responsible for numerous neurological diseases186,188.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Sympathetic nervous system and brain.
What the sources say
- Supportedcites [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
The supplied passage [2] says quinolinic acid can activate NMDA receptors and that elevated levels are associated with numerous neurological diseases. Passage [1] also describes its production as a contributing factor to neurodegenerative diseases. The TLR3 clause has a separate citation (187), so it is not attributed to this source. (LLM, conf=0.91)
- Supportedcites [187] Kigerl, K. A., de Rivero Vaccari, J. P., Dietrich, W. D., Popovich, P. G. & Keane, R. W. Pattern recognition receptors and central nervous system repair. Exp. Neurol. 258, 5–16 (2014). source
Citation 187 is attached to the claim that TLR3 is abundantly expressed in the brain, not to the quinolinic-acid and NMDA-receptor claim cited to 186 and 188. The ‘Cellular expression in the CNS’ section describes TLR3 expression in microglia, astrocytes and cortical neurons, supporting its broad presence in the CNS; the copy does not quantify its abundance. (LLM, conf=0.83)
- Not checked yetcites [188] Maddison, D. C. & Giorgini, F. The kynurenine pathway and neurodegenerative disease. Semin. Cell Dev. Biol. 40, 134–141 (2015). source
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In the paper
“Abnormal sympathetic drive to the bone marrow in hypertension and CKD dramatically shifts the immune properties of haematopoietic cells to a pro-inflammatory state”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Sympathetic nervous system and brain.
What the sources say
- Partly supportedcites [15] Santisteban, M. M. et al. Involvement of bone marrow cells and neuroinflammation in hypertension. Circ. Res. 117, 178–191 (2015). sourceExperimental — accuracy not yet measured
The Discussion proposes that increased sympathetic nerve activity affects bone marrow, increasing inflammatory cells, and the Results find a pro-inflammatory bone-marrow profile in two rat models of hypertension (pages not provided). The paper does not establish the same shift in chronic kidney disease, so extending the claim to CKD is unsupported. (LLM, conf=0.88)
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
The Discussion (page not provided) links increased sympathetic drive to persistently elevated bone-marrow inflammatory cells in spontaneously hypertensive rats, and reports that norepinephrine activates those cells. The paper does not study chronic kidney disease, and its proposed mechanism does not establish that sympathetic drive dramatically shifts the immune properties of haematopoietic cells across both conditions. (LLM, conf=0.88)
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says that bone marrow cells in diseased states may shift toward a more inflammatory phenotype. It does not link that shift to sympathetic drive, establish it in hypertension, or describe a dramatic pro-inflammatory change in CKD. The paper’s cytokine-array results report only reduced VEGF in CKD bone marrow cells. (LLM, conf=0.82)
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Increasing evidence indicates an important role of the gut microbiota in the development of hypertension and CKD.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Abstract
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In the paper
“Thus, blood-pressure lowering is an important and widely used approach to slow CKD progression.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Abstract
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Abstract
What the sources say
- Not checked yetcites [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 yetcites [7] Josefsdottir, K. S., Baldridge, M. T., Kadmon, C. S. & King, K. Y. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood 129, 729–739 (2017). source
- Not checked yetcites [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
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Abstract
What the sources say
- Not checked yetcites [13] Akchurin, O. M. & Kaskel, F. Update on inflammation in chronic kidney disease. Blood Purif. 39, 84–92 (2015). source
- Not checked yetcites [14] Shankland, S. J. & Jefferson, J. A. A bone marrow factor contributes to kidney disease. Nat. Med. 23, 13–14 (2017). source
- Not checked yetcites [15] Santisteban, M. M. et al. Involvement of bone marrow cells and neuroinflammation in hypertension. Circ. Res. 117, 178–191 (2015). source
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In the paper
“Therefore, enteroendocrine cell-derived hormones and gutmicrobiota-derived metabolites exert profound effects on gut homeostasis.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Endocrines and metabolites.
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In the paper
“Intestinal infiltration of pro-inflammatory TH17 cells is induced by segmented filamentous bacteria66, and gut microbial diversity, particularly colonization by Bacteroidetes, is critical for balancing TH1 and TH2 responses64.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Role of the gut in the immune system.
What the sources say
- Not checked yetcites [66] Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Intestinal infiltration of pro-inflammatory TH17 cells is induced by segmented filamentous bacteria66, and gut microbial diversity, particularly colonization by Bacteroidetes, is critical for balancing TH1 and TH2 responses64.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Role of the gut in the immune system.
What the sources say
- Not checked yetcites [64] Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Long-term hypertension leads to high intraglomerular pressure, which subsequently impairs glomerular filtration3.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Abstract
What the sources say
- Not checked yetcites [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
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In the paper
“Hypertension is an important risk factor for CKD, and approximately 85–90% of patients with stage 3–5 CKD have hypertension2.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Abstract
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Abstract
What the sources say
- Not checked yetcites [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
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Neural control of the gut.
What the sources say
- Not checked yetcites [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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In the paper
“In addition, immune and gut microbiota-derived products affect renal function and have important effects on CKD17.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Abstract
What the sources say
- Not checked yetcites [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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In the paper
“Vagal afferents express receptors that sense SCFAs55, and activation of this pathway has been implicated in glucose homeostasis56.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Neural control of the gut.
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Treg cells are induced by a variety of bacterial groups67,68 and by the SCFA butyrate47, which is produced by bacterial fermentation.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Role of the gut in the immune system.
What the sources say
- Not checked yetcites [67] Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011). source
- Not checked yetcites [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
- Not checked yetcites [47] Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Neural control of the gut.
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“The gut microbiota therefore has a critical role not only in determining local immune outcomes but also in maintaining systemic physiology57.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Role of the gut in the immune system.
What the sources say
- Not checked yetcites [57] Chow, J., Lee, S. M., Shen, Y., Khosravi, A. & Mazmanian, S. K. Host-bacterial symbiosis in health and disease. Adv. Immunol. 107, 243–274 (2010). source
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In the paper
“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”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Endocrines and metabolites.
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Role of the gut in the immune system.
What the sources say
- Not checked yetcites [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
- Not checked yetcites [62] Bunker, J. J. et al. Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358, eaan6619 (2017). source
- Not checked yetcites [63] Crabbé, P. A., Bazin, H., Eyssen, H. & Heremans, J. F. The normal microbial flora as a major stimulus for proliferation of plasma cells synthesizing IgA in the gut. The germ-free intestinal tract. Int. Arch. Allergy Appl. Immunol. 34, 362–375 (1968). source
- Not checked yetcites [64] Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A lack of gut microbiota leads to deficient development of the GALT58 and abnormal systemic59 and central immunity60.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Role of the gut in the immune system.
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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 yetcites [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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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The gut microbiota in hypertension
What the sources say
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In the paper
“These findings indicate that SCFAs regulate immune responses and attenuate kidney pathology.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The gut-kidney axis > Communication between the pathways.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The gut-kidney axis > Immune pathway.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The gut microbiota in CKD
hedgeddirectn = 30- Asserted: passes — The authors put it forward as true.
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In the paper
“Expression of adrenergic receptors on immune cells residing in immune organs indicates regulatory effects of sympathetic catecholamines on the immune system154,167.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Sympathetic nervous system and brain.
What the sources say
- Not checked yetcites [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).
- Not checked yetcites [167] Pongratz, G. & Straub, R. H. The sympathetic nervous response in inflammation. Arthritis Res. Ther. 16, 504 (2014). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Gut dysbiosis has been reported in animal models87–89 and in patients with hypertension87,90 (Table 1).”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The gut microbiota in hypertension
What the sources say
- Not checked yetcites [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 yetcites [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
- Not checked yetcites [89] Durgan, D. J. et al. Role of the gut microbiome in obstructive sleep apnea-induced hypertension. Hypertension 67, 469–474 (2016). source
- Not checked yetcites [90] Li, J. et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 5, 14 (2017). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, emerging evidence indicates that the gut microbiota has an essential role in hypertension development.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The gut microbiota in hypertension
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Gut physiology > Role of the gut in the immune system.
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Sympathetic nervous system and brain.
What the sources say
- Not checked yetcites [15] Santisteban, M. M. et al. Involvement of bone marrow cells and neuroinflammation in hypertension. Circ. Res. 117, 178–191 (2015). source
- Not checked yetcites [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
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In CKD, indoxyl sulfate increases neuroinflammation, which may facilitate the neurodegeneration that has been observed in some patients175.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Sympathetic nervous system and brain.
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Sympathetic nervous system and brain.
What the sources say
- Not checked yetcites [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 yetcites [180] Helmer, C. et al. Chronic kidney disease, cognitive decline, and incident dementia: the 3C Study. Neurology 77, 2043–2051 (2011). source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“which is an excitotoxin with high affinity for glutamate N-methyl-d-aspartate (NMDA) receptors186.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Sympathetic nervous system and brain.
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Sympathetic nervous system and brain.
What the sources say
- Not checked yetcites [171] Fisher, J. P., Young, C. N. & Fadel, P. J. Central sympathetic overactivity: maladies and mechanisms. Auton. Neurosci. 148, 5–15 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Dietary interventions.
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The gut microbiome has been shown to induce host epigenetic changes that might contribute to the development of cancer193,194”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Epigenetic factors.
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Pathogenesis of hypertension and CKD.
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Epigenetic factors.
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Pathogenesis of hypertension and CKD.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Dietary interventions.
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Pathogenesis of hypertension and CKD.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Consistent with this postulate, intracerebroventricular administration of minocycline suppresses microglial and sympathetic activation and lowers blood pressure in animal models of hypertension205.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies
What the sources say
- Not checked yetcites [205] Shi, P. et al. Brain microglial cytokines in neurogenic hypertension. Hypertension 56, 297–303 (2010). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Pathogenesis of hypertension and CKD.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Modulation of the gut microbiota reduces systemic inflammation and SNS activity, both of which contribute to hypertension and CKD80,162,208.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies
What the sources say
- Not checked yetcites [80] Yang, T. & Zubcevic, J. Gut-brain axis in regulation of blood pressure. Front. Physiol. 8, 845 (2017). source
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Dietary interventions.
What the sources say
- Not checked yetcites [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).
plaincorrelationaln = 157- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The gut microbiota has a critical role in a variety of diseases, including hypertension and CKD.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Conclusions and future perspectives
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“To date, metabolomics studies of hypertension are limited, but changes in lipid and fatty acid profiles have been reported229.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Metabolite modulation.
What the sources say
- Not checked yetcites [229] Nikolic, S. B., Sharman, J. E., Adams, M. J. & Edwards, L. M. Metabolomics in hypertension. J. Hypertens. 32, 1159–1169 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Faecal transplantation.
What the sources say
- Not checked yetcites [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 yetcites [225] Youngster, I. et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 312, 1772–1778 (2014). source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Probiotics, prebiotics and synbiotics.
What the sources say
- Not checked yetcites [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
plaincorrelationaln = 543- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Probiotics, prebiotics and synbiotics.
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Metabolite modulation.
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Metabolite modulation.
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, in rats with angiotensin-II-induced hypertension, minocycline administration changed the gut micro-biota and lowered blood pressure87.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Antibiotics.
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, high fibre intake seems to retard loss of GFR and is negatively associated with cardiovascular risk.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Potential therapeutic strategies > Dietary interventions.
What the sources say
- Not checked yetcites [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 yetcites [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).
hedgedcorrelationaln = 157- Asserted: passes — The authors put it forward as true.
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In the paper
“The gut epithelium is dynamic, has high regenerative capacity and is epigenetically modified by the gut microbiota and their metabolites194.”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Conclusions and future perspectives
What the sources say
- Not checked yetcites [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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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.”
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“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]
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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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > The brain-gut-kidney axis > Sympathetic nervous system and brain.
“Abnormal sympathetic drive to the bone marrow in hypertension and CKD dramatically shifts the immune properties of haematopoietic cells to a pro-inflammatory state”
§ The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease > Conclusions and future perspectives
“whether sympathetic activation to the bone marrow and gut is increased in CKD and whether changes in kidney function are associated with increased gut permeability remain to be addressed.”
Citations
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Cited by
Sorted by citations
Obesity, kidney dysfunction and hypertension: mechanistic links
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RetractedAssociation of metabolic syndrome and chronic kidney disease
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Metadata
- Authors
- Yang, T., Richards, E. M., Pepine, C. J., & Raizada, M. K.
- Affiliations
- University of Florida (US)
- Corresponding author
- Raizada, Mohan K.
- Venue
- Nature Reviews Nephrology
- Published
- 2018-05-14
- Volume
- 14
- Issue
- 7
- Pages
- 442-456
- ISSN
- 1745-8323 (ISSN-L)
- 1759-5061
- 1759-507X
- 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
- green
- europepmc.org
- 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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