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Probiotics for Prevention and Treatment of Diarrhea

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Abstract

Probiotics are increasingly used for prevention and treatment of diarrhea more in children than in adults. Given the broad spectrum of diarrhea, this review focuses on the main etiologies: acute gastroenteritis, antibiotic-associated diarrhea (AAD), and necrotizing enterocolitis (NEC). For each, we reviewed randomized controlled trials, meta-analyses, and guidelines. For acute gastroenteritis we found 12 guidelines: 5 recommended probiotics and 7 did not. However, the guidelines containing positive recommendations provided proof of evidence from clinical trials and meta-analyses. Lactobacillus rhamnosus GG (LGG) and Saccharomyces boulardii had the most compelling evidence of efficacy as they reduced the duration of the disease by 1 day. For AAD 4 meta-analyses were found, reporting variable efficacy of probiotics in preventing diarrhea, based on the setting, patient's age, and antibiotics. The most effective strains were LGG and S. boulardii. For NEC, we found 3 randomized controlled trials, 5 meta-analyses, and 4 position papers. Probiotics reduced the risk of NEC enterocolitis and mortality in preterm babies. Guidelines did not support a routine use of probiotics and asked for further data for such sensitive implications. In conclusion, there is strong and solid proof of efficacy of probiotics as active treatment of gastroenteritis in addition to rehydration. There is solid evidence that probiotics have some efficacy in prevention of AAD, but the number needed to treat is an issue. For both etiologies LGG and S. boulardii have the strongest evidence. In NEC the indications are more debated, yet on the basis of available data and their implications, probiotics should be carefully considered.
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Biblioteca richiedente: Biblioteca del Dipartimento di Scienze Mediche Traslazionali dell'Università degli Studi di Napoli Federico II
Data richiesta: 12/10/2015 16:57:34
Biblioteca fornitrice: Biblioteca di Medicina e chirurgia, Farmacia. Polo 4, Università di Pisa
Data evasione: 12/10/2015 17:28:42
Titolo rivista/libro: Journal of clinical gastroenterology (Online)
Titolo articolo/sezione: Probiotics for Prevention and Treatment of Diarrhea
Autore/i: Guarino A, Guandalini S, Lo Vecchio A
ISSN: 1539-2031
DOI: 10.1097/MCG.0000000000000349
Anno: 2015
Volume: 49 Suppl 1
Fascicolo: -
Editore:
Pag. iniziale: S37
Pag. finale: S45
... They are commensal inhabitants of the human gastrointestinal tract and contribute to human health. As probiotics, lactic acid bacteria have shown that they may present beneficial effects, such as preventing diarrhea and inflammatory bowel disease [1][2][3]. The quantification of lactic acid bacteria is important for epidemiologic studies and their roles in various niche markets. ...
... ± 0.31 (9) 3.42 ± 0.62 (9) 34.79 ± 0.3 (9) 3.98 ± 0.59 (9) 10 2 ND 3 0.4 ± 0.11 (9) ND 0.25 ± 0.14 (9) 1 Mean ± standard deviation (number of positive replicates on nine replicates analyzed). 2 DNA concentration at which the signal of the ddPCR assay was saturated. 3 ND, not detectable. ...
... Mean ± standard deviation (number of positive replicates on nine replicates analyzed).2 DNA concentration at which the signal of the ddPCR assay was saturated.3 ...
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Droplet digital polymerase chain reaction (ddPCR) is one of the newest and most promising tools providing absolute quantification of target DNA molecules. Despite its emerging applications in microorganisms, few studies reported its use for detecting lactic acid bacteria. This study evaluated the applicability of a ddPCR assay targeting molecular genes obtained from in silico analysis for detecting Lactiplantibacillus plantarum subsp. plantarum, a bacterium mainly used as a starter or responsible for fermentation in food. The performance characteristics of a ddPCR were compared to those of a quantitative real-time PCR (qPCR). To compare the linearity and sensitivity of a qPCR and ddPCR, the calibration curve for a qPCR and the regression curve for a ddPCR were obtained using genomic DNA [102–108 colony-forming units (CFU)/mL] extracted from a pure culture and spiked food sample. Both the qPCR and ddPCR assays exhibited good linearity with a high coefficient of determination in the pure culture and spiked food sample (R2 ≥ 0.996). The ddPCR showed a 10-fold lower limit of detection, suggesting that a ddPCR is more sensitive than a qPCR. However, a ddPCR has limitations in the absolute quantitation of high bacterial concentrations (>106 CFU/mL). In conclusion, a ddPCR can be a reliable method for detecting and quantifying lactic acid bacteria in food.
... Attempts to treat infant colic with Lactobacilli supplementation have shown no benefit [63]. However, it has been shown that supplementation with Lactobacillus rhamnosus reduces the duration of diarrhea [64]. Studies in animals have shown that treatment with Lactobacillus can improve enteritis or intestinal inflammation recovery [65] and inhibit the colonization of the pathogenic E.coli K1 strain [66]. ...
... Attempts to treat infant colic with Lactobacilli supplementation has shown no benefit [63]. However, supplementation with Lactobacillus rhamnosus reduces the duration of diarrhea [64]. Lactobacillus GG has been shown to prevent and reduce the duration of diarrhea caused by rotavirus infections in animals [87,88]. ...
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Since the first bacterial inhabitants of the human gastrointestinal tract were identified, a lot of research into the study of the human microbiome and its effects on health has been conducted. Currently, it is accepted that humans have a symbiotic relationship with the gut microbiome, though the specifics of this relationship are not well understood. The microbiome of neonates constantly changes and appears to influence many facets of the infant’s health and predisposition later in life. This review aims to show how the microbiome develops over time. We discuss its composition, origins and stages of development of microbiota, the possible health benefits of a proper neonatal microbiome, and the dangers associated with dysbiosis. We emphasize the shielding, modulating, and stimulating effects breast milk has on the infant microbiota. The methods commonly used for the study of microbiota are also discussed.
... Specific probiotics have been recommended as adjunctive treatment of gastroenteritis by several guidelines all over the world (Guarino et al., 2018). Many clinical trials showed that diarrhea is rapidly reduced upon administration of Lacticaseibacillus rhamnosus GG (LGG), and the effects are already observed within hours after the onset of therapy (Guarino et al., 2015). However, the mechanisms of action of LGG are not entirely clear. ...
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Background Administration of Lacticaseibacillus rhamnosus GG (LGG) to children with gastroenteritis is recommended by universal guidelines. Rotavirus (RV) causes diarrhea through combined cytotoxic and enterotoxic effects. Aim of this study was to evaluate the mechanisms of efficacy of LGG in an in-vitro model of RV diarrhea in its viable form (LGG) and conditioned medium (mLGG). Methods Ion secretion corresponding to the NSP4 enterotoxic effect, was evaluated by short circuit current ( Isc ) and the cytotoxic effect by transepithelial electrical resistance (TEER) in Ussing chambers, upon exposure to RV in Caco-2 enterocyte monolayers treated or not with living probiotic or its culture supernatant. Mechanisms of enterotoxic and cytotoxic damage were evaluated including oxidative stress measured by reactive oxygen species, apoptosis evaluated by DAPI and nuclear staining, NFkβ immunofluorescence. Results RV induced Isc increase and TEER decrease, respectively indicating ion secretion and epithelial damage, the two established pathways of diarrhea. Both probiotic preparations reduced both diarrheal effects, but their potency was different. Live LGG was equally effective on both enterotoxic and cytotoxic effect whereas mLGG was highly effective on ion secretion and showed minimal protective effects on cytoskeleton, apoptosis and NFkβ. Conclusions LGG counteracts RV-induced diarrhea by inhibiting both cytotoxic and enterotoxic pathogenic mechanisms. Namely, LGG inhibits chloride secretion by specific moieties secreted in the medium with a direct pharmacologic-like action. This is considered a postbiotic effect. Subsequently, live bacteria exert a probiotic effect protecting the enterocyte structure.
... There is increasing evidence suggesting that probiotics can help prevent and treat viral infections (32,33). For instance, clinical trials have demonstrated that certain probiotic strains can reduce the severity of rotavirus gastroenteritis and respiratory virus infections (33,34). Moreover, several studies have confirmed the antiviral effects of certain LAB strains against norovirus, indicating that probiotics could prevent and treat norovirus infections (25,26). ...
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Although noroviruses are the causative agents of most non-bacterial foodborne disease outbreaks, effective antivirals are currently unavailable. Certain probiotic strains have been reported as active antivirals for norovirus infections, but their mechanisms have not been fully elucidated. Herein, we examined the antiviral potential of 122 lactic acid bacteria isolates against murine norovirus (MNV), a human norovirus surrogate. A centenarian gut-derived strain, Limosilactobacillus fermentum PV22, exhibited the strongest MNV antagonism and reduced the viral titer by 2.23 ± 0.38 (log-value) in 5 min with stable activity at 25°C (P < 0.01). Genome mining revealed that its antiviral activity can be attributed to the synthesis of γ-aminobutyric acid, and this finding was experimentally verified. Furthermore, we demonstrated the safety of the isolate and its high intestinal colonization ability. In conclusion, we discovered a centenarian gut-derived L. fermentum strain with strong anti-norovirus activity and identified its antiviral metabolite. Our results will offer new solutions for the prevention and treatment of food-related norovirus infections.
... Following the above inclusion and exclusion criteria, 507 articles (ongoing studies, unexpectedly terminated trials, noncancer patients, not oral probiotic use, in vitro studies, nonchemotherapy studies, and reviews) and 38 duplicate articles were removed after carefully reading their titles and abstract, leaving only 51 articles. After reading the remaining articles, 39 additional studies were further excluded because of that 12 studies did not include cancer patients or they were not receiving chemotherapy (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37), two did not include oral probiotic use (38,39), 20 had no record of diarrhea or oral mucositis in patients (40-59) (18 of them did not include diarrhea or oral mucositis indicators (40)(41)(42)(43)(44)(45)(46)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59), and the other two studies only recorded the frequency of diarrhea or oral mucositis rather than the number of patients who had the adverse reactions (47,48)), and five were not randomized controlled trials (60)(61)(62)(63)(64). Finally, 12 articles were selected for the meta-analysis. ...
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Background Chemotherapy generally causes serious diarrhea and oral mucositis in cancer patients, and subsequently affects treatment. Oral administration of probiotics provides a therapeutic choice to address these limitations. This study aims to conduct a systematic review and meta-analysis on the efficacy of oral probiotic use in the management of the chemotherapy-induced adverse reactions, and to summarize the mechanisms underlying the action. Methods We searched PubMed, Embase, ClinicalTrials.gov , and Web of Science from the start of the study to its completion on Dec. 31, 2021. Risk of bias was assessed using Cochrane Collaboration's Tool. Statistical analysis of the acquired data was performed via the RevMan and the Stata Statistical Software. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42020220650). Results Twelve randomized controlled trials including 1,013 patients were recruited and analyzed via the standard procedure of meta-analysis. In contrast to the control group, orally taking probiotics significantly decreased the risk of chemotherapy-induced diarrhea (≥ 1 grade) ( RR = 0.70; 95% Cl: 0.56, 0.88; P = 0.002) and oral mucositis (≥ 1 grade) (RR: 0.84; 95% Cl: 0.78, 0.91; P < 0.00001) at all grades. Further analysis found that severe diarrhea (≥ 2 grades) (RR: 0.50; 95% Cl: 0.32, 0.78; P = 0.002) and severe oral mucositis also significantly declined (≥ 3 grades) (RR: 0.66; 95% Cl: 0.55, 0.79; P < 0.00001) after oral probiotic use. Interestingly, the beneficial effects of probiotics displayed statistically significant only in Asian patients. Importantly, the more species of bacteria they took, the lower the incidences of the adverse reactions occurred. We used Egger's test P value to confirm that there is no publication bias. Conclusions This meta-analysis demonstrated that orally administrated probiotics has a potential to decrease chemotherapy-induced diarrhea and oral mucositis incidences. However, the efficacy of oral probiotic use against the adverse reactions needs to be further verified through more clinical trials, and the species and number of probiotics have to be optimized and standardized prior to clinical applications. Systematic Review Registration https://www.crd.york.ac.uk , identifier: 220650.
... For example, L. rhamnosus is by far the most studied strain regarding infectious diarrhea, and it has been proven that it is able to reduce diarrhea duration in one day [53]. In the case of antibiotic-associated diarrhea, L. acidophilus, L. casei and L. rhamnosus are some of the most common options [54]. In addition, they have been also utilized for a variety of dental health problems including periodontal infection, halitosis and cavities [55]. ...
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Background: Antibiotics are frequently prescribed in children. They alter the microbial balance within the gastrointestinal tract, commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent AAD via restoration of the gut microflora. Objectives: The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children. Search methods: MEDLINE, EMBASE, CENTRAL, CINAHL, AMED, and the Web of Science (inception to November 2014) were searched along with specialized registers including the Cochrane IBD/FBD review group, CISCOM (Centralized Information Service for Complementary Medicine), NHS Evidence, the International Bibliographic Information on Dietary Supplements as well as trial registries. Letters were sent to authors of included trials, nutraceutical and pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials. Conference proceedings, dissertation abstracts, and reference lists from included and relevant articles were also searched. Selection criteria: Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion. Data collection and analysis: Study selection, data extraction as well as methodological quality assessment using the risk of bias instrument was conducted independently and in duplicate by two authors. Dichotomous data (incidence of diarrhea, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea, mean daily stool frequency) as mean difference (MD), along with their corresponding 95% confidence interval (95% CI). For overall pooled results on the incidence of diarrhea, sensitivity analyses included available case versus extreme-plausible analyses and random- versus fixed-effect models. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea, as well as risk of bias. We also conducted post hoc subgroup analyses by patient diagnosis, single versus multi-strain, industry sponsorship, and inpatient status. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. Main results: Twenty-three studies (3938 participants) met the inclusion criteria. Trials included treatment with either Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., orStreptococcus spp., alone or in combination. Eleven studies used a single strain probiotic, four combined two probiotic strains, three combined three probiotic strains, one combined four probiotic strains, two combined seven probiotic strains, one included ten probiotic strains, and one study included two probiotic arms that used three and two strains respectively. The risk of bias was determined to be high or unclear in 13 studies and low in 10 studies. Available case (patients who did not complete the studies were not included in the analysis) results from 22/23 trials reporting on the incidence of diarrhea show a large, precise benefit from probiotics compared to active, placebo or no treatment control. The incidence of AAD in the probiotic group was 8% (163/1992) compared to 19% (364/1906) in the control group (RR 0.46, 95% CI 0.35 to 0.61; I(2) = 55%, 3898 participants). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate. This benefit remained statistically significant in an extreme plausible (60% of children loss to follow-up in probiotic group and 20% loss to follow-up in the control group had diarrhea) sensitivity analysis, where the incidence of AAD in the probiotic group was 14% (330/2294) compared to 19% (426/2235) in the control group (RR 0.69; 95% CI 0.54 to 0.89; I(2) = 63%, 4529 participants). None of the 16 trials (n = 2455) that reported on adverse events documented any serious adverse events attributable to probiotics. Meta-analysis excluded all but an extremely small non-significant difference in adverse events between treatment and control (RD 0.00; 95% CI -0.01 to 0.01). The majority of adverse events were in placebo, standard care or no treatment group. Adverse events reported in the studies include rash, nausea, gas, flatulence, abdominal bloating, abdominal pain, vomiting, increased phlegm, chest pain, constipation, taste disturbance, and low appetite. Authors' conclusions: Moderate quality evidence suggests a protective effect of probiotics in preventing AAD. Our pooled estimate suggests a precise (RR 0.46; 95% CI 0.35 to 0.61) probiotic effect with a NNT of 10. Among the various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony forming units/day may be appropriate given the modest NNT and the likelihood that adverse events are very rare. It is premature to draw conclusions about the efficacy and safety of other probiotic agents for pediatric AAD. Although no serious adverse events were observed among otherwise healthy children, serious adverse events have been observed in severely debilitated or immuno-compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation. Until further research has been conducted, probiotic use should be avoided in pediatric populations at risk for adverse events. 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Fecal microbiota transplantation (FMT) is recognized as alternative therapeutic modality for recurrent Clostridium difficile infection (RCDI). However, data on its efficacy in children is lacking, including its effect on their growth and fecal microbiota. We report two young children (<3 year-old), who failed available therapeutics for RCDI, however responded remarkably well to FMT. Besides resolution of clinical features of CDI, FMT administration led to marked improvement in their growth, along with increased microbiota diversity, especially proportion of Bacteroides. Our two cases illustrate the efficacy of FMT in children with RCDI and its positive effect on their growth and gut microbiota.
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Background and objective: Late-onset sepsis frequently complicates prematurity, contributing to morbidity and mortality. Probiotics may reduce mortality and necrotizing enterocolitis (NEC) in preterm infants, with unclear effect on late-onset sepsis. This study aimed to determine the effect of administering a specific combination of probiotics to very preterm infants on culture-proven late-onset sepsis. Methods: A prospective multicenter, double-blinded, placebo-controlled, randomized trial compared daily administration of a probiotic combination (Bifidobacterium infantis, Streptococcus thermophilus, and Bifidobacterium lactis, containing 1 × 10(9) total organisms) with placebo (maltodextrin) in infants born before 32 completed weeks' gestation weighing <1500 g. The primary outcome was at least 1 episode of definite late-onset sepsis. Results: Between October 2007 and November 2011, 1099 very preterm infants from Australia and New Zealand were randomized. Rates of definite late-onset sepsis (16.2%), NEC of Bell stage 2 or more (4.4%), and mortality (5.1%) were low in controls, with high breast milk feeding rates (96.9%). No significant difference in definite late-onset sepsis or all-cause mortality was found, but this probiotic combination reduced NEC of Bell stage 2 or more (2.0% versus 4.4%; relative risk 0.46, 95% confidence interval 0.23 to 0.93, P = .03; number needed to treat 43, 95% confidence interval 23 to 333). Conclusions: The probiotics B infantis, S thermophilus, and B lactis significantly reduced NEC of Bell stage 2 or more in very preterm infants, but not definite late-onset sepsis or mortality. Treatment with this combination of probiotics appears to be safe.
Article
Background: Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics (live microbial supplements) may play a role in reducing NEC and the associated morbidity. Objectives: To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC or sepsis, or both, in preterm infants. Search methods: For this update, searches were made of MEDLINE (1966 to October 2013), EMBASE (1980 to October 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 10), and abstracts of annual meetings of the Society for Pediatric Research (1995 to 2013). Selection criteria: Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age or < 2500 g birth weight, or both, were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome. Data collection and analysis: Standard methods of The Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials and for data collection and analysis. Main results: Twenty-four eligible trials were included. Included trials were highly variable with regard to enrolment criteria (that is birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) (typical relative risk (RR) 0.43, 95% confidence interval (CI) 0.33 to 0.56; 20 studies, 5529 infants) and mortality (typical RR 0.65, 95% CI 0.52 to 0.81; 17 studies, 5112 infants). There was no evidence of significant reduction of nosocomial sepsis (typical RR 0.91, 95% CI 0.80 to 1.03; 19 studies, 5338 infants). The included trials reported no systemic infection with the supplemental probiotics organism. Probiotics preparations containing either lactobacillus alone or in combination with bifidobacterium were found to be effective. Authors' conclusions: Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence strongly supports a change in practice. Head to head comparative studies are required to assess the most effective preparations, timing, and length of therapy to be utilized.
Article
The efficacy of each probiotic should be evaluated separately. Previously, we have shown that Lactobacillus GG (LGG) is effective in treating acute gastroenteritis (AGE) in children. To update our 2007 meta-analysis on the effectiveness of LGG in treating AGE in children. The Cochrane Library, MEDLINE and EMBASE databases were searched from August 2006 (end date of last search) to May 2013, with no language restrictions, for randomised controlled trials (RCTs) and meta-analyses. Fifteen RCTs (2963 participants) met the inclusion criteria in this updated meta-analysis. Combined data from 11 RCTs (n = 2444) showed that LGG significantly reduced the duration of diarrhoea compared with placebo or no treatment (mean difference, MD -1.05 days, 95% CI -1.7 to -0.4). LGG was more effective when used at a daily dose ≥10(10 ) CFU (eight RCTs, n = 1488, MD -1.11 days, 95% CI -1.91 to -0.31) than when used at a daily dose <10(10) CFU (three RCTs, n = 956, MD -0.9 day, 95% CI -2.5 to 0.69). LGG was effective in children treated in Europe (five RCTs, n = 744, MD -1.27 days, 95% CI -2.04 to -0.49); in the non-European setting, the difference between the LGG group and the control group was of a borderline statistical significance (six RCTs, n = 1700, MD -0.87, 95% CI -1.81 to 0.08). Lactobacillus GG reduces the duration of diarrhoea. A subset of patients that is more likely to benefit includes subjects treated with a high daily dose of LGG (≥10(10) CFU/day) who are either in-patients or out-patients from geographical Europe. Given the methodological limitations of many of the included trials, the evidence should be viewed with caution.