Article

Dose Escalation, Safety and Impact of a Strain-Specific Probiotic (Renadyl™) on Stages III and IV Chronic Kidney Disease Patients

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Abstract

The primary goal of the open label study of Renadyl™ in stage 3 and 4 chronic kidney disease patients was to confirm the safety and tolerability of several doses of Renadyl™ (90, 180, 270 billion colony forming units). Secondary goals were to quantify quality of life improvement, to confirm efficacy in reducing commonly known uremic toxins, and to investigate the effects on several biomarkers of inflammation and oxidative stress. Participants underwent physical examinations and venous blood testing, and completed quality of life questionnaires. Data were analyzed with SAS V9.2. Of 31 subjects, 28 (90%) completed the study (2 lost to follow-up). The primary goal was met, as no significant adverse events were noted during the dose escalation phase. All patients tolerated the maximum dose (note: 1 subject reported nausea upon initial use). The escalation efficacy was shown in statistically significant changes of serum creatinine (months 2 to 6: -0.23 mg/dL, p<0.05), C-reactive protein (months 2 to 6: -0.28 mg/L, p<0.05), and hemoglobin (base to month 6: 0.35 mg/dL, p<0.01, months 1 to 6: 0.46 mg/dL, p<0.001, months 2 to 6: 0.58 mg/dL, p<0.0001). Trends, but not statistical significance, were noted in blood urea nitrogen (base to month 4: -3.56 mg/dL, p<0.09; months 1 to 4: -3.81 mg/dL, p<0.07). The secondary goal was also met, as QOL measure of physical functioning improved (base to month 6, p<0.05) and a strong trend in reduction of pain was observed (base to month 6, p<0.08).

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... 13,14 Penelitian yang dilakukan oleh Ranganatan et al (2013) pemberian probiotik Renadyl TM dengan beberapa dosis (90 x 10 9 CFU, 180 x 10 9 CFU, dan 270 x 10 9 CFU) dinyatakan aman dan dapat ditoleransi dengan baik oleh pasien PGK stadium akhir. 15 Kadar probiotik dalam sediaan kapsul Lacidofil TM yang berisi bakteri sebanyak 2,0 x 10 9 CFU yang diberikan sebanyak 2 kapsul per hari merupakan dosis yang sesuai dan dalam batas toleransi aman. ...
... Selain itu, menurunkan gejala flatulensi dan diare akibat pemberian antibiotik, sehingga memberikan manfaat bagi kesehatan usus. 22 Ranganathan et al (2013) menyatakan terapi pendamping yang diberikan pada pasien PGK terminal dengan suplemen yang mengandung probiotik dapat mengembalikan keseimbangan antara bakteri non patogen dan bakteri patogen sehingga penyerapan zat gizi dapat optimal. 15 Hasil penelitian ini juga menunjukan bukti bahwa pemberian probiotik Lactobacillus meningkatkan kadar kalsium darah. ...
... 22 Ranganathan et al (2013) menyatakan terapi pendamping yang diberikan pada pasien PGK terminal dengan suplemen yang mengandung probiotik dapat mengembalikan keseimbangan antara bakteri non patogen dan bakteri patogen sehingga penyerapan zat gizi dapat optimal. 15 Hasil penelitian ini juga menunjukan bukti bahwa pemberian probiotik Lactobacillus meningkatkan kadar kalsium darah. Pengobatan standar pada pasien PGK terminal dengan diberikan kalsium karbonat juga membantu suatu bakteri Lactobacillus agar dapat menempel pada lumen usus. ...
... QOL results indicated improvement in physical functioning (baseline to month 6, p<0.05) (Figure 7), a trend toward reduction of pain (baseline to month 6, p<0.08), with no significant change in mental, emotional and social well-being. [13] Ranganathan N et al, 2010, studied the effect of Probiotic Dietary Supplementation for Promoting Healthy Kidney Function in Patients with Chronic Kidney Disease by randomized, double-blind, placebocontrolled crossover trial. Trial of a probiotic bacterial formulation was conducted in four countries, at five institutions, for 6 months on 46 outpatients with CKD stages 3 and 4: USA (n=10), Canada (n=13), Nigeria (n=15), and Argentina (n=8). ...
... log 10 cells/g), between the first and the second samples. Gastrointestinal symptoms scores (scale were reduced in the test group (start 12 [10][11][12][13][14] and end 9 [8][9][10]) compared with control group (start 11 [8][9][10][11][12][13][14][15][16][17][18][19][20][21] and end 11 [9][10][11][12][13][14][15]).Thus Short-term symbiotic treatment in patients with ESRD can lead to the increase of Bifidobacterium counts, maintain the intestinal microbial balance. [23] The first sample of control group (black; n 5 10), the second sample of control group (white; n 5 10), the first sample of test group (black and white; n 5 8), and the second sample of test group (white and black; n 5 8). ...
... log 10 cells/g), between the first and the second samples. Gastrointestinal symptoms scores (scale were reduced in the test group (start 12 [10][11][12][13][14] and end 9 [8][9][10]) compared with control group (start 11 [8][9][10][11][12][13][14][15][16][17][18][19][20][21] and end 11 [9][10][11][12][13][14][15]).Thus Short-term symbiotic treatment in patients with ESRD can lead to the increase of Bifidobacterium counts, maintain the intestinal microbial balance. [23] The first sample of control group (black; n 5 10), the second sample of control group (white; n 5 10), the first sample of test group (black and white; n 5 8), and the second sample of test group (white and black; n 5 8). ...
Article
Chronic kidney disease (CKD) is a global health issue with a high economic cost to health systems and one of the risk factor for cardiovascular disease (CVD). All stages of CKD are associated with decreased quality of life. CKD is usually asymptomatic until later stages. Probiotics are living microorganism very well known for a role they in the prevention and reduction of risk factors for several diseases and are also capable of enhancing certain vital physiological functions. A normal human digestive tract contains about 400 types (strains) of probiotic bacteria that control and reduce the growth of harmful bacteria and promote a healthy digestive system. The application of probiotics to kidney health is an emerging area of medicine that has only recently come into attention of scientists. In CKD patients there is a build-up of poisonous wastes in the bloodstream due to the overloaded and impaired kidneys. Certain probiotic microorganisms can utilize urea, uric acid, creatinine and other toxins as nutrients for growth which helps eliminate them as fecal matter. Probiotic organisms transform the colon into a blood cleansing organ in cases where kidney fails to remove toxins from blood. Thus probiotics are new hope for CKD patients and can be used to delay progression of disease. We aim to compile the data of various researches and clinical trials being conducted to evaluate benefits of probiotics in CKD patients.
... Enteric Dialysis® as a concept originated from Dr. Eli A. Friedman's article, "Can the Bowel Substitute for the Kidney in Advanced Renal Failure?" [30] Enteric Dialysis® is a technology that modulates the gut microbiome in chronic kidney disease patients. By supplementing the gut microbiome with probiotic bacteria, it is possible to metabolize the nitrogenous waste products and other toxins which diffuse into the gut, and thus lower levels of inflammation [31]. These pathogenic bacteria produce harmful middle-molecules and generate additional toxins in micro molar concentrations, which significantly impact the patient's quality of life [32,33]. ...
... Each strain of microbe was selected for their ability to metabolize various specific uremic toxins such as urea, uric acid, creatinine, phenols, indoles, cresols, methylamine, and trimethylamine. Past clinical trials have been conducted using this product towards reducing several uremic toxins and as well to evaluate QoL parameters [31,[34][35][36]. However a survey ascertaining the effect of this product supplement on changes in GFR has not been completed to date. ...
... Three pilot scale clinical trials [31,35,36] and three biennial surveys [34,63] (2017) of customers taking this product showed that these precisely researched and selected probiotic strains in the kidney supplement can indeed benefit the renal failure population by several possible-mechanisms. (A) Removal of nitrogenous wastes by metabolism of uremic toxins urea, uric acid and creatinine resulting in increased growth of beneficial bacteria and reduction in growth of pathogens [25,32,35,64,65]. (B) All three strains produce bacteriocins (antimicrobial molecules) which further inhibits the growth of pathogens [66][67][68]. ...
Article
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Background: Based on the concept of “Enteric Dialysis®” Kibow Biotech’s proprietary patented kidney health supplement, has proven helpful in many suffering from CKD, for healthy kidney function by gut microbiome modulation. Available since 2010, it is continually being studied to assess its effectiveness. This survey was to evaluate GFR changes as measured in mL/min per 1.73 m2 , and quality of life (QoL) improvements in customers taking this synbiotic dietary supplement along with their standard care of therapy. Methods: A survey was distributed to 600 customers taking this product. Questions included GFR before taking this supplement, and at their most recent doctor’s visit, age, race, ethnicity, and QoL. GFR data and QoL was analyzed statistically. 214 (35%) survey responses were received. Results: The average survey participant was 69 years and using this proprietary supplement for 2.05 years. 150 surveys contained complete information, including GFR. Baseline GFR was 4 to 100 with an average of 29. The most recent GFR varied from 5 to 102. The highest impact on GFR was an increase of 65, and the largest decrease in GFR was -43. The average change in GFR for a survey participant was an increase of 3.55 mL/min/1.73 m² . 88% of survey participants reported this product improved their QoL. Conclusion: CKD is generally recognized as a degenerative process. With over 4,000 customers using this pro/prebiotic patented dietary supplement we sought feedback from 15% to assess its impact over an average use of 2.05 years. The longest usage of the product was 7 years, the shortest-6 months. With the ability to stabilize and improve GFR, it may be possible to delay all stages of kidney failure progression. Improved QoL in 88% of participants certainly signifies the advantages of using this patented supplement in patients with compromised renal function worldwide.
... Although urea is non-toxic but can degrade toxic cyanates which in turn capable to bind proteins such as albumin and increases the level of carbamylated albumin causes mortality. Hence, probiotic therapy (lactic acid bacteria) serve as the best medication for patients suffering from renal failure, suggested the key role of probiotic in metabolizing urea (Ranganathan et al., 2013). Notably, hematological constituents are considered important factors to distinguish the pathophysiological and physiological status of the body (Meky et al., 2015). ...
... Notably, hematological constituents are considered important factors to distinguish the pathophysiological and physiological status of the body (Meky et al., 2015). However, there was no significant changes were observed in blood cell counts except mean corpuscular hemoglobin following Renadyl treatment (Ranganathan et al., 2013). In the present study, a reduction in feed intake was observed following GM administration because GM was early reported to increase catabolism and anorexia. ...
Article
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Objective: This Experimental study was organized to investigate the ameliorating effect of Renadyl on some hematological and biochemical changes in young male rats after gentamicin induced nephrotoxicity. Material and Methods: Total of eighteen (18) rats were used and divided into a control group (n=6) and treated groups (n=12). Gentamicin was given through the intraperitoneal route for 8 days. After 8 days half (n=6) rats were sacrificed from the treated group. Renadyl was administered orally to the remaining rats (n=6) for a further 10 days. After this rats were decapitated for investigation. Results: Data were analyzed by one way ANOVA. A significant difference (p≤0.05) was found in mean corpuscular hemoglobin, creatinine, urea, HDL, LDL, glucose, TAC, TOS, kidney, and liver weight in Renadyl treated group as compared to Gentamicin treated group. The results indicated that Renadyl has the potential to reduce toxicity levels induced by gentamicin by using creatinine and other toxic agents as their food ingredients and also remove enteric toxins which further provoke kidney damage. Conclusion: Renadyl possesses a nephroprotective approach against Gentamicin induced nephrotoxicity.
... The first probiotic product patented to maintain renal health is capsule probiotic (Renadyl TM ) consisted of S. thermophilus KB 19, L. acidophilus KB 27, dan B. longum KB 31 strains, containing 3 billion CFU per capsule. This probiotic could decrease uremia toxin accumulation in the blood of ESRD patient (Ranganathan, 2013). Studies on probiotic supplement from Lactobacillus casei Shirota strain showed that there was a reduction of leukocyte and improvement in renal function as shown through increased GFR on gastroenteritis patients with acute kidney injury (Akoglu, 2015). ...
... Recently, most probiotic products are packaged in capsule form in order to be easily consumed. Studies on the 3rd and 4th stage of chronic kidney disease revealed that probiotic supplementation in form of capsule (Renadyl TM ) for 4 months with the highest dosage of 270x10 9 CFU per day is safe and well tolerated (Ranganathan, 2013). This study utilized probiotic supplementation in the form of Lacidofil TM capsule consisting of Lactobacillus helveticus Rossell -52 and Lactobacillus rhamnosus Rosell -11 strains with total bacteria of 2.0x10 9 CFU given as 2 capsules per day, which is a safe from and within safety tolerance CFU and Lactobacillus rhamnosus Rosell-11 1.9 x 10 9 CFU with total bacteria count 2.0 x 10 9 CFU was used as the probiotic in this study. ...
Article
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Elevated monocyte count is correlated to the decrease of renal function and disease progressivity on end-stage renal disease (ESRD) patients. Probiotic that utilize lactobacillus species is known to play a role in maintaining imunity system balance by inducing the monocyte apoptosis. The combination between probiotic and calcium carbonate could increase probiotic colonization in the gatrointestinal tract. The aim of this study was to analyze the effect of probiotic and calcium carbonate combination toward reduction of monocyte count on ESRD patient at Rumah Sehat Terpadu Dompet Dhuafa Bogor Hospital. This study was true experimental research with randomized pre-post test control group design. Twenty four ESRD patient were randomly enrolled into treatment group (n=12) and control (n=12). The treatment group received probiotic and calcium carbonate, whereas control group received standardized calcium carbonate for 21 days. There was a significant decrease of monocyte (p=0.03) after administration of probiotic and calcium carbonate.
... Twenty-seven plasma samples were selected for metabolomics analysis from a previously reported dose escalation study of the probiotic Renadyl™ (Ranganathan, Pechenyak et al. 2013). Of these three were excluded and the remainder were stratified by change in BUN over four months of supplementation. ...
... This observation was consistent with a previous pilot that found BUN was the measure of kidney function most affected by probiotics (Ranganathan, Friedman et al. 2009). The observed change in BUN is an important outcome of the clinical trial (Ranganathan, Pechenyak et al. 2013), because BUN is a marker of kidney function and an indicator of protein carbamylation, an independent mortality risk factor among kidney failure patients (Berg, Drechsler et al. 2013). The observed decrease from 58.5 mg/dL to 48.5 mg/dL BUN among responders can be considered clinically encouraging; however, the four month time scale is too short to evaluate the impacts on clinical decisions such as starting dialysis. ...
Article
Scope: Persistent reduction in Glomerular Filtration Rate (GFR) is a hallmark of Chronic Kidney Disease (CKD) and is associated with an elevation of Blood Urea Nitrogen (BUN). This metabolomics pilot study sought to identify metabolites that differentiated patients with CKD whose BUN decreased on a probiotic and possible mechanisms. Methods and results: Metabolomics was used to analyze baseline plasma samples previously diagnosed with CKD Stage III-IV. Patients had participated in a dose escalation study of the probiotic Renadyl™. A total of 24 samples were categorized depending on whether BUN increased or decreased from baseline after 4 months of probiotic use. Multivariate analysis was used to analyze the data and determine the metabolites that best differentiated the phenotypic groups. The sixteen patients who had a decrease in BUN were not significantly different based on demographic and clinical measures from those whose BUN increased or did not change with the exception of age. Eleven of the fourteen metabolites that differentiated the groups were known to be modulated by gut microflora, which may eventually provide a mechanistic link between probiotic and outcomes. Conclusions: Metabolomics revealed metabolites at baseline that may predict individuals with CKD that would most benefit from a probiotics.
... 24 Natarajan et al showed a statistically significant improvement in hemoglobin, hematocrit, creatinine and C-reactive protein, post treatment in a "dose escalation, safety and impact of a strain specific probiotic study in CKD patients. 1 Health related quality of life (HRQOL) is used almost exclusively in clinical studies, with the nephrology community increasingly realizing the potential importance of HRQOL assessment in the clinical care of its patients. The scores provide additional information on the individual's wellbeing beyond the information gained from the patient's clinical and laboratory assessments. ...
... 24 Ranganathan et al in their study used SF36 and showed significant improvement in physical functioning , a trend toward reduction of pain , with no significant change in mental, emotional and social wellbeing. 1 ...
Article
Background: Chronic Kidney Disease (CKD) is one of the major health disorders associated with significant morbidity and mortality. This was a 6 week’s interventional study of orally administered, symbiotic supplement (probiotic with prebiotic) in stage 5D patients of chronic kidney disease (CKD) on twice a week hemodialysis. The objective was to look for safety of symbiotics (Nitrophage ForteTM) and for its anti-inflammatory effects measured by serum hsCRP (Highly specific C reactive protein), IL-6 (Interleukin- 6) and TNF-α (Tumour Necrosis Factor- α) levels. This translating to improvement in the Quality of life (QOL) assessed using SF-36 QOL questionnaire and Subjective Global Assessment (SGA) scoring. Methods: Subjects on twice a week dialysis for at least 3 months were included. Parameters at baseline (representing previous 3 months) were compared to that at the end of treatment. Oral supplementation of strain specific and unique composition of symbiotic sachet supplementation were administered twice daily containing Lactobacillus acidophilus 400mg, Bifidobacterium longumm 400mg, Streptococcus thermophilus with Fructooligosaccharide 100mg adding to 1 gram was given for 6 weeks.Results: 38 patients out of total 48 enrolled completed the study. Symbiotic therapy was found to be well tolerated with no significant adverse effects. 60.52%, 55.26%, 44.7% of the patients had a decrease in hsCRP, TNF-α and IL-6 respectively. Among responders hsCRP and TNF-α showed significant decrease in levels from the baseline (p <0.05). Modified SF-36 QOL questionnaire mean score revealed significant improvement in general health (p < 0.05). Among secondary parameters renal biomarkers like urea, BUN and sodium showed statistically significant decrease (p <0.05).Conclusions: This study establishes the safety and anti-inflammatory efficacy of this symbiotic supplement. To our knowledge this is the first study looking at anti-inflammatory role of symbiotic in CKD 5D Patients. A placebo controlled, double blinded study with a larger sample size is warranted in future to further establish these findings.
... Due to limited resources, it may become necessary to limit the utilization of dialysis, especially in patients with adequate residual renal function (RRF). Alternative interventions that might decrease the need for dialysis during conflict have been previously proposed in the literature [23,24]. ...
... There are numerous articles on management of ESKD patients during natural disasters and these were reviewed recently [23,24]. However, experiences from natural disaster cannot be extrapolated to man-made disasters such as armed conflicts. ...
Article
Background: Conflicts can lead to significant disruption in the care of endstage kidney disease (ESKD) patients. The purpose of this paper is to review the available literature on the care of ESKD patients in times of armed conflict and make recommendations for action. Method: A review of all PubMed-published reports between 1965 and 2015 about the care of ESKD patients at the time of conflict. We excluded articles that reported on acute kidney injury and natural disasters. Results: We found a total of 12 reports on dialysis care and/or kidney transplant care from five armed conflicts and resulting refugee crises. These conflicts led to significant shortage of staff and resources and caused several obstacles in providing adequate dialysis to ESKD patients. In one study, the mortality rate of patients on automated peritoneal dialysis was as high as 95%. The kidney transplantation rate decreased in all but one of the reports about kidney transplant care and patients had difficulties securing their immunosuppressive medications. Conclusions: ESKD patients, especially dialysis patients, comprise a severely vulnerable population during conflicts. Their care can be disrupted and altered leading to a substantial increase in their mortality rate. Efforts to improve their care during conflicts are needed.
... Specifically formulated probiotic microbial strains keep uremic toxins from accumulating to highly toxic levels. In December 2012, two most recent studies were completed: an open label, observational dose escalation study in CKD stages 3 and 4 patients at Thomas Jefferson University (Philadelphia, PA) [31] and the current study. The former study aimed to confirm the safety and tolerability of several doses of the formulation as well as to quantify the improvements in quality of life (QOL) and to explore several molecular biomarkers. ...
... Previous multicenter trials in cohorts of CKD stages 3-4 patients showed that concentrations of uremic toxins (urea, uric acid, and creatinine) were reduced when study subjects were treated with the study formulation at 90 billion CFU/day dosage [29]. Open label, dose escalation observational study in CKD stages 3-4 patients showed statistically significant reductions in creatinine and C-reactive protein, significant improvements in hemoglobin, hematocrit, and physical functioning (QOL measure), trends toward reduction in BUN, potassium, and pain (QOL), and no significant change in mental, emotional, and social well-being [31]. ...
Article
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Background: Primary goal of this randomized, double-blind, placebo-controlled crossover study of Renadyl in end-stage renal disease patients was to assess the safety and efficacy of Renadyl measured through improvement in quality of life or reduction in levels of known uremic toxins. Secondary goal was to investigate the effects on several biomarkers of inflammation and oxidative stress. Methods: Two 2-month treatment periods separated by 2-month washout and crossover, with physical examinations, venous blood testing, and quality of life questionnaires completed at each visit. Data were analyzed with SAS V9.2. Results: 22 subjects (79%) completed the study. Observed trends were as follows (none reaching statistical significance): decline in WBC count (-0.51 × 10(9)/L, P = 0.057) and reductions in levels of C-reactive protein (-8.61 mg/L, P = 0.071) and total indoxyl glucuronide (-0.11 mg%, P = 0.058). No statistically significant changes were observed in other uremic toxin levels or measures of QOL. Conclusions: Renadyl appeared to be safe to administer to ESRD patients on hemodialysis. Stability in QOL assessment is an encouraging result for a patient cohort in such advanced stage of kidney disease. Efficacy could not be confirmed definitively, primarily due to small sample size and low statistical power-further studies are warranted.
... In a study of stage 3 and 4 CKD patients was to confirm the safety and tolerability of several doses of Renadyl™ (90, 180, 270 billion colonyforming units, showed stabilizing Creatinine. The escalation efficacy was demonstrated in statistically significant changes of serum creatinine (months 2 to 6: -0.23 mg/dL, p<0.05) (Ranganathan et al., 2013). ...
... Nonetheless, there are no conclusive results regarding the beneficial effects of these compounds. A study assessing the probiotic Renadyl® in 28 patients at stages 3 and 4 of CKD noted a trend towards reduced urea levels, although this trend did not reach statistical significance [21]. Additionally, KA have been used for more than 40 years to supplement LPDs and very low protein diets (VLPDs) for patients with CKD [10,22]. ...
Article
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Introduction: Currently, the conservative management of chronic kidney disease (CKD) involves treating the primary disease and its consequences, as well as improving altered biochemical markers. Evidence suggests that the key management strategy for slowing down the progression of the disease is nephroprotection. Objective: This study aimed to evaluate the effect of the supply of TCA cycle intermediates in combination with calcium carbonate, calcium lactate, and sodium bicarbonate in patients with CKD. Methodology: A retrospective observational study was undertaken in nephrology and internal medicine clinics in Mexico. The study enrolled patients aged over 18 with stages 3b, 4, and 5 chronic kidney disease (CKD) who were not undergoing renal replacement therapy (RRT) and had received treatment based on TCA therapy. Results: The study included a total of 55 patients with CKD. The results showed an increase in eGFR from a baseline average of 16.73 ± 1,374 mL/min to a final average of 19.18 ± 1,516 mL/min and a decrease in creatinine values from a baseline average of 4.26 ± 2.44 mg/dL to a final average of 3.77 ± 2.23 mg/dL. These changes had a statistical significance P?0.05.Conclusions: The observed benefits of TCA in combination with sodium bicarbonate, calcium carbonate, and calcium lactate include: 1) Increased eGFR, 2) Decreased serum creatinine, 3) Decreased serum urea, 4) Decreased serum phosphorus, 5) Increased serum hemoglobin, and 6) Maintenance of albumin levels within normal ranges. Adjuvant therapy with the combination of TCA could be a useful tool as a new therapeutic option in patients with CKD.
... Whereas in uremicpatients, higher levels of pathogens such as Clostridia, Enterobacteria sp., and Pseudomonas sp. are found, with low level of Lactobacillus and Bifidobacteria. [4] Patients with end-stage renal disease (ESRD) are also at a higher risk of Clostridium difficile-associated diarrhea. ...
Article
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Chronic kidney disease of unknown etiology (CKDu) is an emerging entity in the South Asian region. This predominately affects the farming community belonging to the lower socioeconomic status.CKDu being a progressive condition often leads to end-stage renal failurerequiring renal replacement therapy (RRT). Due to the high cost and limited availability of RRT in many areas of geographical locations in India and worldwide, there is an unmet need to slow down the progression of CKDu. The intestinal microbiota is different in patients with CKD, with low levels of beneficial bacteria such as Lactobacillus and Bifidobacteria. Prebiotics and probiotics modify the intestinal microbiota and thereby slow down the progression. Soda bicarbonate therapy is cheap and cost-effective in slowing down the progression of CKDu in a subset of patients. There is also evidence of the beneficial effect of N-acetyl cysteine in early stages of CKD and it should benefit CKDu also. Dietary interventions to prevent dehydration, by providing uncontaminated drinking water, sufficient protein containing diet with adequate calories, and tailored salt intake to prevent hypotension, are necessary compared to other causes of CKD.The objective is to prevent malnutrition, and uremic symptoms. Early diagnosis and prompt intervention may delay the progression of CKDu in the early stages.
... La alteración de la microbiota intestinal normal (disbiosis) ha sido implicada en diversas patologías, como obesidad, diabetes tipo 2, enfermedad inflamatoria intestinal, y enfermedades cardiovasculares. 1 En el paciente con enfermedad renal crónica en etapas tempranas y avanzadas se han observado alteraciones cuantitativas y cualitativas en la microbiota intestinal, 1 específicamente, estas alteraciones se basan en la presencia de bacterias aeróbicas, tales como firmicutes, actinobacteria y proteobacteria, y disminución de bacterias anaerobias, como Sutterellaceae, Bacteroidaceae y Lactobacillaceae. [2][3][4] La disbiosis intestinal puede deberse a causas iatrogénicas o uremia per se, la evidencia preliminar indica que las toxinas generadas por un microbioma intestinal alterado puede contribuir a la progresión de la enfermedad renal crónica (ERC) y tener como consecuencia alteraciones tales como: anemia, enfermedad cardiovascular, desgaste energético proteínico, enfermedad mineral-ósea, neuropatía, trastornos funcionales, entre otros, disminuyendo la calidad de vida relacionada a la salud (CVRS) de quien la presenta. ...
... It is a probiotic/prebiotic formulation (i.e., a synbiotic) that has undergone study in in vitro models, animal models (rats, mini-pigs, cats, and dogs) [97][98][99][100], and clinical trials in humans (CKD III and IV, and dialysis patients). Studies indicate that Renadyl™ is able in advanced stages of CKD, to catabolize and remove uremic toxins and preserve renal function (Figure 3) [38,39,[101][102][103][104]. Reduction in levels of urea in 63% of patients given our first generation product called "Kibow Biotics" was seen [38]. ...
... It is a probiotic/prebiotic formulation (i.e., a synbiotic) that has undergone study in in vitro models, animal models (rats, mini-pigs, cats, and dogs) [97][98][99][100] and clinical trials in humans (CKD III and IV, and dialysis patients). Studies indicate that Renadyl™ is able in advanced stages of CKD, to catabolize and remove uremic toxins and preserve renal function (Figure 3) [38,39,[101][102][103][104]. Reduction in levels of urea in 63% of patients given our first generation product called "Kibow Biotics" was seen38. ...
Article
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The primary goal of this invited commentary is to update recent scientific progress, understanding, knowledge gained and also several clinical advances made since the very first review that was published from our commercial efforts in the year 2012 (Title: Probiotics, Prebiotics and Synbiotics: Gut and Beyond in Gastroenterology Research and Practice). The use of probiotics and prebiotics is generally well recognized towards digestive, gut and immune health. However, Kibow Biotech is a R&D Biotech company involved in novel and niche application of probiotics and prebiotics as a dietary supplement in stabilization of Gut Microbiome towards Chronic Kidney Disease (CKD).
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We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus gut bacterial richness. They contain known and previously unknown bacterial species at different proportions; individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities.
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Urea, the toxic end product of protein catabolism, is elevated in end-stage renal disease (ESRD), although it is unclear whether or how it contributes to disease. Urea can promote the carbamylation of proteins on multiple lysine side chains, including human albumin, which has a predominant carbamylation site on Lys. The proportion of serum albumin carbamylated on Lys (%C-Alb) correlated with time-averaged blood urea concentrations and was twice as high in ESRD patients than in non-uremic subjects (0.90% versus 0.42%). Baseline %C-Alb was higher in ESRD subjects who died within 1 year than in those who survived longer than 1 year (1.01% versus 0.77%) and was associated with an increased risk of death within 1 year (hazard ratio, 3.76). These findings were validated in an independent cohort of diabetic ESRD subjects (hazard ratio, 3.73). Decreased concentrations of serum amino acids correlated with higher %C-Alb in ESRD patients, and mice with diet-induced amino acid deficiencies exhibited greater susceptibility to albumin carbamylation than did chow-fed mice. In vitro studies showed that amino acids such as cysteine, histidine, arginine, and lysine, as well as other nucleophiles such as taurine, inhibited cyanate-induced C-Alb formation at physiologic pH and temperature. Together, these results suggest that chronically elevated urea promotes carbamylation of proteins in ESRD and that serum amino acid concentrations may modulate this protein modification. In summary, we have identified serum %C-Alb as a risk factor for mortality in patients with ESRD and propose that this risk factor may be modifiable with supplemental amino acid therapy.
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Olfactory receptors are G protein-coupled receptors that mediate olfactory chemosensation and serve as chemosensors in other tissues. We find that Olfr78, an olfactory receptor expressed in the kidney, responds to short chain fatty acids (SCFAs). Olfr78 is expressed in the renal juxtaglomerular apparatus, where it mediates renin secretion in response to SCFAs. In addition, both Olfr78 and G protein-coupled receptor 41 (Gpr41), another SCFA receptor, are expressed in smooth muscle cells of small resistance vessels. Propionate, a SCFA shown to induce vasodilation ex vivo, produces an acute hypotensive response in wild-type mice. This effect is differentially modulated by disruption of Olfr78 and Gpr41 expression. SCFAs are end products of fermentation by the gut microbiota and are absorbed into the circulation. Antibiotic treatment reduces the biomass of the gut microbiota and elevates blood pressure in Olfr78 knockout mice. We conclude that SCFAs produced by the gut microbiota modulate blood pressure via Olfr78 and Gpr41.
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Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with systemic inflammation and acquired immunodeficiency, which promote cardiovascular disease, body wasting, and infections as leading causes of death. This phenomenon persists despite dialysis-related triggers of immune deregulation having been largely eliminated. Here we propose a potential immunoregulatory role of the intestinal microbiota in CKD/ESRD. We discuss how the metabolic alterations of uremia favor pathogen overgrowth (dysbiosis) in the gut and an increased translocation of living bacteria and bacterial components. This process has the potential to activate innate immunity and systemic inflammation. Persistent innate immune activation involves the induction of immunoregulatory mediators that suppress innate and adaptive immunity, similar to the concept of 'endotoxin tolerance' or 'immune paralysis' in advanced sepsis or chronic infections. Renal science has largely neglected the gut as a source of triggers for CKD/ESRD-related immune derangements and complications and lags behind on the evolving microbiota research. Interdisciplinary research activities at all levels are needed to unravel the pathogenic role of the intestinal microbiota in kidney disease and to evaluate if therapeutic interventions that manipulate the microbiota, such as pre- or probiotics, have a therapeutic potential to correct CKD/ESRD-related immune deregulation and to prevent the associated complications.Kidney International advance online publication, 16 January 2013; doi:10.1038/ki.2012.440.
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The human gut harbors a complex community of microbes that profoundly influence many aspects of growth and development, including development of the nervous system. Advances in high-throughput DNA sequencing methods have led to rapidly expanding knowledge about this gut microbiome. Here, we review fundamental emerging data on the human gut microbiome, with a focus on potential interactions between the microbiome and autism spectrum disorders (ASD) and consider research on atypical patterns of feeding and nutrition in ASD and how they might interact with the microbiome. Finally we selectively survey results from studies in rodents on the impact of the microbiome on neurobehavioral development. The evidence reviewed here suggests that a deeper understanding of the gut microbiome could open up new avenues of research on ASD, including potential novel treatment strategies.
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The human intestinal tract has been colonized by thousands of species of bacteria during the coevolution of man and microbes. Gut-borne microbes outnumber the total number of body tissue cells by a factor of ten. Recent metagenomic analysis of the human gut microbiota has revealed the presence of some 3.3 million genes, as compared to the mere 23 thousand genes present in the cells of the tissues in the entire human body. Evidence for various beneficial roles of the intestinal microbiota in human health and disease is expanding rapidly. Perturbation of the intestinal microbiota may lead to chronic diseases such as autoimmune diseases, colon cancers, gastric ulcers, cardiovascular disease, functional bowel diseases, and obesity. Restoration of the gut microbiota may be difficult to accomplish, but the use of probiotics has led to promising results in a large number of well-designed (clinical) studies. Microbiomics has spurred a dramatic increase in scientific, industrial, and public interest in probiotics and prebiotics as possible agents for gut microbiota management and control. Genomics and bioinformatics tools may allow us to establish mechanistic relationships among gut microbiota, health status, and the effects of drugs in the individual. This will hopefully provide perspectives for personalized gut microbiota management.
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The population of microbes (microbiome) in the intestine is a symbiotic ecosystem conferring trophic and protective functions. Since the biochemical environment shapes the structure and function of the microbiome, we tested whether uremia and/or dietary and pharmacologic interventions in chronic kidney disease alters the microbiome. To identify different microbial populations, microbial DNA was isolated from the stools of 24 patients with end-stage renal disease (ESRD) and 12 healthy persons, and analyzed by phylogenetic microarray. There were marked differences in the abundance of 190 bacterial operational taxonomic units (OTUs) between the ESRD and control groups. OTUs from Brachybacterium, Catenibacterium, Enterobacteriaceae, Halomonadaceae, Moraxellaceae, Nesterenkonia, Polyangiaceae, Pseudomonadaceae, and Thiothrix families were markedly increased in patients with ESRD. To isolate the effect of uremia from inter-individual variations, comorbid conditions, and dietary and medicinal interventions, rats were studied 8 weeks post 5/6 nephrectomy or sham operation. This showed a significant difference in the abundance of 175 bacterial OTUs between the uremic and control animals, most notably as decreases in the Lactobacillaceae and Prevotellaceae families. Thus, uremia profoundly alters the composition of the gut microbiome. The biological impact of this phenomenon is unknown and awaits further investigation.Kidney International advance online publication, 19 September 2012; doi:10.1038/ki.2012.345.
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We explore the microbiota of 18 body sites in over 200 individuals using sequences amplified V1-V3 and the V3-V5 small subunit ribosomal RNA (16S) hypervariable regions as part of the NIH Common Fund Human Microbiome Project. The body sites with the greatest number of core OTUs, defined as OTUs shared amongst 95% or more of the individuals, were the oral sites (saliva, tongue, cheek, gums, and throat) followed by the nose, stool, and skin, while the vaginal sites had the fewest number of OTUs shared across subjects. We found that commonalities between samples based on taxonomy could sometimes belie variability at the sub-genus OTU level. This was particularly apparent in the mouth where a given genus can be present in many different oral sites, but the sub-genus OTUs show very distinct site selection, and in the vaginal sites, which are consistently dominated by the Lactobacillus genus but have distinctly different sub-genus V1-V3 OTU populations across subjects. Different body sites show approximately a ten-fold difference in estimated microbial richness, with stool samples having the highest estimated richness, followed by the mouth, throat and gums, then by the skin, nasal and vaginal sites. Richness as measured by the V1-V3 primers was consistently higher than richness measured by V3-V5. We also show that when such a large cohort is analyzed at the genus level, most subjects fit the stool "enterotype" profile, but other subjects are intermediate, blurring the distinction between the enterotypes. When analyzed at the finer-scale, OTU level, there was little or no segregation into stool enterotypes, but in the vagina distinct biotypes were apparent. Finally, we note that even OTUs present in nearly every subject, or that dominate in some samples, showed orders of magnitude variation in relative abundance emphasizing the highly variable nature across individuals.
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Analysis of human body microbial diversity is fundamental to understanding community structure, biology and ecology. The National Institutes of Health Human Microbiome Project (HMP) has provided an unprecedented opportunity to examine microbial diversity within and across body habitats and individuals through pyrosequencing-based profiling of 16 S rRNA gene sequences (16 S) from habits of the oral, skin, distal gut, and vaginal body regions from over 200 healthy individuals enabling the application of statistical techniques. In this study, two approaches were applied to elucidate the nature and extent of human microbiome diversity. First, bootstrap and parametric curve fitting techniques were evaluated to estimate the maximum number of unique taxa, S(max), and taxa discovery rate for habitats across individuals. Next, our results demonstrated that the variation of diversity within low abundant taxa across habitats and individuals was not sufficiently quantified with standard ecological diversity indices. This impact from low abundant taxa motivated us to introduce a novel rank-based diversity measure, the Tail statistic, ("τ"), based on the standard deviation of the rank abundance curve if made symmetric by reflection around the most abundant taxon. Due to τ's greater sensitivity to low abundant taxa, its application to diversity estimation of taxonomic units using taxonomic dependent and independent methods revealed a greater range of values recovered between individuals versus body habitats, and different patterns of diversity within habitats. The greatest range of τ values within and across individuals was found in stool, which also exhibited the most undiscovered taxa. Oral and skin habitats revealed variable diversity patterns, while vaginal habitats were consistently the least diverse. Collectively, these results demonstrate the importance, and motivate the introduction, of several visualization and analysis methods tuned specifically for next-generation sequence data, further revealing that low abundant taxa serve as an important reservoir of genetic diversity in the human microbiome.
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Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.
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Microbial inhabitants outnumber our body's own cells by about ten to one. These residents have become the subject of intensive research, which is beginning to elucidate their roles in health and disease. See Articles p.207 & p.215
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Microbial communities carry out the majority of the biochemical activity on the planet, and they play integral roles in processes including metabolism and immune homeostasis in the human microbiome. Shotgun sequencing of such communities’ metagenomes provides information complementary to organismal abundances from taxonomic markers, but the resulting data typically comprise short reads from hundreds of different organisms and are at best challenging to assemble comparably to single-organism genomes. Here, we describe an alternative approach to infer the functional and metabolic potential of a microbial community metagenome. We determined the gene families and pathways present or absent within a community, as well as their relative abundances, directly from short sequence reads. We validated this methodology using a collection of synthetic metagenomes, recovering the presence and abundance both of large pathways and of small functional modules with high accuracy. We subsequently applied this method, HUMAnN, to the microbial communities of 649 metagenomes drawn from seven primary body sites on 102 individuals as part of the Human Microbiome Project (HMP). This provided a means to compare functional diversity and organismal ecology in the human microbiome, and we determined a core of 24 ubiquitously present modules. Core pathways were often implemented by different enzyme families within different body sites, and 168 functional modules and 196 metabolic pathways varied in metagenomic abundance specifically to one or more niches within the microbiome. These included glycosaminoglycan degradation in the gut, as well as phosphate and amino acid transport linked to host phenotype (vaginal pH) in the posterior fornix. An implementation of our methodology is available at http://huttenhower.sph.harvard.edu/humann. This provides a means to accurately and efficiently characterize microbial metabolic pathways and functional modules directly from high-throughput sequencing reads, enabling the determination of community roles in the HMP cohort and in future metagenomic studies.
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The complex metabolic relationships between the host and its microbiota change throughout life and vary extensively between individuals, affecting disease risk factors and therapeutic responses through drug metabolism. Elucidating the biochemical mechanisms underlying this human supraorganism symbiosis is yielding new therapeutic insights to improve human health, treat disease, and potentially modify human disease risk factors. Therapeutic options include targeting drugs to microbial genes or co-regulated host pathways and modifying the gut microbiota through diet, probiotic and prebiotic interventions, bariatric surgery, fecal transplants, or ecological engineering. The age-associated co-development of the host and its microbiota provides a series of windows for therapeutic intervention from early life through old age.
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The connection between disease and the disruption of homeostatic interactions between the host and its microbiota is now well established. Drug developers and clinicians are starting to rely more heavily on therapies that directly target the microbiota and on the ecology of the microbiota to understand the outcomes of these treatments. The effects of those microbiota-targeted therapies that alter community composition range in scale from eliminating individual strains of a single species (for example, with antibacterial conjugate vaccines) to replacing the entire community with a new intact microbiota (for example, by fecal transplantation). Secondary infections linked to antibiotic use provide a cautionary tale of the unintended consequences of perturbing a microbial species network and highlight the need for new narrow-spectrum antibiotics with rapid companion diagnostics. Insights into microbial ecology will also benefit the development of probiotics, whose therapeutic prospects will depend on rigorous clinical testing. Future probiotics may take the form of a consortium of long-term community residents: "a fecal transplant in a capsule." The efficacy of microbiota-targeted therapies will need to be assessed using new diagnostic tools that measure community function rather than composition, including the temporal response of a microbial community to a defined perturbation such as an antibiotic or probiotic.
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Childhood malnutrition is a global health problem that cannot be attributed to food insecurity alone. The gut microbiota may contribute to this devastating health disorder. In this Perspective, we call for the application of tools and concepts emerging from studies of the human gut microbiota to better understand the nutritional needs of infants and children and the role of the microbiota in the pathogenesis and treatment of undernutrition. This effort will require elucidation of the interrelationships between breast milk composition and the development of the microbiota and immune system in the context of the maternal-infant dyad.
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The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.
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We describe the need to further integrate the fields of human microbial ecology and anthropology and outline some of the potential goals and benefits of this collaborative work.
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Signals from the intestinal microbiota are important for normal host physiology; alteration of the microbiota (dysbiosis) is associated with multiple disease states. We determined the effect of antibiotic-induced intestinal dysbiosis on circulating cytokine levels and severity of ischemia/reperfusion injury in the heart. Treatment of Dahl S rats with a minimally absorbed antibiotic vancomycin, in the drinking water, decreased circulating leptin levels by 38%, resulted in smaller myocardial infarcts (27% reduction), and improved recovery of postischemic mechanical function (35%) as compared with untreated controls. Vancomycin altered the abundance of intestinal bacteria and fungi, measured by 16S and 18S ribosomal DNA quantity. Pretreatment with leptin (0.12 μg/kg i.v.) 24 h before ischemia/reperfusion abolished cardioprotection produced by vancomycin treatment. Dahl S rats fed the commercially available probiotic product Goodbelly, which contains the leptin-suppressing bacteria Lactobacillus plantarum 299v, also resulted in decreased circulating leptin levels by 41%, smaller myocardial infarcts (29% reduction), and greater recovery of postischemic mechanical function (23%). Pretreatment with leptin (0.12 μg/kg i.v.) abolished cardioprotection produced by Goodbelly. This proof-of-concept study is the first to identify a mechanistic link between changes in intestinal microbiota and myocardial infarction and demonstrates that a probiotic supplement can reduce myocardial infarct size.
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Diet strongly affects human health, partly by modulating gut microbiome composition. We used diet inventories and 16S rDNA sequencing to characterize fecal samples from 98 individuals. Fecal communities clustered into enterotypes distinguished primarily by levels of Bacteroides and Prevotella. Enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella). A controlled-feeding study of 10 subjects showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10-day study. Thus, alternative enterotype states are associated with long-term diet.
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The gut microbiome is the term given to describe the vast collection of symbiotic microorganisms in the human gastrointestinal system and their collective interacting genomes. Recent studies have suggested that the gut microbiome performs numerous important biochemical functions for the host, and disorders of the microbiome are associated with many and diverse human disease processes. Systems biology approaches based on next generation 'omics' technologies are now able to describe the gut microbiome at a detailed genetic and functional (transcriptomic, proteomic and metabolic) level, providing new insights into the importance of the gut microbiome in human health, and they are able to map microbiome variability between species, individuals and populations. This has established the importance of the gut microbiome in the disease pathogenesis for numerous systemic disease states, such as obesity and cardiovascular disease, and in intestinal conditions, such as inflammatory bowel disease. Thus, understanding microbiome activity is essential to the development of future personalized strategies of healthcare, as well as potentially providing new targets for drug development. Here, we review recent metagenomic and metabonomic approaches that have enabled advances in understanding gut microbiome activity in relation to human health, and gut microbial modulation for the treatment of disease. We also describe possible avenues of research in this rapidly growing field with respect to future personalized healthcare strategies.
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Over 70 years have passed since dermatologists John H. Stokes and Donald M. Pillsbury first proposed a gastrointestinal mechanism for the overlap between depression, anxiety and skin conditions such as acne. Stokes and Pillsbury hypothesized that emotional states might alter the normal intestinal microflora, increase intestinal permeability and contribute to systemic inflammation. Among the remedies advocated by Stokes and Pillsbury were Lactobacillus acidophilus cultures. Many aspects of this gut-brain-skin unifying theory have recently been validated. The ability of the gut microbiota and oral probiotics to influence systemic inflammation, oxidative stress, glycemic control, tissue lipid content and even mood itself, may have important implications in acne. The intestinal microflora may also provide a twist to the developing diet and acne research. Here we provide a historical perspective to the contemporary investigations and clinical implications of the gut-brain-skin connection in acne.
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Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are uraemic toxins that have similar protein binding, dialytic clearance and proinflammatory features. However, only a few prospective studies have evaluated possible associations between these two retained solutes and renal disease progression in chronic kidney disease (CKD) patients. This prospective observational study evaluated independent associations between serum total IS and PCS with renal progression in a selected cohort of patients having different stages of CKD. Baseline PCS and IS were correlated with renal progression [defined as decrements in estimated glomerular filtration rate (eGFR) > 50% from baseline or progression to end-stage renal disease (ESRD)] and death during a follow-up period of 24 months. Of 268 patients, 35 (13.1%) had renal progression and 14 (5.2%) died after a mean follow-up of 21 ± 3 months. Univariate Cox regression analysis followed by multivariate analysis showed that high-serum PCS levels were associated with renal progression and all-cause mortality independent of age, gender, diabetes status, albumin levels, serum IS, serum creatinine, Ca × P product, intact parathyroid hormone, haemoglobin or high-sensitivity C-reactive protein level. Serum IS was only associated with renal progression; however, the predictive power of serum IS was weakened when serum PCS was also present in the analytical model. In addition to traditional and uraemia-related risk factors such as renal function, serum IS and PCS levels may help in predicting the risk of renal progression in patients having different stages of CKD.
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Uremic syndrome consists of nitrogenous waste retention, deficiency in kidney-derived hormones, and reduced acid excretion, and, if untreated, may progress to coma and eventual death. Previous experience suggests that oral administration of a probiotic formulation of selected microbial strains may extend renoprotection via intraintestinal extraction of toxic waste solutes in patients with chronic kidney disease (CKD)stages 3 and 4. This report presents preliminary data from a pilot study. This was a 6-month prospective, randomized, double-blind, placebo-controlled crossover trial of a probiotic bacterial formulation conducted in four countries, at five institutions, on 46 outpatients with CKD stages 3 an nd 4: USA (n=10), Canada (n=113), Nigeria (n=115), and Argentina (n=8). Outcomes were compared using biochemical parameters:blood urea nitrogen (BUN), serum creatinine, and uric acid. General well-being was assessed as a secondary parameter by a quality of life (QQOL) questionnaire on a subjective scale of 1-10. Oral ingestion of probiotics (90 billion colony forming units [CFUs]/day) was well tolerated and safe during the entire trial period at all sites. BUN levels decreased in 29 patients (63%, P<0.05), creatinine levels decreased in 20 patients (43%, no statistical significance), and uric acid levels decreased in 15 patients (33%, no statistical significance). Almost all subjects expressed a perceived substantial overall improvement in QOL (86%, P<0.05). The main outcomes of this preliminary trial include a significant reduction of BUN, enhanced well-being, and absence of serious adverse effects, thus supporting the use of the chosen probiotic formulation for bowel-based toxic solute extraction. QOL and BUN levels showed statistically significant differences in outcome (P<0.05) between placebo and probiotic treatment periods at all four sites (46 patients). A major limitation of this trial is the small sample size nd elated inconsistencies.
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Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.
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A clinician, curious about the manufacturer's claims, examined the results of a probiotic combination marketed as Kibow Biotics ® on azotemia in cats. Results indicate a decrease in creatinine levels in six out of seven patients treated (86%) even though dosing was less than the recommended amount in most cats. This study suggests that probiotic therapy is safe and effective and indicates a place for such products in management of renal failure in cats. Further study is indicated to determine optimal dosing and potential adverse side effects, and to assess which cases are most and least responsive. Introduction Feline renal failure is a significant cause of morbidity and mortality in cats in the United States. 1 Reducing morbidity and mortality associated with renal failure is an important goal in companion animal veterinary medicine. Regular screening of geriatric cats can assist in early diagnosis. 2 Ascertaining the cause of renal damage may greatly assist in formulating a therapeutic plan. Sadly, many cases present in more advanced conditions. Therapy involves reducing uremic toxins, normalizing renal blood flow and blood pressure, maintaining hydration and electrolyte balance, and supporting tissue repair when possible. Regardless of cause, it is considered desirable to reduce levels of blood urea nitrogen (BUN) and serum creatinine in renal failure patients. 4 Feeding reduced levels of high biological value protein in advanced failure has been the staple treatment of chronic renal failure in cats. 3 Dietary therapy has been shown to increase survival of feline renal failure patients. 4,5 Use of other agents such as phosphorus binding substances and parathyroid hormone modulation are also utilized. 5,6 There are divergent opinions regarding the make up of an optimal diet for feline renal failure and more data is needed to answer these questions. Feline patients may be difficult to medicate orally over long periods of time, which creates a challenge when designing clinically useful programs for chronic use. Products selected must be well tolerated as well as effective.
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We are aware of no study indicating the effects of synbiotic food consumption on metabolic profiles, inflammation and oxidative stress among diabetic patients. The aim of the current study was to investigate the effects of synbiotic food consumption on metabolic profiles, hs-CRP and biomarkers of oxidative stress in diabetic patients. This randomized double-blinded cross-over controlled clinical trial was performed among 62 diabetic patients aged 35-70 y. After a 2-wk run-in period, subjects were randomly assigned to consume either a synbiotic (n = 62) or control food (n = 62) for 6 weeks. A 3-week washout period was applied following which subjects were crossed over to the alternate treatment arm for an additional 6 weeks. The synbiotic food consisted of a probiotic viable and heat-resistant Lactobacillus sporogenes (1 × 10(7) CFU), 0.04 g inulin (HPX) as prebiotic with 0.38 g isomalt, 0.36 g sorbitol and 0.05 g stevia as sweetener per 1 g. Control food (the same substance without probiotic bacteria and prebiotic inulin) was packed in identical 9-gram packages. Patients were asked to consume the synbiotic and control foods three times a day. Fasting blood samples were taken at baseline and after a 6-wk intervention to measure metabolic profiles, hs-CRP and biomarkers of oxidative stress. Consumption of a synbiotic food, compared to the control, resulted in a significant decrease in serum insulin levels (changes from baseline: -1.75 ± 0.60 vs. +0.95 ± 1.09 μIU/mL, P = 0.03). Although we failed to find a significant effect of synbiotic food consumption on total- and LDL-cholesterol levels and HOMA-IR, the effects on FPG (22.3 vs. 4.2 mg/dL, P = 0.09), serum triglycerides (45.9 vs. 20.6 mg/dL, P = 0.08) and HDL-cholesterol levels (3.1 vs. -2 mg/dL, P = 0.06) tended to be significant. A significant reduction in serum hs-CRP levels (-1057.86 ± 283.74 vs. 95.40 ± 385.38 ng/mL, P = 0.01) was found following the consumption of synbiotic food compared with the control group. Supplementation with the synbiotic food led to a significant increase in plasma total GSH (319.98 vs. 19.73 μmol/L, P < 0.001) and serum uric acid levels (+0.7 vs. -0.1 mg/dL, P = 0.04) compared to the control food. No significant effect of the synbiotic food was observed on plasma TAC levels. In conclusion, consumption of a synbiotic food for 6 weeks among diabetic patients had significant effects on serum insulin, hs-CRP, uric acid and plasma total GSH levels. Clinical trial registration number: www.irct.ir: IRCT201201195623N1.
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Background: Lifetime risk estimates of chronic kidney disease (CKD) can motivate preventative behaviors at the individual level and forecast disease burden and health care use at the population level. Study design: Markov Monte Carlo model simulation study. Setting & population: Current US black and white population. Model, perspective, & timeframe: Markov models simulating kidney disease development, using an individual perspective and lifetime horizon. Outcomes: Age-, sex-, and race-specific residual lifetime risks of CKD stages 3a+ (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²), 3b+ (eGFR <45 mL/min/1.73 m²), 4+ (eGFR <30 mL/min/1.73 m²), and end-stage renal disease (ESRD). Measurements: State transition probabilities of developing CKD and of dying prior to its development were modeled using: (1) mortality rates from the National Vital Statistics Report, (2) mortality risk estimates from a 2-million person meta-analysis, and (3) CKD prevalence from National Health and Nutrition Examination Surveys. Incidence, prevalence, and mortality related to ESRD were supplied by the US Renal Data System. Results: At birth, the overall lifetime risks of CKD stages 3a+, 3b+, 4+, and ESRD were 59.1%, 33.6%, 11.5%, and 3.6%, respectively. Women experienced greater CKD risk yet lower ESRD risk than men; blacks of both sexes had markedly higher CKD stage 4+ and ESRD risks (lifetime risks for white men, white women, black men, and black women, respectively: CKD stage 3a+, 53.6%, 64.9%, 51.8%, and 63.6%; CKD stage 3b+, 29.0%, 36.7%, 33.7%, and 40.2%; CKD stage 4+, 9.3%, 11.4%, 15.8%, and 18.5%; and ESRD, 3.3%, 2.2%, 8.5%, and 7.8%). Risk of CKD increased with age, with approximately one-half the CKD stage 3a+ cases developing after 70 years of age. Limitations: CKD incidence was modeled from prevalence estimates in the US population. Conclusions: In the United States, the lifetime risk of developing CKD stage 3a+ is high, emphasizing the importance of primary prevention and effective therapy to reduce CKD-related morbidity and mortality.
Article
Uremia is an illness that accompanies kidney failure and chronic kidney disease (CKD). Uremic illness is considered to be due largely to the accumulation of organic waste products that are normally cleared by the kidneys. However, uremic retention solutes are generated in part in the gastrointestinal tract (GIT), with the gut microbiota and the ensuing micro-biometabolome playing a significant role in the proliferation of uremic retention solutes. Toxins generated in, or introduced into the body via the intestine, such as advanced glycation end products, phenols, and indoles, all may contribute to the pathogenesis of CKD. Hence, it is biologically plausible, but not well recognized, that an important participant in the toxic load that contributes to CKD originates in the GIT. The microbiota that colonize the GIT perform a number of functions that include regulating the normal development and function of the mucosal barriers; assisting with maturation of immunological tissues, which in turn promotes immunological tolerance to antigens from foods, the environment, or potentially pathogenic organisms; controlling nutrient uptake and metabolism; and preventing propagation of pathogenic micro-organisms. Here, we develop a hypothesis that probiotics and prebiotics have a therapeutic role in maintaining a metabolically balanced GIT, and reducing progression of CKD and associated uremia.
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Trillions of microbes inhabit the human intestine, forming a complex ecological community that influences normal physiology and susceptibility to disease through its collective metabolic activities and host interactions. Understanding the factors that underlie changes in the composition and function of the gut microbiota will aid in the design of therapies that target it. This goal is formidable. The gut microbiota is immensely diverse, varies between individuals and can fluctuate over time - especially during disease and early development. Viewing the microbiota from an ecological perspective could provide insight into how to promote health by targeting this microbial community in clinical treatments.
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The demonstration that immune and epithelial cells can discriminate between different microbial species has extended our understanding of the actions of probiotics beyond simple barrier and antimicrobial concepts. Several probiotic mechanisms of action, relative to inflammatory bowel disease, have been elucidated: (1) competitive exclusion, whereby probiotics compete with microbial pathogens for a limited number of receptors present on the surface epithelium; (2) immunomodulation and/or stimulation of an immune response of gut-associated lymphoid and epithelial cells; (3) antimicrobial activity and suppression of pathogen growth; (4) enhancement of barrier function; and (5) induction of T cell apoptosis in the mucosal immune compartment. The unraveling of these mechanisms of action has led to new support for the use of probiotics in the management of clinical inflammatory bowel disease. Though level 1 evidence now supports the therapeutic use of probiotics in the treatment of postoperative pouchitis, only levels 2 and 3 evidence is currently available in support of the use of probiotics in the treatment of ulcerative colitis and Crohn's disease. Nevertheless, one significant and consistent finding has emerged during the course of research in the past year: not all probiotic bacteria have similar therapeutic effects. Rigorously designed, controlled clinical trials are vital to investigate the unresolved issues related to efficacy, dose, duration of use, single or multi-strain formulation, and the concomitant use of prebiotics, synbiotics, or antibiotics.
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Alterations in the composition of the commensal microbiota have been observed in many complex diseases. Understanding the basis for these changes, how they relate to disease risk or activity, and the mechanisms by which the symbiotic state of colonization resistance and host homeostasis is restored is critical for future therapies aimed at manipulating the microbiota.
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Exploring our gut microbial communities with new tools is allowing us to revisit old questions; to develop new concepts about our evolution, postnatal development, systems physiology, individuality, and definitions of health; and to further delineate the impact of our changing life-styles. It is also allowing us to envision exciting new ways for addressing global health problems. This area is inherently interdisciplinary, offering a wealth of opportunities to create new fields, partnerships, and educational initiatives. It is captivating to the public and carries substantial expectations. As such, participating scientists need to sponsor proactive, solution-focused discussions of its societal implications.
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Multiple sclerosis (MS) and other chronic inflammatory autoimmune diseases represent major public health challenges in industrialised Western society. MS results from an autoimmune attack against myelin structures by self-reactive lymphocytes, which are normal components of the healthy immune repertoire. The nature of the triggers that convert the innocuous self-reactive lymphocytes into an autoaggressive phenotype is poorly understood. In the past, it was primarily suspected that pathogenic infections trigger MS. However, so far, none of the incriminated pathogenic microbes were firmly associated with the disease. A growing body of evidence in animal models of MS implicates the gut microbiota in the induction of central nervous system (CNS) autoimmunity. The mammalian gut harbors a diverse population of microbial organisms which are essential for our well being. There is an increasing understanding that the gut microbiota not only modulates the local immune functions but also affects the systemic immune system. We are only just beginning to understand the nature of the interactions of the gut microbiota with the host's immune system especially in the context of autoimmune diseases. This review will address the influence of intestinal microbiota on immune homeostasis and on the development of autoimmune responses at sites distal to the intestine with a particular emphasis placed on a discussion about CNS autoimmunity.
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Probiotics are live microbial organisms that are present in foods or dietary supplements and that confer health benefits to the host when ingested in sufficient quantities. Probiotics can be bacterial (e.g. Bifidobacteria spp. and Lactobacillus spp.) or yeasts (e.g. Saccharomyces boulardii). The administration of probiotics is often believed to be by and large beneficial for individuals with inflammatory or infectious diseases of the gastrointestinal tract. These positive effects are generally attributed to the ability of probiotics to regulate intestinal permeability, normalize host intestinal flora, improve gut immune barrier function, and equilibrate the balance between proinflammatory and anti-inflammatory cytokines. Of note, however, these claims are not always substantiated by findings from properly conducted clinical trials. Of particular importance, even when results from randomized controlled trials support the beneficial effects of a particular probiotic for a specific indication, the benefits achieved by the probiotic are generally not translatable to other probiotic formulations. This review discusses the gastrointestinal indications for probiotic use and describes the level of evidence that supports the use of specific probiotics for these indications. Several indications are addressed, including enteric infections, gastritis caused by Helicobacter pylori infection, necrotizing enterocolitis, inflammatory bowel diseases, and irritable bowel syndrome.
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For decades, if not centuries, a variety of products with what would now be regarded as prebiotic and probiotic properties have been consumed by the general public and advocated for their benefits on health and, in particular, gastrointestinal well-being. More recently, medical science has taken a great interest in the population of micro-organisms, the gut microbiota that normally populates the human gut, and the range of important functions carried out by the microbiota in health is being progressively defined. As a corollary, the list of disorders and diseases that may result from disruption of the normal microbiota and/or its interaction with the host continues to grow. A scientific basis for the use of probiotics and prebiotics is, therefore, beginning to emerge. Unfortunately, although progress has been made, the clinical evidence to support the use of these preparations lags behind. Nevertheless, a number of human disease states may benefit from the use of probiotics, most notably, diarrheal illnesses, some inflammatory bowel diseases, certain infectious disorders, and irritable bowel syndrome. Prebiotics promote the growth of "good" bacteria, and although a variety of health benefits have been attributed to their use, prebiotics have been subjected to few large-scale clinical trials.
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A two by two experimental study has been designed to determine the effect of gut microbiota on energy metabolism in mouse models. The metabolic phenotype of germ-free (GF, n = 20) and conventional (n = 20) mice was characterized using a NMR spectroscopy-based metabolic profiling approach, with a focus on sexual dimorphism (20 males, 20 females) and energy metabolism in urine, plasma, liver, and brown adipose tissue (BAT). Physiological data of age-matched GF and conventional mice showed that male animals had a higher weight than females in both groups. In addition, conventional males had a significantly higher total body fat content (TBFC) compared to conventional females, whereas this sexual dimorphism disappeared in GF animals (i.e., male GF mice had a TBFC similar to those of conventional and GF females). Profiling of BAT hydrophilic extracts revealed that sexual dimorphism in normal mice was absent in GF animals, which also displayed lower BAT lactate levels and higher levels of (D)-3-hydroxybutyrate in liver, plasma, and BAT, together with lower circulating levels of VLDL. These data indicate that the gut microbiota modulate the lipid metabolism in BAT, as the absence of gut microbiota stimulated both hepatic and BAT lipolysis while inhibiting lipogenesis. We also demonstrated that (1)H NMR metabolic profiles of BAT were excellent predictors of BW and TBFC, indicating the potential of BAT to fight against obesity.
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Active multiple sclerosis lesions show inflammatory changes suggestive of a combined attack by autoreactive T and B lymphocytes against brain white matter. These pathogenic immune cells derive from progenitors that are normal, innocuous components of the healthy immune repertoire but become autoaggressive upon pathological activation. The stimuli triggering this autoimmune conversion have been commonly attributed to environmental factors, in particular microbial infection. However, using the relapsing-remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis, here we show that the commensal gut flora-in the absence of pathogenic agents-is essential in triggering immune processes, leading to a relapsing-remitting autoimmune disease driven by myelin-specific CD4(+) T cells. We show further that recruitment and activation of autoantibody-producing B cells from the endogenous immune repertoire depends on availability of the target autoantigen, myelin oligodendrocyte glycoprotein (MOG), and commensal microbiota. Our observations identify a sequence of events triggering organ-specific autoimmune disease and these processes may offer novel therapeutic targets.
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Mucosal surfaces of the gut are colonized by large numbers of heterogeneous bacteria that contribute to intestinal health and disease. In genetically susceptible individuals, a 'pathogenic community' may arise, whereby abnormal gut flora contributes to alterations in the mucosa and local immune system leading to gastrointestinal disease. These diseases include enteric infections, such as Clostridium difficile infection, small intestinal bacterial overgrowth, functional gastrointestinal disorders (including IBS), IBD and colorectal cancer. Prebiotics, probiotics and synbiotics (a combination of prebiotics and probiotics) have the capacity to reverse pathologic changes in gut flora and local immunity. Intestinal health and disease need to be thoroughly characterized to understand the interplay between the indigenous microbiota, the immune system and genetic host factors. This Review provides a broad overview of the importance of the intestinal microbiota in chronic disorders of the gut.
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Microbes in the colon produce compounds, normally excreted by the kidneys, which are potential uremic toxins. Although p-cresol sulfate and indoxyl sulfate are well studied examples, few other compounds are known. Here, we compared plasma from hemodialysis patients with and without colons to identify and further characterize colon-derived uremic solutes. HPLC confirmed the colonic origin of p-cresol sulfate and indoxyl sulfate, but levels of hippurate, methylamine, and dimethylamine were not significantly lower in patients without colons. High-resolution mass spectrometry detected more than 1000 features in predialysis plasma samples. Hierarchical clustering based on these features clearly separated dialysis patients with and without colons. Compared with patients with colons, we identified more than 30 individual features in patients without colons that were either absent or present in lower concentration. Almost all of these features were more prominent in plasma from dialysis patients than normal subjects, suggesting that they represented uremic solutes. We used a panel of indole and phenyl standards to identify five colon-derived uremic solutes: α-phenylacetyl-l-glutamine, 5-hydroxyindole, indoxyl glucuronide, p-cresol sulfate, and indoxyl sulfate. However, compounds with accurate mass values matching most of the colon-derived solutes could not be found in standard metabolomic databases. These results suggest that colonic microbes may produce an important portion of uremic solutes, most of which remain unidentified.
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I hypothesize here that the ability of probiotics to synthesize neuroactive compounds provides a unifying microbial endocrinology-based mechanism to explain the hitherto incompletely understood action of commensal microbiota that affect the host's gastrointestinal and psychological health. Once ingested, probiotics enter an interactive environment encompassing microbiological, immunological, and neurophysiological components. By utilizing a trans-disciplinary framework known as microbial endocrinology, mechanisms that would otherwise not be considered become apparent since any candidate would need to be shared among all three components. The range of neurochemicals produced by probiotics includes neurochemicals for which receptor-based targets on immune and neuronal elements (intestinal and extra-intestinal) have been well characterized. Production of neurochemicals by probiotics therefore allows for their consideration as delivery vehicles for neuroactive compounds. This unifying microbial endocrinology-based hypothesis, which may facilitate the selection and design of probiotics for clinical use, also highlights the largely unrecognized role of neuroscience in understanding how microbes may influence health. Editor's suggested further reading in BioEssays Harvesting the biological potential of the human gut microbiomeAbstract
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There is growing awareness of the importance of the gut microbiome in health and disease, and recognition that the microbe to host metabolic signalling is crucial to understanding the mechanistic basis of their interaction. This opens new avenues of research for advancing knowledge on the aetiopathologic consequences of dysbiosis with potential for identifying novel microbially-related drug targets. Advances in both sequencing technologies and metabolic profiling platforms, coupled with mathematical integration approaches, herald a new era in characterizing the role of the microbiome in metabolic signalling within the host and have far reaching implications in promoting health in both the developed and developing world.
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Recent data suggest a role for the intestinal microbiota in the pathogenesis of functional bowel disorders (FBDs). Probiotic studies in FBDs generated inconsistent results suggesting a strain-specific and product-specific effect. To investigate the clinical efficacy of Lactobacillus acidophilus NCFM (L-NCFM) and Bifidobacterium lactis Bi-07 (B-LBi07) in nonconstipation FBDs. A double-blind, placebo-control clinical trial of the probiotic bacterias L-NCFM and B-LBi07 twice a day (2×10(11) CFU/d) versus placebo over 8 weeks. Primary endpoints were global relief of gastrointestinal symptoms and satisfaction with treatment. Secondary endpoints were change in symptoms severity, well-being, and quality of life. Microbiological effect was assessed by quantitative real time polymerase chain reaction on fecal samples. Sixty patients (probiotic, n=31; placebo, n=29), 72% females, 84% whites, mean age 37 years. Abdominal bloating improved in the probiotics compared with the placebo group at 4 weeks (4.10 vs 6.17, P=0.009; change in bloating severity P=0.02) and 8 weeks (4.26 vs 5.84, P=0.06; change in bloating severity P<0.01). Analyses on the irritable bowel syndrome subgroup (n=33) showed similar results. L-NCFM and B-LBi07 twice a day improve symptoms of bloating in patients with FBDs. These data supports the role of intestinal bacteria in the pathophysiology of FBD and the role for probiotic bacteria in the management of these disorders.
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The concept that intestinal microbial composition not only affects the health of the gut, but also influences centrally-mediated systems involved in mood, is supported by a growing body of literature. Despite the emergent interest in brain-gut communication and its possible role in the pathogenesis of psychiatric disorders such as depression, particularly subtypes with accompanying gastrointestinal (GI) symptoms, there are few studies dedicated to the search for therapeutic solutions that address both central and peripheral facets of these illnesses. This study aims to assess the potential benefits of the probiotic Bifidobacterium infantis in the rat maternal separation (MS) model, a paradigm that has proven to be of value in the study of stress-related GI and mood disorders. MS adult rat offsprings were chronically treated with bifidobacteria or citalopram and subjected to the forced swim test (FST) to assess motivational state. Cytokine concentrations in stimulated whole blood samples, monoamine levels in the brain, and central and peripheral hypothalamic-pituitary-adrenal (HPA) axis measures were also analysed. MS reduced swim behavior and increased immobility in the FST, decreased noradrenaline (NA) content in the brain, and enhanced peripheral interleukin (IL)-6 release and amygdala corticotrophin-releasing factor mRNA levels. Probiotic treatment resulted in normalization of the immune response, reversal of behavioral deficits, and restoration of basal NA concentrations in the brainstem. These findings point to a more influential role for bifidobacteria in neural function, and suggest that probiotics may have broader therapeutic applications than previously considered.
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CKD is associated with increased cardiovascular mortality and a loss of disability-adjusted life years. Diseases of the genitourinary system were responsible for 928,000 deaths and 14,754,000 disability-adjusted life years in 2004. However, the absence of kidney registries in most of the low- and middle-income countries has made it difficult to ascertain the true burden of CKD in these countries. The global increase in the incidence and prevalence of CKD is being driven by the global increase in the prevalence of diabetes mellitus, hypertension, obesity, and aging. Most patients in low- and middle-income countries die because they cannot access renal replacement therapy because of the exorbitant cost. Community surveys have shown that the number of people with end-stage kidney disease is just the tip of the "CKD iceberg." The preventive strategies to stem the tide of CKD should involve educating the population on how to prevent renal disease; identifying those at risk of developing CKD; raising the awareness of the general public, policy makers, and health care workers; modifying the lifestyle of susceptible individuals; detecting early stage of CKD; arresting or hindering the progression of disease; and creating facilities for global assistance.
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Part of the uremic retention solutes are generated in the intestine, but this option is rarely discussed in the literature. In this publication, we describe consecutively the role of the intestine in generating uremic retention solutes, the pathophysiological importance of the generated solutes and therapeutic options that are inspired by this knowledge. Apart from its role as a route via which uremic toxins or their precursors enter the body, the intestine also acts as an active player by presenting more precursors for fermentation due to disturbances in assimilation caused by uremia, followed by alterations in further processing related to changes in the composition of the fermenting flora. Many of the toxins generated or introduced into the body via the intestine (advanced glycation end products, indoles, phenols) play an active role in vascular damage. Intestinal therapeutic interventions that could help decrease solute concentration are restriction of dietary intake, however at the expense of increasing the risk of malnutrition, rerouting of intestinal metabolism by administration of prebiotics or probiotics and/ or the administration of active sorbents such as AST-120 (Kremezin).