title: Clinical application of probiotics in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes Effect of multi-strain probiotics (multi-strain microbial cell preparation) on glycemic control and other diabetes-related outcomes in people with type 2 diabetes: a randomized controlled trial Effects of probiotic yogurt consumption on inflammatory biomarkers in patients with type 2 diabetes Probiotic yogurt improves antioxidant status in type 2 diabetic patients. The Consumption of Synbiotic Bread Containing Lactobacillus sporogenes and Inulin Affects Nitric Oxide and Malondialdehyde in Patients with Type 2 Diabetes Mellitus: Randomized, Double-Blind, Placebo-Controlled Trial The Impact of Probiotic Soy Milk Consumption on Oxidative Stress Among Type 2 Diabetic Kidney Disease Patients: A Randomized Controlled Clinical Trial. Effect of probiotics on clinical and immune parameters in enthesitis‐related arthritis category of juvenile idiopathic arthritis Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis
abstract: BACKGROUND & AIMS Type 2 diabetes has been associated with dysbiosis and one of the possible routes to restore a healthy gut microbiota is by the regular ingestion of probiotics . We aim ed to investigate the effects of probiotics on glycemic control , lipid profile , inflammation , oxidative stress and short chain fatty acids in T2D . METHODS In a double-blind , r and omized , placebo-controlled trial , 50 volunteers consumed daily 120 g/d of fermented milk for 6 wk . Participants were assigned into two groups : probiotic group , consuming fermented milk containing Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp lactis BB-12 ( 109 colony-forming units/d , each ) and control group , consuming conventional fermented milk .  Anthropometric measurements , body composition , fasting blood and faecal sample s were taken at baseline and after 6 wk . RESULTS 45 subjects out of 50 ( 90 % ) completed follow-up . After 6 wk , there was a significant decrease in fructosamine levels ( -9.91 mmol/L ; p = 0.04 ) and hemoglobin A1c tended to be lower ( -0.67 % ; p=0.06 ) in probiotic group . TNF-α and resistin were significantly reduced in probiotic and control groups ( -1.5 and -1.3 pg/mL , -.1 and -2.8 ng/mL , respectively ) , while IL-10 was significantly reduced ( - 0.65 pg/mL ; p < 0.001 ) only in the control group . Fecal acetic acid was increased in both groups ( 0.58 and 0.59 % in probiotic and control groups , respectively ; p < 0.01 ) . There was a significant difference between groups concerning mean changes of HbA1c ( + 0.31 for control group vs -0.65 for probiotic group ; p=0.02 ) , total cholesterol ( + 0.55 for control group vs -0.15 for probiotic group ; p=0.04 ) and LDL-cholesterol ( + 0.36 for control group vs -0.20 for probiotic group p=0.03 ) . CONCLUSIONS Probiotic consumption improved the glycemic control in T2D subjects , however , the intake of fermented milk seems to be involved with others metabolic changes , such as decrease in inflammatory cytokines ( TNF-α and resistin ) and increase in the acetic acid Microbial modulation of diabetes Short-chain fatty acids ( SCFAs ) are produced by various human gut microbes . SCFAs act as an energy source to the colonic epithelium and are also sensed by host signaling pathways that modulate appetite and inflammation . Deficiency of gut SCFAs is associated with type 2 diabetes . Zhao et al. found that adopting a high-fiber diet promoted the growth of SCFA-producing organisms in diabetic humans . The high-fiber diet induced changes in the entire gut microbe community and correlated with elevated levels of glucagon-like peptide-1 , a decline in acetylated hemoglobin levels , and improved blood-glucose regulation . Science , this issue p. 1151 Increasing dietary fiber intake increases the abundance of short-chain fatty acid – producing gut microbes and relieves diabetes . The gut microbiota benefits humans via short-chain fatty acid ( SCFA ) production from carbohydrate fermentation , and deficiency in SCFA production is associated with type 2 diabetes mellitus ( T2DM ) . We conducted a r and omized clinical study of specifically design ed isoenergetic diets , together with fecal shotgun metagenomics , to show that a select group of SCFA-producing strains was promoted by dietary fibers and that most other potential producers were either diminished or unchanged in patients with T2DM . When the fiber-promoted SCFA producers were present in greater diversity and abundance , participants had better improvement in hemoglobin A1c levels , partly via increased glucagon-like peptide-1 production . Promotion of these positive responders diminished producers of metabolically detrimental compounds such as indole and hydrogen sulfide . Targeted restoration of these SCFA producers may present a novel ecological approach for managing T2DM Aim Evidence of a possible connection between gut microbiota and several physiological processes linked to type 2 diabetes is increasing . However , the effect of multi-strain probiotics in people with type 2 diabetes remains unclear . This study investigated the effect of multi-strain microbial cell preparation — also refers to multi-strain probiotics — on glycemic control and other diabetes-related outcomes in people with type 2 diabetes . Design A r and omized , double-blind , parallel-group , controlled clinical trial . Setting Diabetes clinic of a teaching hospital in Kuala Lumpur , Malaysia . Participants A total of 136 participants with type 2 diabetes , aged 30–70 years , were recruited and r and omly assigned to receive either probiotics ( n = 68 ) or placebo ( n = 68 ) for 12 weeks . Outcomes Primary outcomes were glycemic control-related parameters , and secondary outcomes were anthropomorphic variables , lipid profile , blood pressure and high-sensitivity C-reactive protein . The Lactobacillus and Bifidobacterium quantities were measured before and after intervention as an indicator of successful passage of the supplement through gastrointestinal tract . Statistical analysis Intention-to-treat ( ITT ) analysis was performed on all participants , while per- protocol ( PP ) analysis was performed on those participants who had successfully completed the trial with good compliance rate . Results With respect to primary outcomes , glycated hemoglobin decreased by 0.14 % in the probiotics and increased by 0.02 % in the placebo group in PP analysis ( p < 0.05 , small effect size of 0.050 ) , while these changes were not significant in ITT analysis . Fasting insulin increased by 1.8 µU/mL in placebo group and decreased by 2.9 µU/mL in probiotics group in PP analysis . These changes were significant between groups at both analyses ( p < 0.05 , medium effect size of 0.062 in PP analysis and small effect size of 0.033 in ITT analysis ) . Secondary outcomes did not change  significantly . Probiotics successfully passed through the gastrointestinal tract . Conclusion Probiotics modestly improved HbA1c and fasting insulin in people with type 2 diabetes Introduction : The role of inflammatory cytokines in diabetes and its complications has been shown in some studies . The purpose of this study was to compare the effect of probiotic and conventional yogurt on inflammatory markers in patients with type 2 diabetes . Methods : Forty-four patients with type 2 diabetes were participated in this r and omized , double-blind controlled clinical trial and assigned to two intervention and control groups . The subjects in the intervention group consumed 300 g/d probiotic yogurt and subjects in the control group consumed 300 g/d conventional yogurt for 8 weeks . Anthropometric indices , dietary intakes , and serum levels of glucose , HbA1c , IL-6 , TNF-α and hs-CRP were evaluated at the beginning and end of the intervention . Results : For anthropometric indices and dietary intakes , no significant differences were seen within and between groups post intervention ( p > 0.05 ) . The consumption of probiotic yogurt caused significant decrease in HbA1c and TNF-α levels ( p= 0.032 and p= 0.040 , respectively ) in the intervention group . Conclusion : It is suggested that probiotic yogurt may be used as an alternative prevention approach and treatment method to control diabetic complications OBJECTIVE Oxidative stress plays a major role in the pathogenesis and progression of diabetes . Among various functional foods with an antioxidant effect , probiotic foods have been reported to repress oxidative stress . The objective of this clinical trial was to assess the effects of probiotic and conventional yogurt on blood glucose and antioxidant status in type 2 diabetic patients . METHODS Sixty-four patients with type 2 diabetes mellitus , 30 to 60 y old , were assigned to two groups in this r and omized , double-blind , controlled clinical trial . The patients in the intervention group consumed 300 g/d of probiotic yogurt containing Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 and those in the control group consumed 300 g/d of conventional yogurt for 6 wk .  Fasting blood sample s , 24-h dietary recalls , and anthropometric measurements were collected at the baseline and at the end of the trial . RESULTS Probiotic yogurt significantly decreased fasting blood glucose ( P < 0.01 ) and hemoglobin A1c ( P < 0.05 ) and increased erythrocyte superoxide dismutase and glutathione peroxidase activities and total antioxidant status ( P < 0.05 ) compared with the control group . In addition , the serum malondialdehyde concentration significantly decreased compared with the baseline value in both groups ( P < 0.05 ) . No significant changes from baseline were shown in insulin concentration and erythrocyte catalase activity within either group ( P > 0.05 ) . CONCLUSION The consumption of probiotic yogurt improved fasting blood glucose and antioxidant status in type 2 diabetic patients . These results suggest that probiotic yogurt is a promising agent for diabetes management Objectives : To our knowledge , no reports are available indicating the effects of synbiotic bread consumption on nitric oxide ( NO ) , biomarkers of oxidative stress , and liver enzymes among patients with type 2 diabetes mellitus ( T2DM ) . This study was performed to determine the effects of the daily consumption of synbiotic bread on NO , biomarkers of oxidative stress , and liver enzymes in patients with T2DM . Methods : This r and omized , double-blind , placebo-controlled trial was performed among 81 patients with diabetes , aged 35–70 years old . After a 2-week run-in period , patients were r and omly divided into 3 groups : group A ( n = 27 ) received synbiotic bread containing viable and the heat-resistant probiotic Lactobacillus sporogenes ( 1 × 108 CFU ) and 0.07 g inulin per 1 g , group B ( n = 27 ) received probiotic bread containing Lactobacillus sporogenes ( 1 × 108 CFU ) , and group C ( n = 27 ) received control bread for 8 weeks . Patients were asked to consume the synbiotic , probiotic , or control breads 3 times a day in 40 g packages for a total of 120 g/day . Fasting blood sample s were taken at baseline and after an 8-week intervention for quantificationof related markers . Results : After 8 weeks , the consumption of synbiotic bread compared to the probiotic and control breads result ed in a significant rise in plasma NO ( 40.6 ± 34.4 vs 18.5 ± 36.2 and −0.8 ± 24.5 µmol/L , respectively , p < 0.001 ) and a significant reduction in malondialdehyde ( MDA ) levels ( −0.7 ± 0.7 vs 0.6 ± 1.7 and 0.5 ± 1.5 µmol/L , respectively , p = 0.001 ) . We did not find any significant effect of the synbiotic bread consumption on plasma total antioxidant capacity ( TAC ) , plasma glutathione ( GSH ) , catalase , serum liver enzymes , calcium , iron , magnesium levels , and blood pressure compared to the probiotic and control breads . Conclusion : In conclusion , consumption of the synbiotic bread for 8 weeks among patients with T2DM had beneficial effects on plasma NO and MDA levels ; however , it did not affect plasma TAC , GSH , catalase levels , serum liver enzymes , calcium , iron , magnesium levels , and blood pressure OBJECTIVE Diabetic kidney disease ( DKD ) is one the most important complications of diabetes leading to end-stage renal disease . This study aim ed to determine the effects of probiotic soy milk consumption on oxidative stress biomarkers in type 2 DKD patients . METHODS Forty-eight patients were r and omly assigned to consume a diet containing 200 mL/day probiotic soy milk in the intervention group or soy milk in the control condition . As determinants of oxidative stress , malondialdehyde , 8-iso-prostagl and in F2α , oxidized glutathione , total antioxidant capacity , reduced glutathione ( GSH ) , glutathione peroxidase , and glutathione reductase were measured after 8 weeks of intervention according to the st and ard protocol . RESULTS Between groups analysis showed that DKD patients in the probiotic soy milk group had a higher mean value of GSH compared with those in the soy milk group . In the final adjusted model , this difference remained significant . Consistently , oxidized glutathione concentration was significantly reduced among patients in the probiotic soy milk group . Also , for activity levels of antioxidant enzymes including glutathione peroxidase and glutathione reductase , significant increased levels were observed between 2 intervention groups in the final adjusted model . However , no significant reduction of the serum 8-iso-prostagl and in F2α or malondialdehyde and no induction of TAC concentrations within and between the 2 groups in the crude and adjusted models were detected . CONCLUSION Overall , the results demonstrate that probiotic soy milk consumption could improve some oxidative stress factors among DKD patients . Further longitudinal studies with consideration of individual variation should be conducted Gut microflora and dysbiosis as an environmental factor has been linked to the pathogenesis of enthesitis‐related arthritis ( JIA‐ERA ) ; thus , we performed a proof‐of‐concept study of probiotics to modulate the gut‐flora and study the effects on immune and clinical parameters of children having JIA‐ERA . Forty‐six children with active JIA‐ERA were r and omized to placebo or probiotic therapy along with non‐steroidal anti‐inflammatory drugs ( NSAIDs ) for 12 weeks . Patients were assessed using a six‐point composite disease activity index ( mJSpADA ) based on morning stiffness , joint count , enthesitis count , sacroiliitis/inflammatory back pain , uveitis and erythrocyte sedimentation rate/C‐reactive protein ( ESR/CRP ) . Frequencies of T helper type 1 ( Th1 ) , Th2 , Th17 and regulatory T cells in blood were measured using flow cytometry . Serum cytokines interferon (IFN)‐γ , interleukin (IL)−4 , IL‐17 , IL‐10 , tumour necrosis factor (TNF)‐α and IL‐6 were measured by cytokine bead array using flow cytometer . The average age of 46 children ( 44 boys ) was 15 ± 2.5 years and duration of disease was 3.5 ± 3 years . There was no significant difference in improvement in mJSpADA between the two groups ( P = 0·16 ) . Serum IL‐6 levels showed a decrease ( P < 0·05 ) in the probiotic‐group . Th2 cell frequency ( P < 0·05 ) and serum IL‐10 levels ( P < 0·01 ) showed an increase in the placebo group , but again the probiotic use did not show a significant change in immune parameters when compared to the placebo . Adverse effects among the probiotic and placebo groups were diarrhea ( 36 versus 45 % ) , abdominal pain ( 9 versus 20 % ) , minor infections ( 4·5 versus 20 % ) and flatulence ( 23 versus 15 % ) , respectively . Thus , we can conclude that  probiotic therapy in JIA‐ERA children is well tolerated , but failed to show any significant immune or clinical effects over NSAID therapy Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects . However , probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive . We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation ( aFMT ) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche . Contrary to homeostasis , antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice . Compared to spontaneous post-antibiotic recovery , probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration , while aFMT induced a rapid and near-complete recovery within days of administration . In vitro , Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition . Collectively , potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery , highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention . However , evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial . We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome . A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage . In colonized , but not germ-free mice , probiotics encountered a marked mucosal colonization resistance . In contrast , humans featured person- , region- and strain-specific mucosal colonization patterns , hallmarked by predictive baseline host and microbiome features , but indistinguishable by probiotics presence in stool . Consequently , probiotics induced a transient , individualized impact on mucosal community structure and gut transcriptome . Collectively , empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa , meriting development of new personalized probiotic approaches Background Gastroenteritis accounts for approximately 1.7 million visits to the emergency department ( ED ) by children in the United States every year . Data to determine whether the use of probiotics improves outcomes in these children are lacking . Methods We conducted a r and omized , double‐blind trial involving 886 children 3 to 48 months of age with gastroenteritis who presented to six pediatric EDs in Canada . Participants received a 5‐day course of a combination probiotic product containing Lactobacillus rhamnosus R0011 and L. helveticus R0052 , at a dose of 4.0 × 109 colony‐forming units twice daily or placebo . The primary outcome was moderate‐to‐severe gastroenteritis , which was defined according to a post‐enrollment modified Vesikari scale symptom score of 9 or higher ( scores range from 0 to 20 , with higher scores indicating more severe disease ) . Secondary outcomes included the duration of diarrhea and vomiting , the percentage of children who had unscheduled physician visits , and the presence or absence of adverse events . Results Moderate‐to‐severe gastroenteritis within 14 days after enrollment occurred in 108 of 414 participants ( 26.1 % ) who were assigned to probiotics and 102 of 413 participants ( 24.7 % ) who were assigned to placebo ( odds ratio , 1.06 ; 95 % confidence interval [ CI ] , 0.77 to 1.46 ; P=0.72 ) . After adjustment for trial site , age , detection of rotavirus in stool , and frequency of diarrhea and vomiting before enrollment , trial‐group assignment did not predict moderate‐to‐severe gastroenteritis ( odds ratio , 1.06 ; 95 % CI , 0.76 to 1.49 ; P=0.74 ) . There were no significant differences between the probiotic group and the placebo group in the median duration of diarrhea ( 52.5 hours [ interquartile range , 18.3 to 95.8 ] and 55.5 hours [ interquartile range , 20.2 to 102.3 ] , respectively ; P=0.31 ) or vomiting ( 17.7 hours [ interquartile range , 0 to 58.6 ] and 18.7 hours [ interquartile range , 0 to 51.6 ] , P=0.18 ) , the percentages of participants with unscheduled visits to a health care provider ( 30.2 % and 26.6 % ; odds ratio , 1.19 ; 95 % CI , 0.87 to 1.62 ; P=0.27 ) , and the percentage of participants who reported an adverse event ( 34.8 % and 38.7 % ; odds ratio , 0.83 ; 95 % CI , 0.62 to 1.11 ; P=0.21 ) . Conclusions In children who presented to the emergency department with gastroenteritis , twice‐daily administration of a combined L. rhamnosus – L. helveticus probiotic did not prevent the development of moderate‐to‐severe gastroenteritis within 14 days after enrollment . ( Funded by the Canadian Institutes of Health Research and others ; PROGUT Clinical Trials.gov number , NCT01853124 .
target: The results of this systematic review and meta‐ analysis suggest that probiotic and synbiotic supplementation may help to improve biomarkers of inflammation and oxidative stress in diabetic patients .
background: Abstract The role of gut microbiota in the management of diabetes has been shown .
  Several current trials are investigating the effect of probiotics and prebiotics , which are widely used to modulate intestinal microbiota , on inflammatory factors and biomarkers of oxidative stress in diabetic patients ; however , their findings are controversial .
  The aim of the current meta‐ analysis was to evaluate the effects of probiotic and synbiotic supplementation on levels of serum high‐sensitivity C‐reactive protein ( hs‐CRP ) and biomarkers of oxidative stress in diabetic patients .