Alterations in the gut microbiota and host responses have been implicated in the progression of end-stage renal disease, increased cardiovascular risk, uremic toxicity, and inflammation. The purpose of this study was to evaluate the clinical efficacy of probiotics on malnutrition and health-related quality of life in patients undergoing peritoneal dialysis (PD).
Design and Methods
A total of 116 patients undergoing PD were randomly divided into an intervention group (n = 58) and a control group (n = 58). The intervention group received a daily dose of probiotics (1 × 109 CFU/day, i.e., 2 capsules, tid) for 2 months, while the control group did not receive probiotics during the same period. Biochemical indicators, physical measurements, and scores on the SF-36 were measured before and 2 months after the intervention.
A total of 98 patients completed the study (50 in the intervention group and 48 in the control group). Among patients receiving probiotics, the levels of high-sensitivity C-reactive protein and interleukin-6 decreased after 2 months of treatment, while the serum albumin levels, upper arm circumference, and triceps skinfold thickness increased significantly. The probiotic group had higher scores on the physical functioning and social functioning domains than the control group after 2 months.
Probiotics could significantly decrease the serum levels of high-sensitivity C-reactive protein and interleukin-6 and increase the serum albumin levels, upper arm circumference, and triceps skinfold thickness in patients undergoing PD. As a result, malnutrition and health-related quality of life partially improved after probiotic supplementation in patients undergoing PD.
and the number of patients with end-stage renal disease is expected to increase by nearly 60% in 2020.
Peritoneal dialysis (PD) is an important treatment method for end-stage renal disease. Data from the Chinese Research Data Services show that approximately 86,000 uremic patients have undergone PD in China through 2017. However, patients undergoing PD often suffer complications such as peritonitis and malnutrition. Moreover, their quality of life (QOL) is poorer than that of the general population.
In patients with stage 3–4 CKD, p-cresyl sulfate and indoxyl are associated with increased levels of inflammatory markers, such as glutathione peroxidase and interleukin-6 (IL-6).
Recent studies have shown that probiotics improve epithelial barrier function in various clinical settings.
In patients undergoing hemodialysis (HD), inhibition of the production of precursors of uremic toxins is an effective way to reduce the accumulation of these toxins. Probiotic treatment is effective in improving the intestinal environment and reducing the production of uremic toxins in patients undergoing HD.
Another study suggested that probiotic dietary supplements were more effective than placebo in reducing blood urea nitrogen and improving the QOL of patients with stage 3 or 4 CKD.
In addition, the potential beneficial metabolic effects of probiotics have been demonstrated in the context of uremia.
Although there are several studies on the effects of probiotics in patients undergoing PD,
data on whether probiotics improve the QOL of patients undergoing PD have not been reported. Therefore, we hypothesized that the administration of a multispecies probiotic over 2 months would help reduce malnutrition and improve QOL in patients undergoing PD. To test this hypothesis, we designed and conducted this randomized open trial testing the effects of probiotics among patients undergoing PD.
Patients and Study Design
Between March 2017 and February 2018, patients aged between 18 and 75 years who are undergoing PD at the outpatient clinic were eligible to participate in the study if none of the following conditions were met: PD duration ≤3 months, advanced malignant disease, a history of drug or alcohol abuse, intolerance to probiotic supplements, more than 2 episodes of peritonitis within the last year, active infectious disease, or uncontrolled autoimmune disease such as systemic lupus erythematosus. This study was conducted according to the principles of the Declaration of Helsinki of the World Medical Association and was approved by the ethics committee. All participants were informed of the research purposes and provided written informed consent for the collection and use of their serum and clinical data.
After providing written informed consent, eligible patients undergoing PD were randomized in a 1:1 ratio to one of two parallel groups (Randomization assignment was conducted using computer-generated random numbers.). Patients were included in the study for 2 months. They received either a daily dose of a probiotic (1 × 109 CFU/d, i.e., 2 capsules, tid) or a placebo. The probiotic capsules consisted of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus. The probiotic supplements were produced by the Shanghai Xinyi pharmaceutical factory (S10950032, Shanghai, China). The control group received similar capsules containing maltodextrin for the same duration. Medications known to affect the gut microbiome (such as proton pump inhibitor phosphate binders) were not used during the study. Detailed assessments were performed after 2 months of intervention. Various indicators including body mass index (BMI), upper arm circumference (AC), left calf circumference (LCC), triceps skinfold thickness (TSF), fat mass, and biochemical parameters were measured for assessment of malnutrition status.
Anthropometric Measurements and Body Composition Analysis
To evaluate nourishment status in the subjects, their height (cm) and weight (kg) were assessed while they were wearing light clothes. BMI was calculated as weight/height2 (kg/m2). Upper AC and LCC were measured while participants were barefoot. The measuring point of the AC was at the midpoint between the shoulder and the olecranon connection when the upper limbs were hanging naturally, and that of the LCC was at the widest level of the left calf. TSF was measured with calipers, and the needle was read to the nearest 0.1 mm approximately. To minimize intraoperator variability, the averages of 3 consecutive measurements were recorded. Upper arm muscle circumference was calculated as AC − 3.14 × TSF.
Lean body mass and fat mass were assessed using a five-compartment model of a bioelectrical impedance analyzer (Biodynamic BIA 450; Biodynamic Corp., Seattle, WA) with an electrical current of 50 kHz. Measurements were performed before and after the end of the intervention. Patients were lying in a quiet room maintained at a temperature of 22°C to 24°C. Two pairs of sensor electrodes were placed on the patient’s right hand and wrist and on the right foot and ankle.
At baseline and at 2 months, blood samples were also obtained from each patient in the morning after an 8-h overnight fast. Laboratory parameters included serum creatinine, blood urea nitrogen, hemoglobin (Hb), albumin (Alb), high-sensitivity C-reactive protein (hs-CRP), IL-6, total triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol. Biochemical indicators were tested by using an automatic biochemical detector (Olympus, Tokyo, Japan) with an enzymatic colorimetric test. Hb was determined by routine blood examination.
Short-form Health Survey Assessment
SPSS 17.0 software was used for statistical analysis. The differences in the variables between the control and intervention groups were evaluated using a two-sample t-test for continuous variables in addition to age. The differences in age between the control and intervention groups were evaluated using a two independent samples t-test. In addition, the differences in the variables between the control and intervention groups were evaluated using the chi-square test or Fisher’s exact test for categorical variables. The index differences before and after treatment between the control and intervention groups were compared by repeated-measures analysis. P < .05 was considered statistically significant.
We tested probiotics in a cohort of patients undergoing PD to investigate their effect on malnutrition and QOL. Although some parameters could not be determined, we found that administration of the probiotic for 2 months significantly improved AC, TSF, and Alb levels. Moreover, the average scores of physical functioning and social functioning were higher than those in the control group after 2 months.
The natural intestinal microbiota is altered in uremic patients. Fecal ammonia is mainly derived from the bacteria-mediated hydrolysis of urea that accumulates in the blood of uremic patients and diffuses into the intestinal tract. High fecal ammonia concentrations in uremic patients are responsible for the PH increase in feces and result in fecal aerobic bacterial overgrowth.
Changes in the composition and function of the intestinal microbiome and the biochemical environment of the gut can lead to the generation and translocation of products that can potentially contribute to local and systemic inflammation, uremic toxicity, malnutrition, and other complications in patients with advanced CKD. This assumption is confirmed by the results of a study by Aronov et al.
In the study by Aronov et al.,
they compared plasma from patients undergoing HD with and without colons to identify and further characterize colon-derived uremic solutes. High performance liquid chromatography confirmed the levels of p-cresol sulfate and indoxyl sulfate were significantly lower in patients without colons.
The use of probiotics has been shown to have beneficial effects on lipid and glycemic profiles, blood levels of inflammatory biomarkers, and kidney function indexes.
Our data also showed that triglycerides, LDL-C, hs-CRP, and IL-6 decreased after probiotic treatment. Moreover, probiotics regulate the balance of the intestinal flora and reduce the production and absorption of uremic toxins derived from the intestine, which can delay the progression of CKD.
Lactobacilli and bifidobacteria are the two most common types of probiotics. In our trial, the probiotic capsules contained lactobacilli and bifidobacteria. It is believed that Lactobacillus and Bifidobacterium species help maintain the proper balance between the different forms of microorganisms in the intestine.
Uremic patients show greatly increased counts of pathogenic microorganisms in the intestine, and the absorption of nutrients is hampered that more substrate enters the intestine. Probiotics enhance intestinal health by reducing the number of pathogenic microorganisms, thereby reducing the production of uremia toxins. Moreover, prebiotics are nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and activity of probiotics.
On the other hand, another randomized clinical trial of probiotics failed to show a reduction in the plasma concentration of protein-bound uremic toxin or markers of systemic inflammation and did not demonstrate improvement in the QOL parameters in patients undergoing HD. However, the sample size of the trial was only 22 participants, which affected the statistical power of the study results.
There are several possible explanations for the different results of the two studies. As we all know, HD and PD are different dialysis modes. Patients undergoing HD may have more obvious systemic microinflammation because of their blood contacting dialyzer and dialysis pipeline during dialysis. HD is stronger in removing small molecules, while PD is more advantageous in removing mid-sized molecules. HD may remove probiotics more than PD during dialysis, thus reducing the blood concentration of probiotics. Moreover, HD and PD appear to be associated with different changes in the gut microbiome, for example, a decrease in proteobacteria relative abundance in patients undergoing HD and an increase of the same in patients undergoing PD.
Moreover, probiotics are nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and activity of probiotics. Probiotics may result in synergistic effects on gastrointestinal function, which indirectly may benefit the inflammatory and nutritional status of patients undergoing dialysis.
The eight scales of the SF-36 are categorized into two dimensions: physical health and mental health. Both the mental and physical health dimensions of the SF-36 were previously shown to be significantly associated with nutritional status and mortality in patients undergoing maintenance HD.
Our data showed that the malnutrition of patients undergoing PD was improved after probiotic supplementation and that probiotics improved the QOL of patients undergoing PD. To answer this question, we used the SF-36 for HRQOL data collection. Although our data did not show a significant difference between baseline and 2 months regarding the physical component scale or the mental component scale of the SF-36, the index of physical functioning and social functioning improved markedly in the probiotics group but not in the control group. The results demonstrated that QOL of patients undergoing PD was partially improved after probiotic supplementation. It seems that a higher QOL is a response to improved nutritional status and decreased inflammatory mediators.
found that the aforementioned cytokine levels changed after probiotic treatment in patients undergoing PD.
In conclusion, probiotic supplementation significantly increased AC, TSF, and Alb levels and decreased hs-CRP and IL-6 levels. The SF-36 survey showed that physical functioning and social functioning scores increased in the probiotic group. However, this investigation highlights the need for larger-scale research to confirm the benefits of probiotics in patients undergoing PD.
Credit Authorship Contribution Statement
Yangbin Pan: Supervision, Methodology, Writing – review & editing. Liyan Yang: Data curation, Writing – original draft, Writing – review & editing. Binbin Dai: Data curation, Writing – original draft, Writing – review & editing. Beiduo Lin: Data curation, Formal analysis, Writing – review & editing. Songhua Lin: Data curation, Formal analysis, Writing – review & editing. Enqin Lin: Data curation, Formal analysis, Writing – review & editing.