Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S, Bengmark S, Neuhaus P. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation- a randomized, double-blind trial. Am J Transplant 2005;5:125-130. (Reprinted with permission from Blackwell Publishing Ltd.: www.blackwell-synergy.com).
Bacterial infections frequently occur early after liver transplantation. We recently reported significant progress with a synbiotic composition, consisting of one lactic acid bacteria (LAB) and one fiber, which reduced the infection rate from 48% (with selective bowel decontamination) to 13%. Now, our aim is to study if a combination of different LAB and fibers would further improve outcome. A prospective randomized double-blind trial was undertaken in 66 liver transplant recipients. All patients received enteral nutrition immediately post-operatively. Comparison was made between one group (A) receiving a composition of four LAB and four fibers and another group (B) receiving the fibers only. The treatment started the day before surgery and continued for 14 days. Thirty-day infection rate, length of hospital stay, duration of antibiotic therapy, non-infectious complications and side effects of enteral nutrition were recorded. The incidence of post-operative bacterial infections was significantly reduced; being 48% with only fibers and 3% with LAB and fibers. In addition, the duration of antibiotic therapy was significantly shorter in the latter group. In both groups, mainly mild or moderate infections occurred. Fibers and LAB were well tolerated. Early enteral nutrition supplemented with a mixture of LAB and fibers reduces bacterial infection rates following liver transplantation. Treatment with only fibers led to a low incidence of severe infections.
The study of probiotics, nonpathogenic beneficial bacteria, in basic and clinical investigation is growing. Different classes and species of probiotics (Table 1) are now being investigated in a number of gastrointestinal disorders, including inflammatory bowel disease, pouchitis, traveler's diarrhea, C. difficile infection, and irritable bowel syndrome. Prebiotics, dietary elements such as lactosucrose, fructo-oligosaccharides, inulin, bran, psyllium, and germinated barley extracts, enhance the growth of protective lactic acid bacteria and the production of essential short chain fatty acids.1 Prebiotics are administered alone or in combination with probiotics (synbiotics) to enhance various aspects of intestinal function.
|Lactic Acid Bacteria|
|Lactococci||Lactococcus lactis||Lactic acid|
|Lactobacillus casei||Lactic acid + small amounts of CO2|
|Lactobacillus bifermentans||Lactic acid, ethanol, CO2|
|Bifidobacteria||Bifidobacterium breve||Lactic acid, acetic acid|
|Other Lactic Acid Bacteria||Enterococcus faecium SF68||Lactic acid|
|Leuconostoc mesenteroides||Lactic acid, ethanol, CO2|
|Other bacteria (Gram-positive)||Streptococcus thermophilus||Lactic acid|
|Clostridium butyricum||Lactic acid, acetic acid, butyric acid|
|Other bacteria (Gram-negative)||Escherichia coli Nissle 1917||Lactic acid, acetic acid, formic acid, ethanol, CO2|
|Yeast||Saccharomyces (cerevisiae subsp.) boulardii||Ethanol, CO2|
In experimental studies, probiotics affect the gastrointestinal tract via a wide range of mechanisms that reduce intestinal inflammation and the negative effects of enteric bacteria. First, probiotics shift the balance of intestinal flora toward beneficial, noninvasive bacteria. They colonize the intestinal tract, form bacteriocidal short chain organic acids, and alter the glycosylation, adherence, and invasion of pathogenic bacteria.2 Probiotics also downregulate cascades involved in intestinal inflammation. They compete with enteric pathogens by interacting with gut epithelial Toll-like receptors involved in immunoregulation and promoting a counter anti-inflammatory response.3, 4 Reduction of intestinal proinflammatory cytokines (TNF-α, IL-8) and stimulation of IgA and anti-inflammatory cytokine (IL-10, TGF-β) production occur after probiotic administration.4–6 Experimental colitis in IL-10 gene-deficient mice is attenuated by lactobacillus administration.7, 8 Finally, probiotics stabilize the gut epithelial barrier to protect the internal milieu from luminal environmental and bacterial toxins. They stimulate mucus production, reinforce tight junctions and the epithelial cytoskeleton, and promote epithelial regeneration over apoptosis.9–13 Maintenance of the intestinal barrier and immune function is critical in preventing translocation of bacteria and/or toxins across the gut lumen to blood, mesenteric lymph nodes, and other sites.
It is well defined that cirrhosis is associated with gut bacterial overgrowth, impaired intestinal motility, and increased permeability, all of which facilitate bacterial translocation. Animal models of cirrhosis have illustrated this phenomenon.14 Similarly, in clinical studies, patients with ascites and encephalopathy have significantly altered intestinal permeability compared to those without these complications.15–18 Bacterial translocation can stimulate a cascade of inflammatory cytokine and endotoxin production and lead to severe clinical consequences, e.g., exacerbation of the hyperdynamic circulatory state, spontaneous bacterial peritonitis, hepatic encephalopathy, and renal dysfunction.19 Agents, such as probiotics and fiber, directed at reducing pathogenic bacterial overgrowth and improving the intestinal mucosal barrier might lead to a lower incidence of these potentially life-threatening complications. In fact, minimal and overt hepatic encephalopathy improve with administration of either synbiotic (prebiotic and probiotic) or fiber (prebiotic) alone.20–24 Probiotics have also been shown to improve the Child-Pugh score and decrease levels of ammonia, endotoxin, inflammatory cytokines, and oxidative/nitrosative stress parameters.20, 25 The basic mechanisms of probiotics and fiber on gut function and permeability in patients with liver disease have not been elucidated.
It is therefore not surprising that bacterial infections are the most common cause of morbidity and mortality immediately after liver transplantation (LT). Major abdominal surgery such as LT in a malnourished patient with cirrhosis and with baseline impaired intestinal function can lead to further perturbations in intestinal permeability due to volume and blood pressure shifts and clamping of the portal vein. Furthermore, calcineurin inhibitors administered after LT also impair intestinal permeability. In experimental work, tacrolimus alters intestinal cell uptake of glucose, decreases mitochondrial activity, and significantly increases intestinal permeability.26 Similarly, in clinical studies, tacrolimus inhibits cellular energy production, leading to increased intestinal permeability and endotoxemia.27 Fortunately, the effects of calcineurin inhibitors on energy production and gut permeability appear to be limited to the immediate posttransplant timeframe.28 However, maintenance of the intestinal barrier immediately after LT would likely lead to a lower incidence of bacterial translocation and prevention of systemic infections.
To investigate the effect of probiotics and fiber on infections complications immediately after LT, Rayes et al. performed a randomized, double blind trial of synbiotic (probiotic + fiber) compared to fiber alone in 66 recipients.29 Surveillance cultures were performed from urine, blood, bile (t-tube), wounds and drainage catheters three times per week and when infection was clinically suspected. Bacterial infections were defined when all of the following criteria were met: fever >38°C, elevation of C-reactive protein, clinical symptoms of infection, and positive culture. Oral administration of four different lactic acid bacteria (Pediacoccus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei, Lactobacillus plantarum) and four fibers (betaglucan, inulin, pectin, resistant starch) for the first 14 postoperative days was associated with a significant reduction in bacterial infections (3%) at day 30 compared to fibers alone (48%). A significantly shorter duration of antibiotic therapy was required in the synbiotic group. Gastrointestinal side effects, length of hospital stay, complications, and mortality were not significantly different between the groups.
While the reduction in infections is significant, aspects of the study are in question. First, most of the infections were from the urinary tract and uncomplicated. No differences in intensive care unit and hospital stays and other morbidity or mortality were seen as a result of these infections. In addition, the inverse relationship between enteral administration of probiotics and the development of urinary infections does not have biological plausibility. This requires further investigation into other potential variables that may have led to this association. Second, while not statistically significant, more patients (n = 12) in the synbiotic arm had noninfectious complications than those (n = 4) in the fiber alone group. Whether differences in immunosuppressive regimens between the groups played a role in this is unclear. Third, the trial was not placebo-controlled nor did it have a probiotic-only arm. While it is clear that fiber was ineffective compared to synbiotic in this trial, it is uncertain if probiotics are beneficial alone or require the synergistic effect of fiber. Finally, potential physiological mechanisms of probiotics and fiber were not analyzed in this study. Measurements of serum cytokine and endotoxin levels, intestinal permeability, and change in fecal content from pathogens to healthy flora would have provided further supportive evidence for synbiotic therapy.
Despite these shortcomings, the significant reduction in bacterial infections with synbiotics after LT is compelling. A previous study by Rayes also found fewer post-LT bacterial infections in patients given a fiber formula plus living Lactobacillus plantarum 299 compared to those given fiber formula plus killed Lactobacillus or standard formula plus selective bowel decontamination.30 While the length of intensive care unit and hospital stays, morbidity and mortality were not different, clinically significant infections, such as cholangitis and pneumonia, were reduced in the Lactobacillus group. In both Rayes' studies, lactic acid bacteria were chosen because of their ability to survive the gastrointestinal tract, stimulate mucosal growth, increase immunoglobulin production, and decrease intestinal permeability.31, 32 While speculative, maintenance of the intestinal barrier with synbiotic therapy is likely responsible for the clinical improvement in patients with cirrhosis and the reduction in bacterial complications after LT.
While promising preliminary data exist, there are concerns regarding the use of probiotics in immunocompromised patients. In critically ill patients, probiotics do not have significant effects on the intestinal microflora or permeability and are typically ineffective in preventing morbidity or mortality.33 Critically ill transplant recipients, in particular, would likely gain little from probiotic administration. In addition, while rare and not described in either of Rayes' studies, sepsis attributed to probiotic bacteria, such as Lactobacillus and Saccharomyces cerevisiae, has been reported.34, 35 In fact, recent discussions and editorials have highlighted the concerns of probiotic use, particularly in critically ill or immunocompromised individuals. These include the potential for sepsis, the variability of different preparations, and the possibility of transmission of antimicrobial resistance from probiotic bacteria to enteric pathogens.36, 37
Further lines of investigation are required before prebiotics, probiotics, and synbiotics are used in clinical practice in the post-LT setting. First, the specific physiological mechanisms of action of these preparations on gut function after LT should be elucidated in experimental and clinical studies. This would involve quantitative measures of intestinal permeability, pro- and anti-inflammatory markers, and intestinal flora alterations before and after administration of these agents. Next, the safety of probiotic regimens in transplant recipients needs to be carefully examined. Are there issues of contamination, antimicrobial resistance, and significant variability among different preparations? Finally, the study by Rayes et al. highlights the need for further trials investigating the reduction in bacterial infections after LT with probiotic and fiber therapy. Such trials should be placebo-controlled and have adequate power to determine differences in complications, morbidity, and mortality associated with probiotic use. The future of probiotic use in LT requires a stepwise, careful approach to understand basic mechanisms and ensure safety — the risk/benefit ratio is the critical issue.
The author would like to acknowledge Ger Bongaerts, M.Sc., Ph.D. in the Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands for his assistance in preparing the probiotic classification table.