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NDT Advance Access originally published online on June 8, 2006
Nephrology Dialysis Transplantation 2006 21(8):2057-2060; doi:10.1093/ndt/gfl281
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorial Comment

Intestinal bacterial microflora—a potential source of chronic inflammation in patients with chronic kidney disease

Peter Kotanko, Mary Carter and Nathan W. Levin

Renal Research Institute, New York, NY, USA

Correspondence and offprint requests to: Nathan W. Levin, Renal Research Institute, 207 East 94th Street, Suite 303, New York, NY 10128, USA. Email: nlevin{at}rriny.com

Keywords: bacterial translocation; chronic inflammation; chronic kidney disease; gut; intestinal microflora



   Introduction
Top
 Introduction
Bacterial translocation
 Intestinal microflora,...
 Strategies to decrease...
 Conclusion
 References
 
Inflammation is prevalent in a large proportion of dialysis patients, irrespective of the dialysis modality used. Central catheters, periodontal disease, exposure to endotoxins from non-ultrapure water dialysis and persistent chronic infections are well-established causes of chronic inflammation, but many infections go unrecognized [1].

Despite the fact that 10–100 trillion microorganisms populate the intestine in adult humans, the gastrointestinal tract has received little attention as a possible source contributing to the chronic inflammation noted in dialysis patients.

The mucosal surface is the physical interface of the immune system with the outside world, encompassing an extensive surface area of 300–400 m2, which constitutes the largest body interface between the host and microorganisms. The intestinal barrier is composed of different domains [2], the ecological barrier (the normal intestinal microflora), the mechanical barrier (single layer of polarized intestinal epithelial cells, the enterocytes, covered by mucus) and the immune barrier [secreted immunoglobulin A (IgA), immune cells including intraepithelial lymphocytes and macrophages, neutrophils, natural killer cells, Peyer's plaques and mesenteric lymph nodes]. The gut also harbours the largest and most diverse ecosystem of microbes in the human body, consisting of more than 400 species of bacteria. The bacterial diversity within the human colon is greater than previously thought [3]. Absolute bacterial counts vary along the length of the bowel, increasing from a concentration of ~108 organisms/ml intestinal fluid in the distal ileum to ~1012 organisms/ml beyond the ileocecal valve. A rapid rate of enterocyte turnover helps to maintain the integrity of the intestinal barrier [4].

Commensal microorganisms play a crucial role in maintaining physiological bacterial–host interactions at the intestinal surface.



   Bacterial translocation
Top
 Introduction
 Bacterial translocation
Intestinal microflora,...
 Strategies to decrease...
 Conclusion
 References
 
‘Bacterial translocation’ describes the passage of viable resident bacteria and of macro-molecules such as lipopolysaccharide endotoxin across the intestinal barrier to the blood. There are two pathways for the passage of substances from the intestinal lumen to the blood, a paracellular and a transcellular route. Specific membrane pumps and channels govern the transcellular transport, whereas tight junctions control the paracellular pathway [5].

Numerous insults, such as infections, both in the intestinal tract and in other sites (such as pneumonia), inflammatory bowel disease, parenteral nutrition, malnutrition, surgical stress, burns, shock, obstructive jaundice, thermal injury, stress, circulatory compromise, congestion in heart failure and hypoxia, bacterial overgrowth and reduced intestinal motility may be causative of impaired intestinal barrier function [2]. Endotoxin concentrations were shown to be higher in oedematous than in stable congestive heart failure (CHF) patients. Gut-derived endotoxin may trigger immune activation and inflammatory responses in CHF patients during oedematous episodes [6].

Pathogens impair the integrity of the intestinal barrier with a number of different virulence factors. Escherichia coli, Salmonella typhimurium, Clostridium perfringens, Bacteroides fragilis, Vibrio cholerae and rotavirus directly disrupt tight-junction proteins [5]. Transcellular migration of E. coli and Proteus mirabilis have been visualized within intact enterocytes [7]. Host factors have an effect on bacterial proliferation and mucosal adhesion. Stress mediators such as norepinephrine and adrenocorticotropic hormone have been shown to directly enhance the virulence characteristics and adherence of enterohaemorrhagic E. coli to the colonic mucosa [8,9]. It is conceivable that sympathetic overactivity, as observed in uraemia, may also alter intestinal susceptibility to bacterial translocation.

The cellular processes underlying bacterial translocation have been studied in the rat common bile duct ligation model. In this model xanthine oxidase (XO) is activated presumably by translocated bacterial products and XO-derived reactive oxygen species (ROS) are significantly increased. Inhibition or inactivation of XO by allopurinol or by a tungsten-supplemented diet normalized the mucosal ROS and attenuated bacterial translocation significantly [10]. ROS activate nuclear factor kappa B (NFkB) and the expression of genes encoding cytokines such as tumour necrosis factor-{alpha} (TNF{alpha}), interleukin-2 (IL2), IL8, intercellular adhesion molecule-1 (ICAM-1), and others. Some of these cytokines may promote a disruption of tight junctions and facilitate bacterial translocation [11].



   Intestinal microflora, intestinal barrier function and bacterial translocation in uraemia
Top
 Introduction
 Bacterial translocation
 Intestinal microflora,...
Strategies to decrease...
 Conclusion
 References
 
In uraemia, greatly increased concentrations of urea, creatinine and other nitrogenous metabolites reach the gut and become subject to microbial metabolism. Uraemic patients show greatly increased counts of both aerobic (~106 bacteria/ml) and anaerobic (~107 bacteria/ml) organisms in the duodenum and the jejunum, sites with very low or no intestinal bacterial counts in healthy subjects [12]. Intestinal bacteria are involved in the generation of uraemic toxins such as indoxyl sulphate and p-cresol, and the latter has recently been linked with mortality in dialysis patients [13].

There is evidence of impaired intestinal barrier function in uraemia. Magnusson et al. reported an increased intestinal permeability to differently sized polyethylene glycols (range 326–1254 Da) in uraemic rats [14] and chronic kidney disease (CKD) patients [15]. Constipation, a frequent problem in uraemic patients [16], promotes bacterial overgrowth, which in turn may increase intestinal barrier permeability and promote bacterial translocation. Bacterial translocation was recently reported in a rat 5/6 nephrectomy model [17]. In this study, bacterial translocation occurred at day 60 in 8/20 uraemic animals as compared with 1/20 controls (P = 0.02). Translocation in uraemic rats was observed in samples of the mesenteric lymph nodes (all eight cases) and of blood (two cases). No data are available on bacterial translocation in CKD patients. As mentioned earlier, the constant and rapid renewal of the epithelial lining of the digestive tract is essential to maintain the integrity of the intestinal barrier and the small intestinal epithelial lining is normally replaced every 3–6 days in humans [4]. Malnutrition impairs enterocyte turnover and may thus contribute to the breakdown of the intestinal barrier function.

Oral iron—a potential stimulus for intestinal bacterial growth
Iron is an important growth factor for bacteria (Table 1), and many bacteria produce siderophores to attract iron away from the host iron-binding proteins transferrin and lactoferrin [18]. Mammals lack a regulated means to excrete iron, and therefore dietary iron content and intestinal iron absorption defines iron stores. Individuals with iron overload, whether induced by excess dietary iron intake or due to diseases, such as ß-thalassaemia major, haemochromatosis and sickle cell disease, are more susceptible to infection [19,20]. While oral iron supplementation has been shown clearly to be disadvantageous in certain settings such as in malarious regions [21], it is not clear whether oral iron supplementation increases the susceptibility of dialysis patients to infection. Interestingly, intestinal iron deposition is a frequent finding in uraemia, presumably because of reduced iron uptake [16]. Intravenous (i.v.) iron in haemodialysis patients is associated with an increased risk of infection [22]. Intravenous iron undergoes biliary secretion and may contribute to the intestinal iron load [23]. In chronically inflamed patients, intestinal iron uptake is blocked via the hepcidin pathway. The decrease in plasma iron levels during inflammation is a protective response of the body to combat the infection and to limit oxidative damage. As hepcidin is an acute-phase protein, it sequesters the body's iron stores and prevents this iron from being requisitioned by bacteria [24]. When oral iron is given to an inflamed subject, e.g. a dialysis patient, the amount of iron accessible to intestinal bacteria increases. It is tempting to speculate that increased iron availability stimulates the proliferation of intestinal bacteria and increases the production of gut-derived uraemic toxins and bacterial translocation. Moreover, unabsorbed iron may act as a catalyst in the production of hydroxyl radicals [25]. Reducing intestinal iron availability in inflamed patients may therefore be beneficial. Iron-binding tannins in tea, phytic acid in bran and synthetic oral iron chelators such as deferiprone reduce the intestinal free-iron concentration.


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  		Table 1. Bacteria that require iron for growth and whose virulence is enhanced by excess iron (adapted from [20])

 


   Strategies to decrease intestinal permeability and bacterial translocation
Top
 Introduction
 Bacterial translocation
 Intestinal microflora,...
 Strategies to decrease...
Conclusion
 References
 
Nutrients protecting the gastrointestinal tract and maintaining the integrity of the intestinal barrier have received great attention in recent years [26]. Glutamine, arginine, zinc, vitamin A, probiotics (live microorganisms in fermented foods that establish and improve the intestinal microflora) and prebiotics (non-digestible food ingredients, that beneficially affect the host by selectively stimulating the growth and activity of a limited number of bacteria in the colon) have been tested in multiple trials. Although many of these trials have been criticized on methodological grounds [26], current evidence points towards a beneficial effect of these interventions on intestinal barrier function. In a prospective trial on patients with CHF, intensified diuretic treatment reduced intestinal congestion and normalized endotoxin concentrations [6]. No interventional trial on gut permeability is available in humans with impaired renal function. In 5/6 nephrectomized rats, probiotics treatment improved azotaemia [27]. Studies are limited by the tools available to follow changes of intestinal microflora dynamically. New technologies, such as analysis of volatile organic compounds by selected ion flow tube mass spectrometry (SIFT-MS) [28] and molecular biology [3] approaches may prove to be particularly useful in studying the intestinal microbiology in uraemic patients.



   Conclusion
Top
 Introduction
 Bacterial translocation
 Intestinal microflora,...
 Strategies to decrease...
 Conclusion
References
 
Intestinal bacteria contribute to the uraemic syndrome by the production of uraemic toxins. Additional evidence suggests that translocation of bacteria and endotoxins from the gut to the blood takes place in kidney failure. Consequently, it is plausible to assume that the gut contributes to the chronic inflammatory state in dialysis patients. The availability of iron in the intestinal lumen may increase growth and virulence of intestinal bacteria and affect the intestinal barrier adversely. Oral iron chelation may be beneficial in reducing the intestinal iron load. Basic research and clinical studies are needed to further define the significance of intestinal bacteria and their products in uraemia. Interventions aimed at restoring and maintaining the physiological intestinal microflora in dialysis patients should be tested rigorously in clinical trials.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Bacterial translocation
 Intestinal microflora,...
 Strategies to decrease...
 Conclusion
 References
 

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Received for publication: 25. 4.06
Accepted in revised form: 25. 4.06


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