The Influence of Prebiotic Arabinoxylan Oligosaccharides on Microbiota Derived Uremic Retention Solutes in Patients with Chronic Kidney Disease: A Randomized Controlled Trial

Ruben Poesen, Pieter Evenepoel, Henriette de Loor, Jan A Delcour, Christophe M Courtin, Dirk Kuypers, Patrick Augustijns, Kristin Verbeke, Björn Meijers, Ruben Poesen, Pieter Evenepoel, Henriette de Loor, Jan A Delcour, Christophe M Courtin, Dirk Kuypers, Patrick Augustijns, Kristin Verbeke, Björn Meijers

Abstract

The colonic microbial metabolism is a key contributor to uremic retention solutes accumulating in patients with CKD, relating to adverse outcomes and insulin resistance. Whether prebiotics can reduce intestinal generation of these microbial metabolites and improve insulin resistance in CKD patients not yet on dialysis remains unknown. We performed a randomized, placebo-controlled, double-blind, cross-over study in 40 patients with eGFR between 15 and 45 ml/min/1.73 m2. Patients were randomized to sequential treatment with prebiotic arabinoxylan oligosaccharides (AXOS) (10 g twice daily) and maltodextrin for 4 weeks, or vice versa, with a 4-week wash-out period between both intervention periods. Serum levels and 24h urinary excretion of p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate, trimethylamine N-oxide and phenylacetylglutamine were determined at each time point using liquid chromatography-tandem mass spectrometry. In addition, insulin resistance was estimated by the homeostatic model assessment (HOMA-IR). A total of 39 patients completed the study. We observed no significant effect of AXOS on serum p-cresyl sulfate (P 0.42), p-cresyl glucuronide (P 0.59), indoxyl sulfate (P 0.70) and phenylacetylglutamine (P 0.41) and a small, albeit significant decreasing effect on serum trimethylamine N-oxide (P 0.04). There were neither effect of AXOS on 24h urinary excretion of p-cresyl sulfate (P 0.31), p-cresyl glucuronide (P 0.23), indoxyl sulfate (P 0.87) and phenylacetylglutamine (P 0.43), nor on 24h urinary excretion of trimethylamine N-oxide (P 0.97). In addition, we observed no significant change in HOMA-IR (P 0.93). In conclusion, we could not demonstrate an influence of prebiotic AXOS on microbiota derived uremic retention solutes and insulin resistance in patients with CKD not yet on dialysis. Further study is necessary to elucidate whether prebiotic therapy with other characteristics, higher cumulative exposure or in different patient populations may be of benefit.

Trial registration: Clinicaltrials.gov NCT02141815.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. CONSORT flow diagram.
Fig 1. CONSORT flow diagram.
Fig 2. Study design.
Fig 2. Study design.
Schematic representation of the study design. AXOS, arabinoxylan oligosaccharides; BID, twice a day.
Fig 3. Serum levels of microbial metabolites…
Fig 3. Serum levels of microbial metabolites during treatment with arabinoxylan oligosaccharides (AXOS).
Evolution of serum urea (A), p-cresyl sulfate (B), p-cresyl glucuronide (C), indoxyl sulfate (D), trimethylamine N-oxide (E) and phenylacetylglutamine (F) during treatment with AXOS.

References

    1. Meijers B, Glorieux G, Poesen R, Bakker SJ. Nonextracorporeal methods for decreasing uremic solute concentration: a future way to go? Semin Nephrol 2014. March;34(2):228–43. 10.1016/j.semnephrol.2014.02.012
    1. Meyer TW, Hostetter TH. Uremia. N Engl J Med 2007. September 27;357(13):1316–25.
    1. Aronov PA, Luo FJ, Plummer NS, Quan Z, Holmes S, Hostetter TH, et al. Colonic contribution to uremic solutes. J Am Soc Nephrol 2011. September;22(9):1769–76. 10.1681/ASN.2010121220
    1. Meyer TW, Hostetter TH. Uremic solutes from colon microbes. Kidney Int 2012. May;81(10):949–54. 10.1038/ki.2011.504
    1. Bammens B, Evenepoel P, Keuleers H, Verbeke K, Vanrenterghem Y. Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients. Kidney Int 2006. March;69(6):1081–7.
    1. Liabeuf S, Barreto DV, Barreto FC, Meert N, Glorieux G, Schepers E, et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant 2010. April;25(4):1183–91. 10.1093/ndt/gfp592
    1. Meijers BK, Bammens B, De Moor B, Verbeke K, Vanrenterghem Y, Evenepoel P. Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney Int 2008. May;73(10):1174–80. 10.1038/ki.2008.31
    1. Meijers BK, Claes K, Bammens B, de Loor H, Viaene L, Verbeke K, et al. p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin J Am Soc Nephrol 2010. July;5(7):1182–9. 10.2215/CJN.07971109
    1. Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M, et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 2009. October;4(10):1551–8. 10.2215/CJN.03980609
    1. Wu IW, Hsu KH, Lee CC, Sun CY, Hsu HJ, Tsai CJ, et al. p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol Dial Transplant 2011. March;26(3):938–47. 10.1093/ndt/gfq580
    1. Meert N, Schepers E, Glorieux G, Van LM, Goeman JL, Waterloos MA, et al. Novel method for simultaneous determination of p-cresylsulphate and p-cresylglucuronide: clinical data and pathophysiological implications. Nephrol Dial Transplant 2012. June;27(6):2388–96. 10.1093/ndt/gfr672
    1. Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 2015. January 30;116(3):448–55. 10.1161/CIRCRESAHA.116.305360
    1. Stubbs JR, House JA, Ocque AJ, Zhang S, Johnson C, Kimber C, et al. Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden. J Am Soc Nephrol 2015. [Epub ahead of print].
    1. Shafi T, Meyer TW, Hostetter TH, Melamed ML, Parekh RS, Hwang S, et al. Free Levels of Selected Organic Solutes and Cardiovascular Morbidity and Mortality in Hemodialysis Patients: Results from the Retained Organic Solutes and Clinical Outcomes (ROSCO) Investigators. PLoS One 2015;10(5):e0126048 10.1371/journal.pone.0126048
    1. Poesen R, Meijers B, Evenepoel P. The Colon: An Overlooked Site for Therapeutics in Dialysis Patients. Semin Dial 2013. March 4;26:323–32. 10.1111/sdi.12082
    1. Roberfroid M, Gibson GR, Hoyles L, McCartney AL, Rastall R, Rowland I, et al. Prebiotic effects: metabolic and health benefits. Br J Nutr 2010. August;104 Suppl 2:S1–63. 10.1017/S0007114510003363
    1. Meijers BK, De Preter V, Verbeke K, Vanrenterghem Y, Evenepoel P. p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin. Nephrol Dial Transplant 2010. January;25(1):219–24. 10.1093/ndt/gfp414
    1. Sirich TL, Plummer NS, Gardner CD, Hostetter TH, Meyer TW. Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients. Clin J Am Soc Nephrol 2014. September 5;9(9):1603–10. 10.2215/CJN.00490114
    1. Koppe L, Pillon NJ, Vella RE, Croze ML, Pelletier CC, Chambert S, et al. p-Cresyl sulfate promotes insulin resistance associated with CKD. J Am Soc Nephrol 2013. January;24(1):88–99. 10.1681/ASN.2012050503
    1. Broekaert WF, Courtin CM, Verbeke K, Van de Wiele T, Verstraete W, Delcour JA. Prebiotic and other health-related effects of cereal-derived arabinoxylans, arabinoxylan-oligosaccharides, and xylooligosaccharides. Crit Rev Food Sci Nutr 2011. February;51(2):178–94. 10.1080/10408390903044768
    1. Cloetens L, Broekaert WF, Delaedt Y, Ollevier F, Courtin CM, Delcour JA, et al. Tolerance of arabinoxylan-oligosaccharides and their prebiotic activity in healthy subjects: a randomised, placebo-controlled cross-over study. Br J Nutr 2010. March;103(5):703–13. 10.1017/S0007114509992248
    1. Damen B, Cloetens L, Broekaert WF, Francois I, Lescroart O, Trogh I, et al. Consumption of breads containing in situ-produced arabinoxylan oligosaccharides alters gastrointestinal effects in healthy volunteers. J Nutr 2012. March;142(3):470–7. 10.3945/jn.111.146464
    1. Francois IE, Lescroart O, Veraverbeke WS, Marzorati M, Possemiers S, Evenepoel P, et al. Effects of a wheat bran extract containing arabinoxylan oligosaccharides on gastrointestinal health parameters in healthy adult human volunteers: a double-blind, randomised, placebo-controlled, cross-over trial. Br J Nutr 2012. February 28;1–14.
    1. Francois IE, Lescroart O, Veraverbeke WS, Marzorati M, Possemiers S, Hamer H, et al. Effects of wheat bran extract containing arabinoxylan oligosaccharides on gastrointestinal parameters in healthy preadolescent children. J Pediatr Gastroenterol Nutr 2014. May;58(5):647–53. 10.1097/MPG.0000000000000285
    1. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006. August 15;145(4):247–54.
    1. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985. July;28(7):412–9.
    1. Salmean YA, Segal MS, Palii SP, Dahl WJ. Fiber Supplementation Lowers Plasma p-Cresol in Chronic Kidney Disease Patients. J Ren Nutr 2014. November 5;25:316–20. 10.1053/j.jrn.2014.09.002
    1. Poesen R, Windey K, Neven E, Kuypers D, De Preter V, Augustijns P, et al. The Influence of CKD on Colonic Microbial Metabolism. J Am Soc Nephrol 2015. [Epub ahead of print].

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa