Lactobacillus Rhamnosus GG Supplementation Research Articles

Effects of dietary Lactobacillus rhamnosus GG supplementation on the production performance, egg quality, eggshell ultrastructure, and lipid metabolism of late-phase laying hens

BackgroundToward the late phase of laying, the production performance of laying hens decreases, egg quality deteriorates, lipid metabolism weakens, and hepatic lipid accumulation is exacerbated. Probiotics as an alternative to antimicrobials have been employed in poultry-related industries. Lactobacillus rhamnosus GG (LGG) is currently the most researched and clinically validated probiotic, showing promising effects in multiple application areas. However, few studies have been conducted on livestock (including poultry) production.ResultsCompared with the CON group, the feed conversion ratio (P < 0.01) declined significantly in the LGG group. Eggshell strength (P < 0.001) and eggshell thickness (P < 0.001) were significantly increased by supplementation with LGG in the diet. The height (P < 0.001) and proportion (P < 0.05) of the effective layer and the mammillary knob density (P < 0.01) in the eggshell ultrastructure of the LGG group increased significantly, while the mammillary layer (P < 0.05) and knob width (P < 0.01) decreased significantly. The LGG-treated hens had significantly lower serum concentrations of low-density lipoprotein (P < 0.05), free fatty acids (P < 0.01), and liver triglyceride (P < 0.05) levels than those in the CON group.ConclusionsLGG supplementation significantly decreases the feed conversion ratio, improves eggshell quality by altering the ultrastructure, and improves lipid metabolism in the late laying period.

Lactobacillus rhamnosus GG and butyrate supplementation in rats with bone cancer reduces mechanical allodynia and increases expression of μ-opioid receptor in the spinal cord.

Chronic cancer pain is one of the most unbearable symptoms for the patients with advanced cancer. The treatment of cancer pain continues to possess a major challenge. Here, we report that adjusting gut microbiota via probiotics can reduce bone cancer pain (BCP) in rats. The model of BCP was produced by tumor cell implantation (TCI) to the tibia in rats. Continuous feeding of Lactobacillus rhamnosus GG (LGG) was used to modulate the gut microbiota. Mechanical allodynia, bone destruction, fecal microbiota, and neurochemical changes in the primary dorsal root ganglion (DRG) and the spinal dorsal horn (DH) were assessed. LGG supplementation (109 CFU/rat/day) delayed the production of BCP for 3-4 days and significantly alleviated mechanical allodynia within the first 2 weeks after TCI. TCI-induced proinflammatory cytokines TNF-α and IL-β in the DH, and TCI-induced bone destruction in the tibia were both significantly reduced following LGG supplementation examined on day 8 after TCI. Meanwhile, we found that LGG supplementation, in addition to inhibiting TCI-induced pain, resulted in a significantly increased expression of the μ-opioid receptor (MOR) in the DH, but not in the DRG. LGG supplementation significantly potentiated the analgesic effect of morphine. Furthermore, LGG supplementation led to an increase in butyrate levels in the feces and serum and a decrease in histone deacetylase 2 (HDAC2) expression in the DH. Feeding TCI-rats with sodium butyrate solution alone, at a dose of 100 mg/kg, resulted in decreased pain, as well as decreased HDAC2 expression and increased MOR expression in the DH. The increased expression of MOR and decreased HDAC2 were also observed in neuro-2a cells when we treated the cells with serum from TCI rats with supplementation of LGG or sodium butyrate. This study provides evidence that reshaping the gut microbiota with probiotics LGG can delay the onset of cancer pain. The butyrate-HDAC2-MOR pathway may be the underlying mechanism for the analgesic effect of LGG. These findings shed light on an effective, safe, and non-invasive approach for cancer pain control and support the clinical implication of probiotics supplementation for patients with BCP.

The Detrimental Effects of Peripartum Antibiotics on Gut Proliferation and Formula Feeding Injury in Neonatal Mice Are Alleviated with Lactobacillus rhamnosus GG.

Peripartum antibiotics can negatively impact the developing gut microbiome and are associated with necrotizing enterocolitis (NEC). The mechanisms by which peripartum antibiotics increase the risk of NEC and strategies that can help mitigate this risk remain poorly understood. In this study, we determined mechanisms by which peripartum antibiotics increase neonatal gut injury and evaluated whether probiotics protect against gut injury potentiated by peripartum antibiotics. To accomplish this objective, we administered broad-spectrum antibiotics or sterile water to pregnant C57BL6 mice and induced neonatal gut injury to their pups with formula feeding. We found that pups exposed to antibiotics had reduced villus height, crypt depth, and intestinal olfactomedin 4 and proliferating cell nuclear antigen compared to the controls, indicating that peripartum antibiotics impaired intestinal proliferation. When formula feeding was used to induce NEC-like injury, more severe intestinal injury and apoptosis were observed in the pups exposed to antibiotics compared to the controls. Supplementation with the probiotic Lactobacillus rhamnosus GG (LGG) reduced the severity of formula-induced gut injury potentiated by antibiotics. Increased intestinal proliferating cell nuclear antigen and activation of the Gpr81-Wnt pathway were noted in the pups supplemented with LGG, suggesting partial restoration of intestinal proliferation by probiotics. We conclude that peripartum antibiotics potentiate neonatal gut injury by inhibiting intestinal proliferation. LGG supplementation decreases gut injury by activating the Gpr81-Wnt pathway and restoring intestinal proliferation impaired by peripartum antibiotics. Our results suggest that postnatal probiotics may be effective in mitigating the increased risk of NEC associated with peripartum antibiotic exposure in preterm infants.

Lactobacillus rhamnosus GG supplementation on eradication rate and dyspepsia in Helicobacter pylori infection treated with three-in-one bismuth quadruple therapy.

Helicobacter pylori (Hp)-related dyspepsia has been related to gastroduodenal dysbiosis. The role of probiotic supplementation in the clinical management of Hp infection has been the object of several studies in terms of improvement of efficacy and tolerability of eradication treatments but data on their effects on the outcomes of post-eradication dyspepsia are lacking. The aim of the present study was to evaluate the influence of Lactobacillus rhamnosus GG (LGG) supplementation on bismuth quadruple therapy (BQT) in the clinical management of Hp-related infection both in terms of efficacy and tolerability and persistence of post-treatment dyspepsia. A total of 164 (121 women) Hp-positive adult patients were enrolled in this pilot study and assigned to two different treatment regimens: group A received BQT for 10 days (three capsules qid, IPP bid) and group B received BQT for 10 days in combination with 6 × 109CFU LGG (ATCC53103) taken for 24 days (7 days before, 10 days during, and 7 days after therapy). Eradication was assessed after 45 days using the 13C-urea breath test (13C-UBT). Dyspepsia, distinguished into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), was assessed at the time of enrollment and 6 months after eradication. Approximately 98 patients were enrolled in group A and 66 patients in group B. At the enrollment, dyspepsia was present in 76.5% of group A and 86.5% of group B. No significant differences were observed in eradication rate between the 2 groups, both in intention-to-treat (ITT) analysis (82.3 vs. 75.0%) and per-protocol (PP) analysis (95 vs. 96%), and in the presence of side effects during the treatment (70.6 vs. 65.4%). At 6 months after eradication of Hp infection, the persistence of dyspepsia was statistically higher in patients of group A than in group B (38.8 vs. 16.1%; p = 0.032). The positive influence of LGG supplementation in improving post-eradication dyspepsia resulted in statistically more effectiveness in PDS dyspepsia, whose remission was 41.7% in group A and 84% in group B patients (p = 0.011). In conclusion, LGG supplementation during Hp eradication therapy, even if not affecting eradication rates and therapy-related side effects, significantly impacts the remission of dyspepsia.

Ameliorative effect of Lactobacillus rhamnosus GG on acetaminophen-induced hepatotoxicity via PKC/Nrf2/PGC-1α pathway

BackgroundAcetaminophen (APAP) overdose is a common cause of hepatotoxicity. Antioxidants like N-acetyl cysteine are recommended as a therapeutic option; nevertheless, it has limitations. The search for efficient alternatives is ongoing. Probiotics are live microorganisms that maintain a healthy gut microecology. Lactobacillus rhamnosus GG (LGG) is one of the widely used probiotics. Our study aimed to assess the protective and therapeutic effects of probiotic LGG on APAP-induced hepatotoxicity and evaluate the molecular pathways behind this effect. MethodsWistar Albino male rats were randomly distributed into the following experimental groups: group 1, non-treated rats (vehicle); group 2, rats received oral gavage of suspension of probiotic LGG (5 × 1010 CFU GG/0.5 ml in PBS) daily for 2 weeks (probiotic control); group 3, rats received APAP dose of 2 g/kg body weight (positive control); group 4, rats received oral gavage of suspension of probiotic LGG for 2 weeks followed by a single dose of APAP injection (prophylactic); and group 5, rats received a single dose of APAP and then 24 h later treated with oral gavage of probiotic LGG daily for 2 weeks (treatment). ResultsOur study revealed that administration of probiotic LGG (either as prophylactic or treatment) exhibited a remarkable reduction in APAP-induced liver injury as resembled by the decrease in liver enzymes (ALT and AST) and the histopathological features of liver sections. Moreover, the significant reduction in the oxidative marker malondialdehyde, along with the enhancement in glutathione reductase, and the significant reduction in inflammatory markers (nitric oxide and tumor necrosis factor-α) were all indicators of the efficiency of LGG in ameliorating the alterations accompanied with APAP-induced hepatotoxicity. Our findings also demonstrate that LGG administration boosted the expression of Nrf2 and PGC-1 while decreasing the expression of protein kinase C (PKC). As a result, the nuclear abundance of Nrf2 is increased, and the expression of various antioxidants is eventually upregulated. ConclusionOur study shows that probiotic LGG supplementation exerts a prophylactic and therapeutic effect against APAP-induced hepatotoxicity through modulating the expression of PKC and the Nrf2/PGC-1α signaling pathway and eventually suppressing oxidative damage from APAP overdose.

The gut microbiome, mild cognitive impairment, and probiotics: A randomized clinical trial in middle-aged and older adults

Advancing age coincides with changes in the gut microbiome and a decline in cognitive ability. Psychobiotics are microbiota-targeted interventions that can result in mental health benefits and protect the aging brain. This study investigated the gut microbiome composition and predicted microbial functional pathways of middle-aged and older adults that met criteria for mild cognitive impairment (MCI), compared to neurologically healthy individuals, and investigated the impact of probiotic Lactobacillus rhamnosus GG (LGG) in a double-blind, placebo-controlled, randomized clinical trial. A total of 169 community-dwelling middle-aged (52-59 years) and older adults (60-75 years) received a three-month intervention and were randomized to probiotic and placebo groups. Participants were further subdivided based on cognitive status into groups with intact or impaired cognition and samples were collected at baseline and post supplementation. Microbiome analysis identified Prevotella ruminicola, Bacteroides thetaiotaomicron, and Bacteroides xylanisolvens as taxa correlated with MCI. Differential abundance analysis at baseline identified Prevotella as significantly more prevalent in MCI subjects compared to cognitively intact subjects (ALDEx2 P =0.0017, ANCOM-BC P =0.0004). A decrease in the relative abundance of the genus Prevotella and Dehalobacterium in response to LGG supplementation in the MCI group was correlated with an improved cognitive score. Our study points to specific members of the gut microbiota correlated with cognitive performance in middle-aged and older adults. Should findings be replicated, these taxa could be used as key early indicators of MCI and manipulated by probiotics, prebiotics, and symbiotics to promote successful cognitive aging. Registered under ClinicalTrials.gov Identifier no. NCT03080818.

Lactobacillus rhamnosus GG Evaluation in Acute Diarrhea (LEAD): An Observational Study.

Background and objectiveProbiotics with documented efficacy such as Lactobacillus rhamnosus GG(LGG) and Saccharomyces boulardii might be utilized as adjuncts to rehydration for the management of acute gastroenteritis (AGE) in children. In this study, we aimed to evaluate the potential role of LGG in acute diarrhea in the Indian pediatric population.MethodsAn observational, cross-sectional study [Lactobacillus rhamnosus GG Evaluation in Acute Diarrhea (LEAD)] was conducted among children aged one month to 12 years with acute watery diarrhea. In addition to standard management of diarrhea, LGG was given as an adjuvant treatment at the discretion of treating physicians based on their routine practice. Observations were documented on days one, three, and five. Outcomes such as frequency and duration of diarrhea, time to change in consistency of stools, Bristol Stool Chart (BSC) reading, and global assessment by healthcare practitioners (HCPs) and patients were also recorded.ResultsOf the 2,080 patients enrolled, 1,900 completed the five-day follow-up. There was marked improvement observed in the number of incidences of loose stools from day one (mean: 7.33) to day five (mean: 1.6). The mean time to improvement in stool consistency was 34 hours. The mean duration of diarrhea was 44.63 hours. A relatively shorter duration of diarrhea was reported among participants in this study. There was also a significant improvement in the number of vomiting episodes. Most patients and HCPs reported the product to be excellent/very good on the global assessment scale. No adverse effects were noted in any of the groups.ConclusionBased on our findings, LGG supplementation may be a beneficial adjuvant treatment in reducing the severity and duration of acute diarrheal episodes.

Effect of Early Infant Probiotic Supplementation on Eczema, Asthma, and Rhinitis at 7 Years of Age.

We previously reported the initial results of the Trial of Infant Probiotic Supplementation (TIPS) study to determine if daily administration of a probiotic, Lactobacillus rhamnosus GG (LGG), during the first 6 months of life to children at high risk for allergic disease because of asthma in a parent can decrease their cumulative incidence of eczema.1 To date, the TIPS study is the only of its type performed in the United States.urour initial report, when all children were at least 2 years of age, we noted no effect on the incidence of eczema. We now present additional results, with the participants at least 7 years of age, on the cumulative incidence of eczema, asthma, and rhinitis.The TIPS study is a randomized, double-masked, parallel-arm, controlled trial designed to evaluate the effectiveness of daily LGG supplementation for the first 6 months of life to decrease the incidence of eczema, a potential early marker of asthma.1 For this analysis, we used physician-diagnosed asthma and physician-diagnosed rhinitis as secondary outcomes.To determine the effects of LGG on cumulative incidence of study outcomes, we performed modified intention-to-treat analyses with all participants who received treatment in the study arm to which they had been randomly assigned. We used survival analysis approaches to estimate Kaplan-Meier curves for each treatment group. We used nonparametric log-rank tests to determine differences between treatment groups and failure plots to visualize the cumulative probability of experiencing each outcome during follow-up.We used separate Cox proportional hazards regression models to compare the incidence of each outcome between the intervention and control groups, adjusting for mode of delivery and breastfeeding duration. Breastfeeding duration (in months up to 12) was treated as a time-dependent covariate.All analyses were performed using SAS version 9.4 software (SAS Institute Inc, Cary, NC). P < .05 was set for statistical significance. The protocol was approved by the Albert Einstein College of Medicine Institutional Review Board.Over the 7-year follow-up, 49 (53%) of 92 intervention and 54 (59%) of 92 control participants remained in the study for an overall 56% retention rate. Eczema was diagnosed in 78 participants, asthma in 32, and rhinitis in 15. The mean follow-up time was 5.7 years (median, 7 years). Incidence of eczema was high during infancy but low thereafter. In contrast, incidence rates for asthma and rhinitis were constant during childhood. Although the initial cumulative incidence seemed to favor the intervention in the early years of life for eczema and asthma, this trajectory was not sustained. The results showed no difference in the primary or secondary outcomes (Fig 1). Main findings from the Cox proportional hazards regression model are presented in Table 1. Cesarean delivery was associated with a greater incidence of rhinitis, with a hazard ratio (HR) of 3.33 (95% confidence interval [CI], 1.21–9.21).This follow-up report reveals that early infant LGG supplementation does not affect the cumulative incidence of eczema, asthma, and rhinitis at 7 years of age. Kalliomäki et al2 reported that early LGG supplementation decreases the likelihood of eczema and wheezing; however, their LGG supplementation occurred through both postnatal infant and prenatal maternal supplementation. The effect of LGG supplementation may only be discernable in infants born into high-risk scenarios because of altered gastrointestinal microbiota development3,4 (eg, cesarean delivery, lack of breast milk exposure); however, few TIPS study infants were exclusively fed formula or were cesarean delivered. Although LGG supplementation in infants is associated with significant increases in the similarity of the infant gut microbiota and metabolome to that of an infant at low risk for allergic disease, it does so only for the 6-month period in which LGG is administered.5 It is possible that probiotic supplementation to the mother during pregnancy and/or the infant for a longer period may be more effective.The results presented in Table 1 reveal that breastfeeding may increase the risk of eczema (HR, 11.97); however, the CIs are extremely wide (95% CI, 6.81–21.02), suggesting an unstable estimate. In addition, the effect of breastfeeding is not consistent, as there is no association with asthma or rhinitis incidence; therefore, we cannot clearly interpret this result. There is the potential of a type II error, as the TIPS study was designed to have 80% power to detect an HR <0.66, corresponding with a 10% absolute reduction in the 2-year cumulative incidence of eczema.Despite these limitations of the results, we can build on our earlier report regarding eczema. For this population of infants at higher risk for allergic disease, we cannot support the use of early infant LGG probiotic supplementation for the prevention of eczema, asthma, or rhinitis.

Lactobacillus rhamnosus GG ameliorates deoxynivalenol-induced kidney oxidative damage and mitochondrial injury in weaned piglets.

Deoxynivalenol (DON) is a common mycotoxin that pollutes food crops and adversely affects the health of animals, even humans. Lactobacillus rhamnosus GG (LGG) can alleviate intestinal injury, and anti-inflammatory and antioxidant effects. However, the potential of LGG in alleviating kidney injury induced by DON in piglets remains to be studied. The objective of this study was to investigate the adverse effect of DON on kidney injury and the protective ability of LGG. A total of twenty-seven weaned piglets were divided into three groups: CON group, DON group (3.11 mg kg-1 feed) and LGG + DON group (LGG powder 1 g kg-1 + DON 3.15 mg kg-1 feed). DON increased the MDA content, and decreased antioxidant enzyme activity (GSH-Px) and total antioxidant capacity (P < 0.05). Meanwhile, DON activated the Nrf2 antioxidant pathway. However, LGG supplementation alleviated the damage of DON to the kidney antioxidant system of piglets. Notably, DON significantly reduced the Sirt3 expression (P < 0.05), which was alleviated by LGG addition. The expression of mitochondrial biogenesis related factors such as VDAC1 and Cyt C was up-regulated by DON (P < 0.05), and LGG could improve mitochondrial ultrastructural abnormalities and mitochondrial dysfunction. In addition, LGG mitigated DON-induced mitochondrial fusion inhibition, and prevented DON-mediated mitochondrial autophagy. In conclusion, LGG play a protective role in DON-induced kidney toxicity, and dietary intervention may be a strategy to reduce mycotoxins.

Probiotic Lactobacillus rhamnosus GG (LGG) restores intestinal dysbacteriosis to alleviate upregulated inflammatory cytokines triggered by femoral diaphyseal fracture in adolescent rodent model.

The aim of the study was to examine the influence of femoral shaft fracture on systemic inflammation and gut microbiome in adolescent rats and evaluate the anti-inflammatory effect of Lactobacillus rhamnosus GG (LGG) and its regulation of intestinal flora, as well as illustrate the mechanism by which LGG ameliorates the inflammatory response and restores intestinal dysbacteriosis. Twenty-four male Sprague Dawley rats of 5 to 6 weeks of age were subjected to a standard femoral shaft fracture and internally fixed with LGG supplementation in advance or on the same day of injury or with saline solution for 1 week. The levels of TNF-α, IL-6, IL-10, and CRP were assessed using standard protocols. Furthermore, gut microbiota composition was analyzed in the fecal samples using 16S rDNA gene sequencing, and the relationship between gut microbiota variation and inflammatory response was tested. The serum indices of the above-mentioned inflammatory cytokines were significantly increased, and the gut microbial balance was significantly disturbed in adolescent rats by diaphyseal fractures of the femur and surgery. Moreover, L. rhamnosus strains manipulated the gut microbiota by decreasing the relative abundance of Proteobacteria and increasing that of Firmicutes, Actinobacteria and Bacteroidetes, which in turn increased the levels of IL-10 and alleviated the levels of IL-6, CRP, and TNF-α. LGG exhibited anti-inflammatory effects by alleviating the inflammatory response and regulating the gut microbiota in adolescent rats who underwent skeletal fracture and surgery. Our results suggested that the L. rhamnosus strains could be considered as an alternative dietary supplement for the prevention or treatment of skeletal injury and its associated complications.

Effect of Lactobacillus rhamnosus GG on Energy Metabolism, Leptin Resistance, and Gut Microbiota in Mice with Diet-Induced Obesity.

Obesity is closely associated with various metabolic disorders, including leptin resistance, which is characterized by high circulating leptin levels. Probiotics can decrease circulating leptin levels by alteration of the gut microbiota. Thus, they may have anti-obesogenic effects. In this study, the effects of administration of a probiotic bacterium, Lactobacillus rhamnosus GG (LGG), on gut microbiota and modulation of leptin resistance were evaluated in mice. Male Balb/C mice aged 7 weeks were fed either a normal diet (ND), high-fat diet (HFD), HFD supplemented with low-dose LGG (108 CFU/mouse/day), or HFD supplemented with high-dose LGG (1010 CFU/mouse/day) for 10 weeks. Significantly increased body weight, epididymal fat weight, and decreased leptin responsiveness to exogenous leptin treatment and ratio of villus height to crypt depth were observed in the HFD-fed mice compared to the ND-fed mice. Moreover, a remarkable increase in the proportion of Proteobacteria and ratio of Firmicutes/Bacteroidetes in the fecal microbiota were also observed in the HFD-fed mice. Supplementation of HFD with high-dose LGG restored exogenous leptin responsiveness, increased the ratio of villus height to crypt depth, and decreased the proportion of Proteobacteria in fecal microbiota. These findings suggest that LGG supplementation might alleviate leptin resistance caused by an HFD through the improvement of the digestive health of the host.

Abstract 3344: The human commensal lactobacillus rhamnosus GG orchestrates an anti-tumor immune response

Abstract Only 10% of patients with colorectal cancer (CRC) are approved for immunotherapy and only 50% of approved patients are responsive to this treatment. The 95% of CRC patients that are refractory to immunotherapy are so because of low anti-tumor immune responses in the gut mucosa. Mucosal immunity is sensitive to changes in the microbiome community structure, and to dietary supplementation with beneficial bacteria, known as ‘probiotics' which are known to augment mucosal immunity. Therefore, we supplemented the murine microbiome by daily oral gavage with the human commensal bacteria, Lactobacillus rhamnosus GG (LGG). We discovered that LGG increases colonic CD8 T cell responses by flow cytometry and immunofluorescence analysis. We did not believe that LGG was having a direct effect on CD8 T-cell function but was being augmented through an innate cell population. Using BATF3-null mice which lack conventional dendritic cells, we did not detect LGG-induced CD8 T-cell changes determining that this response is dendritic cell dependent. In addition, we sought to determine how LGG was being sensed by dendritic cells. Based off preliminary data and published reports, we utilized Toll like Receptor 2 (TLR2)-null mice and found that LGG-induced CD8 T cell induction also required TLR2 signaling. These data describe a novel mechanism whereby LGG induces colonic CD8 T cells activation through a dendritic cell and TLR2-dependent manner. As CD8 T-cells are critical in the anti-tumor response, we induced colonic tumors in mice by performing the DSS-AOM model. After tumors were established, we administered LGG daily by oral gavage. LGG supplementation resulted in significantly reduced tumor burden compared to control mice fed vehicle or a non-probiotic bacterium. Furthermore, this reduction in tumor burden was CD8 T cell dependent, as depletion of CD8 T cells abrogated this effect. In summary, oral supplementation with LGG may hold clinical promise in augmenting colonic anti-tumor immune responses and may increase immunotherapy response rates in patients. Citation Format: Josh Owens, Bejan Saeedi, Crystal Naudin, Sarah Hunter-Chang, Trevor Darby, Brian Robinson, Rheinallt Jones. The human commensal lactobacillus rhamnosus GG orchestrates an anti-tumor immune response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3344.

A Pilot Randomized Control Trial With the Probiotic Strain Lactobacillus rhamnosus GG (LGG) in ADHD: Children and Adolescents Report Better Health-Related Quality of Life.

Objectives: This double-blind pilot randomized placebo-controlled trial examined the possible effect of the probiotic strain Lactobacillus rhamnosus GG ATCC53103 (LGG) on symptoms of attention-deficit/hyperactivity disorder (ADHD), health-related quality of life (QoL), and serum levels of cytokines in children and adolescents with ADHD.Methods: This trial evaluated 32 drug-naive children and adolescents aged between four and 17 years with a diagnosis of ADHD. The study subjects were randomly assigned to either the group that received LGG or the group that received the placebo. Assessments, comprising the ADHD Parent-Report Rating Scale-IV: Home Version; the Child Self-Report and Parent Proxy-Report of the Pediatric Quality of Life InventoryTM (PedsQLTM) 4.0 Generic Core Scale; the Parent Form (CBCL/6-18) and the Teacher Report Form (TRF) of the Child Behavior Checklist (CBCL) for ages 6–18 of the Achenbach System of Empirically Based Assessment (ASEBA); and the serum cytokines; were compared between the groups at the baseline and after 3 months.Results: Thirty-five participants were randomized, with 32 completing the study (91.4% retention). There was a significant improvement in the PedsQL Child Self-Report Total Score after 3 months of treatment in the probiotic (p = 0.021, d = 0.53), whereas there was no significant improvement in the placebo group (p = 0.563, d = 0.04). The results of psychometric parameters assessed by parents and teachers were not so straightforward. There were statistically significant differences in the levels of serum cytokines between the groups after the 3-month treatment period: IL-6 in both the probiotic (p = 0.004, d = 0.73) and the placebo groups (p = 0.035, d = 0.94); IL-10 (p = 0.035, d = 0.6); IL-12 p70 (p = 0.025, d = 0.89); and TNF-α (p = 0.046, d = 0.64) in the probiotic group only.Conclusions: Children and adolescents with ADHD who received LGG supplementation reported better health-related QoL compared to their peers who received the placebo. This suggests that LGG supplementation could be beneficial. But results with psychometric tests conducted by parents and teachers as well as differences in the levels of inflammatory cytokines were ambiguous. Based on these results, we propose some study modifications: a longer observation period (6–12 months); inclusion of more children's self-report assessments; recruitment of non-drug naive patients and the possible omission of serum cytokines measurements.Clinical Trial Registration: Medical Ethics Committee (UKC-MB-KME-19-06/16).

Probiotic Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice.

Background and AimsCholestatic liver disease is characterized by gut dysbiosis and excessive toxic hepatic bile acids (BAs). Modification of gut microbiota and repression of BA synthesis are potential strategies for the treatment of cholestatic liver disease. The purpose of this study was to examine the effects and to understand the mechanisms of the probiotic Lactobacillus rhamnosus GG (LGG) on hepatic BA synthesis, liver injury, and fibrosis in bile duct ligation (BDL) and multidrug resistance protein 2 knockout (Mdr2−/−) mice.Approach and ResultsGlobal and intestine‐specific farnesoid X receptor (FXR) inhibitors were used to dissect the role of FXR. LGG treatment significantly attenuated liver inflammation, injury, and fibrosis with a significant reduction of hepatic BAs in BDL mice. Hepatic concentration of taurine‐β‐muricholic acid (T‐βMCA), an FXR antagonist, was markedly increased in BDL mice and reduced in LGG‐treated mice, while chenodeoxycholic acid, an FXR agonist, was decreased in BDL mice and normalized in LGG‐treated mice. LGG treatment significantly increased the expression of serum and ileum fibroblast growth factor 15 (FGF‐15) and subsequently reduced hepatic cholesterol 7α‐hydroxylase and BA synthesis in BDL and Mdr2−/− mice. At the molecular level, these changes were reversed by global and intestine‐specific FXR inhibitors in BDL mice. In addition, LGG treatment altered gut microbiota, which was associated with increased BA deconjugation and increased fecal and urine BA excretion in both BDL and Mdr2−/− mice. In vitro studies showed that LGG suppressed the inhibitory effect of T‐βMCA on FXR and FGF‐19 expression in Caco‐2 cells.ConclusionLGG supplementation decreases hepatic BA by increasing intestinal FXR–FGF‐15 signaling pathway–mediated suppression of BA de novo synthesis and enhances BA excretion, which prevents excessive BA‐induced liver injury and fibrosis in mice.

Lactobacillus rhamnosus GG supplementation modulates the gut microbiota to promote butyrate production, protecting against deoxynivalenol exposure in nude mice

Deoxynivalenol (DON) is the most common mycotoxin in grains, and DON exposure causes gastrointestinal inflammation and systemic immunosuppression. The immunosuppression caused by DON has raised serious concerns about whether it is safe to use probiotics in immunocompromised hosts. Gut microbiota remodeling by Lactobacillus is a potential effective strategy to prevent DON exposure. The athymic nude mice were chose as the model of immunocompromised animals. We tested the effect of the probiotic Lactobacillus rhamnosus GG (LGG) or Lactobacillus acidophilus (LA) supplementation on host protection against DON exposure and the underlying mechanisms in nude mice. DON exposure induced endoplasmic reticulum (ER) stress and impaired intestinal barrier function and microbiota, which were relieved by LGG supplementation but not LA supplementation. LGG supplementation significantly enhanced the intestinal barrier function, increased the body weight and the survival rate in nude mice that exposed to DON for two weeks. Furthermore, LGG supplementation modulated the gut microbiota by increasing the abundance of Bacteroidetes and the levels of the butyrate-producing genes But and Buk to promote butyrate production. Butyrate inhibited the IRE1α/XBP1 signaling pathway to reduce DON-induced intestine injury. In conclusion, LGG supplementation modulated the gut microbiota to promote butyrate production, protecting against DON exposure in nude mice. Both LGG and butyrate show promise for use in protecting against DON exposure.

Effect of probiotic supplementation on cognitive function in children and adolescents: a systematic review of randomised trials.

Available reviews have shown potential effects of probiotics on neurobehavioral outcomes through 'gut-brain axis' mechanism in adults. However, reviews on cognitive function in children and adolescents are lacking. Therefore, we conducted a systematic review of randomised controlled trials (RCTs) of the effect of probiotic supplementation on cognitive function in children and adolescents. A search of four databases (Cochrane Central Register of Controlled Trials, PsycARTICLES, Scopus, PubMed) was conducted to identify RCTs published from January 1990 to December 2018. Seven studies met the inclusion criteria and their cognitive outcomes were analysed. Only one study found a positive result with Lactobacillus rhamnosus GG (LGG) 1×1010 cfu supplementation with outcomes on attention deficit hyperactivity disorder (ADHD) or Asperger syndrome (AS) manifestations as diagnosed using the International Classification of Diseases-10 criteria. The supplementations were administered to Finnish mothers for 4 weeks before delivery and continuously given for 6 months after delivery if they breastfed, or to the children. ADHD or AS was diagnosed at the age of 13 years in 17.1% children in the placebo and none in the probiotic group (P=0.008). This study found significant differences in species composition and number of cells belonging to the genus Bifidobacterium between healthy children and children who later developed ADHD or AS at different time points. Six remaining studies with varying strains, durations of intervention, start-time of administration, and outcomes demonstrated no difference in cognition after probiotic supplementation. Metagenomic analyses on gut microbiota composition were not performed in any of these studies. In conclusion, the favourable effect of probiotic supplementation on cognitive function in children and adolescents was observed in one study with LGG supplementation by a risk reduction of developing ADHD or AS (i.e. autism). More long-term and follow-up trials using probiotics identifying the effect on cognition are warranted before routine use.

Efficacy of probiotic supplementary therapy for asthma, allergic rhinitis, and wheeze: a meta-analysis of randomized controlled trials.

Background: Probiotic supplementary therapy to prevent allergic diseases, including asthma in children, has been widely explored in many randomized controlled trials. However, there is conflicting evidence on the effect of probiotic supplementation during pregnancy and infancy to the incidence of asthma and allergic rhinitis. Method: This study was designed to systematically explore the potential effects of probiotic supplementation on the occurrence and development of asthma, wheeze, and allergic rhinitis. Randomized controlled trials were searched in several medical literature data bases. A meta-analysis was undertaken by using the fixed-effects model or the random effects model to calculate the pooled risk of significant heterogeneity. Two writers were designated to perform the study selection and data extraction. The primary outcome was clinically diagnosed asthma; the secondary outcomes included wheeze, allergic rhinitis, and a positive aeroallergen skin-prick test result. Results: Seventeen randomized controlled trials, which composed a total of 5264 children, were analyzed. The pooled data for risk of developing asthma after probiotic supplementation showed no significant reduction compared with controls (risk ratio [RR] 0.86 [95% confidence interval {CI}, 0.73-1.01]; I² = 0%; p = 0.06). A subgroup of strains indicated that Lactobacillus rhamnosus GG supplementation only had a reduction to the occurrence of asthma (RR 0.75 [95% CI, 0.57-0.99]; I² = 11%; p = 0.04). The supplement in the postnatal group had a similar result, but the incorporated data were limited. Meanwhile, it is failed to identify that probiotic supplementary therapy have a clear benefit to the secondary outcomes: wheeze, allergic rhinitis, positive aeroallergen skin-prick test result. Conclusion: This study showed a significant benefit that supplementation with probiotics in pre- and postnatal periods was likely to play an essential strategic role in the prevention of asthma. However, these effects were based on the type of probiotics used, which also need more large-sample and high-quality RCTs to confirm the reliability of this study.

Pilot Analysis of Early Lactobacillus rhamnosus GG for Infant Colic Prevention.

We conducted a secondary analysis of data from a trial of Lactobacillus rhamnosus GG (LGG) supplementation as a pilot study to assess whether LGG prevents infant colic. For the first 6 months of life, infants received a daily dose of 10 billion colony-forming units of LGG or a control (n = 184). We compared the likelihood of a diagnosis of colic before 4 months of age, based on parent-reported symptoms or a physician diagnosis of colic. Out of the 184 infants, 18 (9.8%) had colic. There were no differences between the 2 groups in the percentage of infants with colic based on symptoms (control 5.4% vs LGG 9.8%; P = 0.19); physician diagnosis (control 3.2% vs LGG 7.6%; P = 0.26); or either symptoms or diagnosis combined (control 6.5% vs LGG 13.0%; P = 0.13). In this pilot study, early infant LGG supplementation does not appear to prevent the later development of colic.

Mucosal adhesion and anti-inflammatory effects of Lactobacillus rhamnosus GG in the human colonic mucosa: A proof-of-concept study.

AIMTo investigate the adhesion and anti-inflammatory effects of Lactobacillus rhamnosus GG (LGG) in the colonic mucosa of healthy and ulcerative colitis (UC) patients, both in vivo and ex vivo in an organ culture model.METHODSFor the ex vivo experiment, a total of 98 patients (68 UC patients and 30 normal subjects) were included. Endoscopic biopsies were collected and incubated with and without LGG or LGG-conditioned media to evaluate the mucosal adhesion and anti-inflammatory effects [reduction of tumor necrosis factor alpha (TNFα) and interleukin (IL)-17 expression] of the bacteria, and extraction of DNA and RNA for quantification by real-time (RT)-PCR occurred after the incubation. A dose-response study was performed by incubating biopsies at “regular”, double and 5 times higher doses of LGG. For the in vivo experiment, a total of 42 patients (20 UC patients and 22 normal controls) were included. Biopsies were taken from the colons of normal subjects who consumed a commercial formulation of LGG for 7 d prior to the colonoscopy, and the adhesion of the bacteria to the colonic mucosa was evaluated by RT-PCR and compared with that of control biopsies from patients who did not consume the formulation. LGG adhesion and TNFα and IL-17 expression were compared between UC patients who consumed a regular or double dose of LGG supplementation prior to colonoscopy.RESULTSIn the ex vivo experiment, LGG showed consistent adhesion to the distal and proximal colon in normal subjects and UC patients, with a trend towards higher concentrations in the distal colon, and in UC patients, adhesion was similar in biopsies with active and quiescent inflammation. In addition, bioptic samples from UC patients incubated with LGG conditioned media (CM) showed reduced expression of TNFα and IL-17 compared with the corresponding expression in controls (P < 0.05). Incubation with a double dose of LGG increased mucosal adhesion and the anti-inflammatory effects (P < 0.05). In the in vivo experiment, LGG was detectable only in the colon of patients who consumed the LGG formulation, and bowel cleansing did not affect LGG adhesion. UC patients who consumed the double LGG dose had increased mucosal concentrations of the bacteria and reduced TNFα and IL-17 expression compared with patients who consumed the regular dose (48% and 40% reduction, respectively, P < 0.05).CONCLUSIONIn an ex vivo organ culture model, LGG showed consistent adhesion and anti-inflammatory effects. Colonization by LGG after consumption for a week was demonstrated in vivo in the human colon. Increasing the administered dose increased the adhesion and effectiveness of the bacteria. For the first time, we demonstrated that LGG effectively adheres to the colonic mucosa and exerts anti-inflammatory effects, both ex vivo and in vivo.

Lactobacillus rhamnosus GG in the Primary Prevention of Eczema in Children: A Systematic Review and Meta-Analysis.

Current guidelines recommend the use of probiotics to reduce the risk of eczema. It remains unclear which strain(s) to use. We systematically evaluated data on the efficacy of Lactobacillus rhamnosus GG (LGG) supplementation prenatally and/or postnatally for the primary prevention of eczema. The Cochrane Library, MEDLINE, and EMBASE databases were searched up to August 2018, with no language restrictions, for systematic reviews of randomized controlled trials (RCTs) and RCTs published afterwards. The primary outcome was eczema. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI). A random-effects model was used to pool data. Heterogeneity was explored using the I2 statistics. The GRADE criteria were used to assess the overall quality of evidence supporting the primary outcome. Seven publications reporting 5 RCTs (889 participants) were included. High to moderate certainty in the body of evidence suggests that LGG supplementation (regardless of the timing of administration) did not reduce the risk of eczema. There was also no consistent effect on other allergic outcomes. This meta-analysis shows that LGG was ineffective in reducing eczema. It does not support the general recommendation to use probiotics for preventing eczema, unless specific strains would be indicated.