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

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.”

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
• Supported

  Citation 7 is attached specifically to “bone marrow,” not to the other organ systems listed. The Discussion and the section on suppression of myelopoiesis report that changes in the intestinal microbiota affect bone marrow blood-cell production in mice, supporting that attributed connection. (LLM, conf=0.93)

  cites [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
• Supported

  Citation 8 is attached to “vasculature,” not to the other organ systems in the sentence. The Discussion reports that the absence of gut microbiota protected mice from AngII-induced vascular dysfunction, supporting the attributed connection between gut microbiota and the vasculature. (LLM, conf=0.92)

  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

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.”

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
• Supported

  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)

  cites [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

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.”

What the sources say

• Supported

  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)

  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
• Supported

  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)

  cites [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
• Not checked yetcites [188] Maddison, D. C. & Giorgini, F. The kynurenine pathway and neurodegenerative disease. Semin. Cell Dev. Biol. 40, 134–141 (2015). source

In the paper

“Neuroinflammation in central sympathetic regions is observed in hypertension172,173”

What the sources say

• Supported

  The Results section reports increased pro-inflammatory cytokine expression in the PVN of hypertensive mice compared with normotensive controls and identifies it as a primary site of neuroinflammation among central cardiovascular control centers. The Introduction identifies the PVN as a region involved in regulating sympathetic outflow. (LLM, conf=0.92)

  cites [172] Shi, P. et al. Direct pro-inflammatory effects of prorenin on microglia. PLoS ONE 9, e92937 (2014). source
• Supported

  The ‘Renin-Ang-II system and neuroinflammation’ section reports an inflammatory state in the nucleus tractus solitarius in spontaneously hypertensive rats and links cytokine levels in the rostral ventrolateral medulla to hypertensive responses. These are central regions involved in sympathetic control, supporting the citing sentence. (LLM, conf=0.92)

  cites [173] Winklewski, P. J., Radkowski, M., Wszedybyl-Winklewska, M. & Demkow, U. Brain inflammation and hypertension: the chicken or the egg? J. Neuroinflamm. 12, 85 (2015). source

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”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

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

In the paper

“Thus, blood-pressure lowering is an important and widely used approach to slow CKD progression.”

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.”

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

In the paper

“Therefore, enteroendocrine cell-derived hormones and gutmicrobiota-derived metabolites exert profound effects on gut homeostasis.”

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.”

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

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.”

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

In the paper

“Peripheral stimuli influence the ANS to subsequently modify neural inputs to the kidney, intestine and lymphoid organs16.”

What the sources say

• Not checked yetcites [16] Carabotti, M., Scirocco, A., Maselli, M. A. & Severi, C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann. Gastroenterol. 28, 203–209 (2015).

In the paper

“Innate immunity is also regulated by the gut microbiota as evidenced by reduced numbers and compromised functions of antigen-presenting cells and microglia in germ-free animals60,69.”

What the sources say

• 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
• Not checked yetcites [69] Thaiss, C. A., Zmora, N., Levy, M. & Elinav, E. The microbiome and innate immunity. Nature 535, 65–74 (2016). source

In the paper

“Gut microbial metabolites, including SCFAs that are generated by the fermentation of dietary fibre, influence the host endocrine system.”

What the sources say

• Not checked yetcites [41] Psichas, A. et al. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 39, 424–429 (2015). source
• Not checked yetcites [42] Tolhurst, G. et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61, 364–371 (2012). source

In the paper

“In germ-free mice, colonization of the gut microbiota is critical for the development and maturation of the ENS51.”

What the sources say

• Not checked yetcites [51] McVey Neufeld, K. A., Perez-Burgos, A., Mao, Y. K., Bienenstock, J. & Kunze, W. A. The gut microbiome restores intrinsic and extrinsic nerve function in germ-free mice accompanied by changes in calbindin. Neurogastroenterol. Motil. 27, 627–636 (2015). source

In the paper

“Gut dysbiosis has an important role in many chronic diseases, and amelioration of this dysbiosis could be a potential strategy for the prevention and management of these diseases18.”

What the sources say

• Not checked yetcites [18] Konturek, P. C. et al. Emerging role of fecal microbiota therapy in the treatment of gastrointestinal and extra-gastrointestinal diseases. J. Physiol. Pharmacol. 66, 483–491 (2015).

In the paper

“The gut microbiota and its metabolites are potent stimulators of the production of serotonin by enterochromaffin cells52.”

What the sources say

• Not checked yetcites [52] Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015). source

In the paper

“In a rat model of obesity, changes in the gut microbiota induced by an energy-dense diet were associated with alterations in brain-gut vagal (NTS) communication53, which may alter vagal satiety signalling and stimulate energy intake and adiposity54.”

What the sources say

• Not checked yetcites [53] Vaughn, A. C. et al. Energy-dense diet triggers changes in gut microbiota, reorganization of gut-brain vagal communication and increases body fat accumulation. Acta Neurobiol. Exp. 77, 18–30 (2017). source

In the paper

“These results suggest a role of gut-microbiota-derived SCFAs in the production of endocrine hormones.”

In the paper

“This essential process depends to a great extent on the presence of a balanced gut microbiota25.”

What the sources say

• Not checked yetcites [25] Ulluwishewa, D. et al. Regulation of tight junction permeability by intestinal bacteria and dietary components. J. Nutr. 141, 769–776 (2011). source

In the paper

“The ANS conveys physiological conditions in the gut, such as acidity, levels of nutrients, osmolarity and pain, to the brain49.”

What the sources say

• Not checked yetcites [49] Berthoud, H. R., Blackshaw, L. A., Brookes, S. J. & Grundy, D. Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract. Neurogastroenterol. Motil. 16 (Suppl. 1), 28–33 (2004). source

In the paper

“Vagal afferents express receptors that sense SCFAs55, and activation of this pathway has been implicated in glucose homeostasis56.”

What the sources say

• Not checked yetcites [55] Lal, S., Kirkup, A. J., Brunsden, A. M., Thompson, D. G. & Grundy, D. Vagal afferent responses to fatty acids of different chain length in the rat. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G907–G915 (2001). source

In the paper

“Emerging evidence has led to expansion of this concept to that of the brain-gut-kidney axis9,118,160,161 (TABLE 2).”

What the sources say

• Not checked yetcites [9] Evenepoel, P., Poesen, R. & Meijers, B. The gut-kidney axis. Pediatr. Nephrol. 32, 2005–2014 (2017). source
• Not checked yetcites [118] Al Khodor, S. & Shatat, I. F. Gut microbiome and kidney disease: a bidirectional relationship. Pediatr. Nephrol. 32, 921–931 (2017). source
• Not checked yetcites [160] Ramezani, A. et al. Role of the gut microbiome in uremia: a potential therapeutic target. Am. J. Kidney Dis. 67, 483–498 (2016). source

In the paper

“The gut-kidney axis can be subdivided into metabolism-dependent and immune pathways9.”

What the sources say

• Not checked yetcites [9] Evenepoel, P., Poesen, R. & Meijers, B. The gut-kidney axis. Pediatr. Nephrol. 32, 2005–2014 (2017). source

In the paper

“Deficits in renal function associated with a leaky gut exacerbate the accumulation of metabolic wastes in the blood and may eventually cause uraemia.”

In the paper

“This finding highlights the importance of maintaining an exquisitely balanced gut microbiota in CKD.”

In the paper

“Although these changes were more profound in adult SHRs than in juvenile SHRs that had not yet developed hypertension, the prehypertensive juvenile SHRs had reduced levels of multiple tight junction proteins but similar gut permeability compared with juvenile WKY rats91.”

What the sources say

• Not checked yetcites [91] Santisteban, M. M. et al. Hypertension-linked pathophysiological alterations in the gut. Circ. Res. 120, 312–323 (2017). source

In the paper

“However, persistent activation of the SNS results in changes in signalling within immune organs and cells towards pro-inflammatory pathways168, as observed in hypertension and CKD169,170.”

What the sources say

• Not checked yetcites [168] Lorton, D. & Bellinger, D. L. Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int. J. Mol. Sci. 16, 5635–5665 (2015). source
• Not checked yetcites [169] Singh, M. V., Chapleau, M. W., Harwani, S. C. & Abboud, F. M. The immune system and hypertension. Immunol. Res. 59, 243–253 (2014). source
• Not checked yetcites [170] Grassi, G. et al. Early sympathetic activation in the initial clinical stages of chronic renal failure. Hypertension 57, 846–851 (2011). source

In the paper

“The brain has considerable involvement in the gut-kidney axis through communication with metabolism-dependent and immune pathways via the sympathetic nervous system (SNS).”

In the paper

“These data suggest the involvement of gut microbiota in the immune-cell-mediated genesis of hypertension.”

In the paper

“These findings indicate that the gut microbiota has a global impact on host immunity.”

In the paper

“These data indicate altered bidirectional autonomic communication between the brain and the kidney in CKD.”

In the paper

“Our research group was the first to demonstrate a contribution of the brain-gut-bone-marrow axis to blood pressure elevation15,87,91,154–159.”

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 [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 [91] Santisteban, M. M. et al. Hypertension-linked pathophysiological alterations in the gut. Circ. Res. 120, 312–323 (2017). source

In the paper

“Therefore, alteration and disruption of homeostasis in the gut have negative effects on intestinal and systemic physiological functions.”

In the paper

“Finally, studies in animal models and in patients with hypertension have reported that interventions that target the gut microbiota, such as a high-fibre diet, probiotics and antibiotics, have blood-pressure lowering effects87,92–99.”

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 [92] Wilck, N. et al. Salt-responsive gut commensal modulates T. Nature 551, 585–589 (2017). source
• Not checked yetcites [93] Pluznick, J. L. et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc. Natl Acad. Sci. USA 110, 4410–4415 (2013). source
• Not checked yetcites [94] Natarajan, N. et al. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41. Physiol. Genom. 48, 826–834 (2016). source
• Not checked yetcites [95] Marques, F. Z. et al. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation 135, 964–977 (2017). source
• Not checked yetcites [96] Aleixandre, A. & Miguel, M. Dietary fiber and blood pressure control. Food Funct. 7, 1864–1871 (2016). source
• 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
• 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
• Not checked yetcites [99] Qi, Y., Aranda, J. M., Rodriguez, V., Raizada, M. K. & Pepine, C. J. Impact of antibiotics on arterial blood pressure in a patient with resistant hypertension — a case report. Int. J. Cardiol. 201, 157–158 (2015). source

In the paper

“These findings indicate that gut pathology occurs before the onset of blood pressure elevation in the SHRs.”

In the paper

“The occur-rence of increased SNS activity in hypertension and CKD is well established83,162.”

What the sources say

• Not checked yetcites [83] Mancia, G. & Grassi, G. The autonomic nervous system and hypertension. Circ. Res. 114, 1804–1814 (2014). 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

In the paper

“Both anti-inflammatory and pro-inflammatory effects of adrenergic signalling have been demonstrated, depending upon the subtype of adrenergic receptors expressed167, the level of activation of specific cell types and the stage of disease progression168.”

What the sources say

• Not checked yetcites [167] Pongratz, G. & Straub, R. H. The sympathetic nervous response in inflammation. Arthritis Res. Ther. 16, 504 (2014). source
• Not checked yetcites [168] Lorton, D. & Bellinger, D. L. Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int. J. Mol. Sci. 16, 5635–5665 (2015). source

In the paper

“The gut microbiota also seems to be a key factor that mediates the onset of kidney disease.”

In the paper

“Therefore, the colonic microbiota makes a considerable contribution to the production of uraemic toxins.”

In the paper

“Moreover, spontaneously hypertensive rats (SHRs) showed patho-physiological changes in the gut, including decreased numbers of goblet cells and villi length and increased fibrosis compared with age-matched normotensive Wistar Kyoto (WKY) controls91.”

What the sources say

• Not checked yetcites [91] Santisteban, M. M. et al. Hypertension-linked pathophysiological alterations in the gut. Circ. Res. 120, 312–323 (2017). source

In the paper

“The SNS directly innervates both primary (bone marrow) and secondary (spleen) immune organs80.”

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

In the paper

“and the release of these inflammatory immune cells from the bone marrow contributes to the pathogenesis of hypertension and CKD15,156,189.”

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

In the paper

“suggesting a direct role of these compounds in cognitive impairment.”

What the sources say

• Not checked yetcites [182] De Deyn, P. P., Vanholder, R., Eloot, S. & Glorieux, G. Guanidino compounds as uremic (neuro)toxins. Semin. Dial 22, 340–345 (2009). source

In the paper

“Germ-free mice had reduced kynurenine pathway activity that was normalized by colonization of a conventional gut microbiota184.”

What the sources say

• Not checked yetcites [184] Clarke, G. et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 18, 666–673 (2013). source

In the paper

“indicating crosstalk between the kidney and the brain in the context of hypertension and CKD.”

What the sources say

• Not checked yetcites [176] Nishihara, M., Takesue, K. & Hirooka, Y. Renal denervation enhances GABA-ergic input into the PVN leading to blood pressure lowering in chronic kidney disease. Auton. Neurosci. 204, 88–97 (2017). source

In the paper

“In the 5/6 nephrectomized mouse, renal denervation lowers blood pressure”

What the sources say

• Not checked yetcites [176] Nishihara, M., Takesue, K. & Hirooka, Y. Renal denervation enhances GABA-ergic input into the PVN leading to blood pressure lowering in chronic kidney disease. Auton. Neurosci. 204, 88–97 (2017). source

In the paper

“This finding indirectly suggests a role of immune activation in the regulation of the kynure-nine pathway.”

What the sources say

• Not checked yetcites [184] Clarke, G. et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 18, 666–673 (2013). source

In the paper

“and the central renin-angiotensin system has an important role in mediating neuroinflammation174.”

What the sources say

• Not checked yetcites [174] de Kloet, A. D., Liu, M., Rodríguez, V., Krause, E. G. & Sumners, C. Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R444–R458 (2015). source

In the paper

“An impaired renorenal reflex in hypertension and CKD leads to augmented sympathetic excitation to the blood vessels, heart and kidney161.”

What the sources say

• Not checked yetcites [161] Afsar, B. et al. Brain-kidney cross-talk: definition and emerging evidence. Eur. J. Intern. Med. 36, 7–12 (2016). source

In the paper

“Such dys-regulation was associated with eGFR decline and CKD incidence in a population-based study183.”

What the sources say

• Not checked yetcites [183] Goek, O. N. et al. Metabolites associate with kidney function decline and incident chronic kidney disease in the general population. Nephrol. Dial. Transplant. 28, 2131–2138 (2013). source

In the paper

“Activation of Toll-like receptor 3 (TLR3) in peripheral monocytes facilitates production of the metabolite quinolinic acid185”

What the sources say

• Not checked yetcites [185] Orhan, F. et al. Tryptophan metabolism along the kynurenine pathway downstream of Toll-like receptor stimulation in peripheral monocytes. Scand. J. Immunol. 84, 262–271 (2016). source

In the paper

“Microbial metabolites including folate, butyrate and acetate are cofactors and allosteric regulators of epigenetic processes such as DNA methylation, histone acetylation and RNA interference190–192.”

What the sources say

• Not checked yetcites [190] Romano, K. A. et al. Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption. Cell Host Microbe 22, 279–290.e7 (2017). source
• Not checked yetcites [191] Savidge, T. C. Epigenetic regulation of enteric neurotransmission by gut bacteria. Front. Cell Neurosci. 9, 503 (2015).
• Not checked yetcites [192] Li, L., Ma, L. & Fu, P. Gut microbiota-derived short-chain fatty acids and kidney diseases. Drug Des. Devel Ther. 11, 3531–3542 S150825 (2017). source

In the paper

“Uraemic guanidino compounds with neuroexcitatory effects have been found in brain regions responsible for cognition (thalamus and mammillary bodies) in patients with CKD182”

What the sources say

• Not checked yetcites [182] De Deyn, P. P., Vanholder, R., Eloot, S. & Glorieux, G. Guanidino compounds as uremic (neuro)toxins. Semin. Dial 22, 340–345 (2009). source

In the paper

“In cross-sectional and longitudinal studies, each 10 ml/min/1.73 m2 reduction in estimated GFR (eGFR) below 60 ml/min/1.73 m2 was associated with an approximately 11% increase in the prevalence of cognitive impairment177,178.”

What the sources say

• Not checked yetcites [177] Kurella, M., Yaffe, K., Shlipak, M. G., Wenger, N. K. & Chertow, G. M. Chronic kidney disease and cognitive impairment in menopausal women. Am. J. Kidney Dis. 45, 66–76 (2005). source
• Not checked yetcites [178] Kurella Tamura, M. et al. Kidney function and cognitive impairment in US adults: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Am. J. Kidney Dis. 52, 227–234 (2008). source

In the paper

“The renorenal reflex is an inhibitory feedback loop that constitutes renal afferent nerves that convey signals to the CNS, governing sympathetic outflow163.”

What the sources say

• Not checked yetcites [163] Johns, E. J., Kopp, U. C. & DiBona, G. F. Neural control of renal function. Compr. Physiol. 1, 731–767 (2011). source

In the paper

“and reduced sympathetic nerve activity is associated with increased GABA input into the PVN176”

What the sources say

• Not checked yetcites [176] Nishihara, M., Takesue, K. & Hirooka, Y. Renal denervation enhances GABA-ergic input into the PVN leading to blood pressure lowering in chronic kidney disease. Auton. Neurosci. 204, 88–97 (2017). source

In the paper

“In DOCA-salt hypertensive mice, a high-fibre diet led to substantial reductions in both SBP and DBP (~20 mmHg)95.”

What the sources say

• Not checked yetcites [95] Marques, F. Z. et al. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation 135, 964–977 (2017). source

In the paper

“Epigenetic inheritance may explain much of the heritability of hypertension202.”

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

In the paper

“In a genome-wide DNA methylation study of human kidney tubules, several genes that are associated with kidney fibrosis were characterized by methylation changes and alterations of downstream transcript levels in CKD samples compared with controls197.”

What the sources say

• Not checked yetcites [197] Ko, Y. A. et al. Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development. Genome Biol. 14, R108 (2013). source

In the paper

“Consistent with our hypothesis, transplantation of bone marrow15,122, gut microbiota90 or kidney204 has been demonstrated to induce disorders not only in the organs of the proposed brain-gut-kidney axis but also in the interconnected pathways of this axis.”

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 [122] Hingorani, S., Guthrie, K. A., Schoch, G., Weiss, N. S. & McDonald, G. B. Chronic kidney disease in long-term survivors of hematopoietic cell transplant. Bone Marrow Transplant. 39, 223–229 (2007). source
• Not checked yetcites [90] Li, J. et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 5, 14 (2017). source

In the paper

“In a rat model of salt-sensitive hypertension, stimulation of sympathetic signalling led to reduced expression of a regulator of sodium reabsorption, protein kinase lysine-deficient 4 (WNK4), owing to hyper-acetylation of the promoter198.”

What the sources say

• Not checked yetcites [198] Mu, S. et al. Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat. Med. 17, 573–580 (2011). source

In the paper

“The chromatin accessibility of intestinal intraepithelial lymphocytes was quantitatively changed in germ-free mice colonized by conventional microbiota, resulting in determination of functional features ofhost immune cell lineages201.”

What the sources say

• Not checked yetcites [201] Semenkovich, N. P. et al. Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes. Proc. Natl Acad. Sci. USA 113, 14805–14810 (2016). source

In the paper

“Moreover, upregulation of angiotensin-converting enzyme 1 in SHR compared with WKY controls was associated with multiple epi-genetic modifications in several tissues, such as the adrenal gland, aorta, heart and kidney199.”

What the sources say

• Not checked yetcites [199] Lee, H. A. et al. Tissue-specific upregulation of angiotensin-converting enzyme 1 in spontaneously hypertensive rats through histone code modifications. Hypertension 59, 621–626 (2012). source

In the paper

“Moreover, beneficial effects of renal denervation, which targets sympathetic drive, have been reported in patients with resistant hypertension and CKD206,207.”

What the sources say

• Not checked yetcites [206] Hering, D. et al. Effect of renal denervation on kidney function in patients with chronic kidney disease. Int. J. Cardiol. 232, 93–97 (2017). source
• Not checked yetcites [207] Ott, C. et al. Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension. J. Hypertens. 33, 1261–1266 (2015). source

In the paper

“and notable changes in epigenetic modifications have been reported in hyper-tension and CKD85,195.”

What the sources say

• Not checked yetcites [85] Wise, I. A. & Charchar, F. J. Epigenetic modifications in essential hypertension. Int. J. Mol. Sci. 17, 451 (2016). source
• Not checked yetcites [195] Shiels, P. G., McGuinness, D., Eriksson, M., Kooman, J. P. & Stenvinkel, P. The role of epigenetics in renal ageing. Nat. Rev. Nephrol. 13, 471–482 (2017). source

In the paper

“Together, the available data suggest that epigenetic changes mediated by the gut microbiota are involved in the pathogenesis of dysbiosis-associated hypertension and CKD.”

What the sources say

• Not checked yetcites [190] Romano, K. A. et al. Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption. Cell Host Microbe 22, 279–290.e7 (2017). source
• Not checked yetcites [191] Savidge, T. C. Epigenetic regulation of enteric neurotransmission by gut bacteria. Front. Cell Neurosci. 9, 503 (2015).
• Not checked yetcites [192] Li, L., Ma, L. & Fu, P. Gut microbiota-derived short-chain fatty acids and kidney diseases. Drug Des. Devel Ther. 11, 3531–3542 S150825 (2017). source

In the paper

“These events culminate in the development of CKD and hypertension.”

In the paper

“indicating an epigenetic connection between the gut and the brain.”

What the sources say

• Not checked yetcites [200] Hoban, A. E. et al. Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. Microbiome 5, 102 (2017). source

In the paper

“In germ-free mice, colonization by gut microbiota normalized the deregulation of microRNA in the amygdala and prefrontal cortex of the brain200”

What the sources say

• Not checked yetcites [200] Hoban, A. E. et al. Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. Microbiome 5, 102 (2017). source

In the paper

“For example, podocyte-specific inactivation of Dicer, one of the enzymes responsible for production of microRNAs, results in proteinuria and glomerulosclerosis196.”

What the sources say

• Not checked yetcites [196] Shi, S. et al. Podocyte-selective deletion of dicer induces proteinuria and glomerulosclerosis. J. Am. Soc. Nephrol. 19, 2159–2169 (2008). source

In the paper

“Clinical studies have shown a moderate blood-pressure lowering effect of dietary fibre210,211.”

What the sources say

• Not checked yetcites [210] Jenkins, D. J. et al. Soluble fiber intake at a dose approved by the US Food and Drug Administration for a claim of health benefits: serum lipid risk factors for cardiovascular disease assessed in a randomized controlled crossover trial. Am. J. Clin. Nutr. 75, 834–839 (2002). source
• Not checked yetcites [211] Pins, J. J. et al. Do whole-grain oat cereals reduce the need for antihypertensive medications and improve blood pressure control? J. Fam. Pract. 51, 353–359 (2002).

In the paper

“In addition, activation of renal sympathetic nerve activity might directly influence renal physiology, altering body fluid balance and plasma metabolite secretion and retention.”

In the paper

“A meta-analysis of nine clinical trials with a total of 543 participants demonstrated that probiotic consumption modestly but significantly reduced both SBP (3.65 mmHg) and DBP (2.38 mmHg) in populations with baseline BP ≥135/85 mmHg98.”

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

In the paper

“Notably, the conclusions of the individual trials included in this meta-analysis were inconsistent, likely owing to substantial differences in participant numbers, baseline blood pressures, treatment durations and type and dose of probiotics.”

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

In the paper

“In contrast to Lactobacillus, the population of Enterobacteriaceae of the Proteobacteria phylum is expanded in CKD101,105.”

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
• Not checked yetcites [105] Wang, F. et al. Gut bacterial translocation is associated with microinflammation in end-stage renal disease patients. Nephrology 17, 733–738 (2012). source

In the paper

“A diet with high levels of resistant starch (a prebiotic) favourably altered the gut microbiota and caecal, serum and urine metabolite profiles in rats with adenine-induced CKD217.”

What the sources say

• Not checked yetcites [217] Kieffer, D. A. et al. Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats. Am. J. Physiol. Renal Physiol. 310, F857–F871 (2016). source

In the paper

“The risk of secondary infection may be lower with FFT than with FMT, as FFT does not involve the transfer of live bacteria226.”

What the sources say

• 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

In the paper

“Following successful treatment of C. difficile infection by FFT transplantation, the gut microbiota of a patient with loss of renal function resembled that of the faecal donor with remarkable elimination of Proteobacteria, which had dominated before FFT226.”

What the sources say

• 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

In the paper

“In particular, metabolites of the spermidine and kynurenine pathways are associated with the gut microbiota as well as the physiology of the host231,232.”

What the sources say

• Not checked yetcites [231] O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G. & Cryan, J. F. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav. Brain Res. 277, 32–48 (2015). source
• Not checked yetcites [232] Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018). source

In the paper

“In a case of patient with treatment-resistant hypertension, antibiotic therapy using a combination of vancomycin, rifampin and ciprofloxacin decreased SBP by ~70 mmHg in the absence of antihypertensive drugs99.”

What the sources say

• Not checked yetcites [99] Qi, Y., Aranda, J. M., Rodriguez, V., Raizada, M. K. & Pepine, C. J. Impact of antibiotics on arterial blood pressure in a patient with resistant hypertension — a case report. Int. J. Cardiol. 201, 157–158 (2015). source

In the paper

“Such beneficial effects of Lactobacillus could be the result of effects of this bacteria on the permeability and immune status of the gut epithelium.”

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

In the paper

“Administration of propionate has also been reported to modulate blood pressure in mice, likely via binding to the G protein-coupled receptor 41 (GPR41) and olfactory receptor 78 (OLFR78; also known as OR51E2)93,94.”

What the sources say

• Not checked yetcites [93] Pluznick, J. L. et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc. Natl Acad. Sci. USA 110, 4410–4415 (2013). source
• Not checked yetcites [94] Natarajan, N. et al. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41. Physiol. Genom. 48, 826–834 (2016). source

In the paper

“For example, antibiotic treatment of Escherichia coli O157:H7 infection increases the risk of haemolytic uraemic syndrome221.”

What the sources say

• Not checked yetcites [221] Smith, K. E. et al. Antibiotic treatment of Escherichia coli O157 infection and the risk of hemolytic uremic syndrome, Minnesota. Pediatr. Infect. Dis. J. 31, 37–41 (2012). source

In the paper

“In addition, numerous plasma metabolites have been associated with longitudinal eGFR183 or cross-sectional eGFR decline230 in the general population.”

What the sources say

• Not checked yetcites [183] Goek, O. N. et al. Metabolites associate with kidney function decline and incident chronic kidney disease in the general population. Nephrol. Dial. Transplant. 28, 2131–2138 (2013). source
• Not checked yetcites [230] Goek, O. N. et al. Serum metabolite concentrations and decreased GFR in the general population. Am. J. Kidney Dis. 60, 197–206 (2012). source

In the paper

“A meta-analysis of 14 controlled feeding trials involving 143 participants with CKD showed that supplementation of dietary fibre intake significantly reduced serum levels of uraemic toxins, urea and creatinine212.”

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

In the paper

“As the abundance of Lactobacillus is decreased in CKD101,106”

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
• Not checked yetcites [106] Kikuchi, M., Ueno, M., Itoh, Y., Suda, W. & Hattori, M. Uremic toxin-producing gut microbiota in rats with chronic kidney disease. Nephron 135, 51–60 (2017). source

In the paper

“The spherical carbon adsorbent AST-120 absorbs indole produced in the intestine and thereby reduces serum and urinary levels of indoxyl sulfate228.”

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