Subacute safety assessment of recombinant Lactococcus lactis on the gut microbiota of male Sprague-Dawley rats.

BACKGROUND: Lactococcus lactis strain pGSMT/MG1363 is a genetically modified microorganism (GMM) that constitutively expresses human metallothionein-I fusion protein to combine with intracellular lead. Unlike traditional probiotics, pGSMT/MG1363 lacks a history of safe use in food. Administration of microorganism could influence the gut microbial community and consequently confer health benefits or cause disadvantages to the host. To date, little has been done to assess the influence of recombinant strain pGSMT/MG1363 on the stability of gut microbiota. RESULTS: Liver, testis and kidney sections of male Sprague-Dawley rats orally administered pGSMT/MG1363 for 6 weeks showed normal structure and no pathological damage. There were no adverse effects on the analyzed serum biochemical parameters between the pGSMT/MG1363 group and the MG1363 group. Principal coordinate analysis showed that, compared with the MG1363 group, the 6-week-old fecal gut microbiota of rats fed with pGSMT/MG1363 was not significantly different (Adonis, P = 0.802). pGSMT/MG1363 treatment for 6 weeks did not significantly change the relative abundance of gut microbiota at the phylum and genus levels in comparison with MG1363 treatment. CONCLUSION: Compared to the non-GM strain MG1363 group, administration of the recombinant strain pGSMT/MG1363 for 6 weeks showed no adverse effects on the analyzed physiological parameters and gut microbial compositions of male Sprague-Dawley rats. The results suggested that, in terms of gut microbiota stability, pGSMT/MG1363 could be considered as safe as MG1363, at least for short-term intake. Further toxicological evaluations still need to be considered before drawing a definite conclusion concerning the safe use of pGSMT/MG1363. © 2021 Society of Chemical Industry.

Safety Assessment of Bacillus subtilis MB40 for Use in Foods and Dietary Supplements.

With the growing popularity of probiotics in dietary supplements, foods, and beverages, it is important to substantiate not only the health benefits and efficacy of unique strains but also safety. In the interest of consumer safety and product transparency, strain identification should include whole-genome sequencing and safety assessment should include genotypic and phenotypic studies. Bacillus subtilis MB40, a unique strain marketed for use in dietary supplements, and food and beverage, was assessed for safety and tolerability across in silico, in vitro, and in vivo studies. MB40 was assessed for the absence of undesirable genetic elements encoding toxins and mobile antibiotic resistance. Tolerability was assessed in both rats and healthy human volunteers. In silico and in vitro testing confirmed the absence of enterotoxin and mobile antibiotic resistance genes of safety concern to humans. In rats, the no-observed-adverse-effect level (NOAEL) for MB40 after repeated oral administration for 14 days was determined to be 2000 mg/kg bw/day (equivalent to 3.7 × 1011 CFU/kg bw/day). In a 28 day human tolerability trial, 10 × 109 CFU/day of MB40 was well tolerated. Based on genome sequencing, strain characterization, screening for undesirable attributes and evidence of safety by appropriately designed safety evaluation studies in rats and humans, Bacillus subtilis MB40 does not pose any human health concerns under the conditions tested.

Safety Assessment of Potential Probiotic Lactobacillus fermentum MTCC-5898 in Murine Model after Repetitive Dose for 28 Days (Sub-Acute Exposure).

Safety assessment of probiotic Lactobacillus fermentum MTCC-5898 (LF) with three doses (107, 109, and 1011 cfu/day/animal) was carried on Swiss albino mouse weanlings for 28 days using oral route. Health status of animals was monitored by physical assessment of body weight, organ indices, and histological appearances of liver and intestine along with measurement of hematological parameters (Hb, WBC, RBC count, MCHC, MCV, MCH), biochemical analytes in blood involving glucose, serum enzymes (ALT, AST and LDH), urea, creatinine, and lipid profile (total cholesterol, triglycerides, HDL, VLDL, LDL, and atherogenic index). LF showed no adverse effects on above parameters of general health status after continuous consumption for the experimental period. On the other hand, significant increase (p ≤ 0.05) in TGF-ß (regulatory cytokine) and considerable decrease (p ≤ 0.05) in IFN-γ (pro-inflammatory cytokine) without any major changes in IL-4 and IL-12 in intestinal fluid on consumption of 109 cfu/animal/day confirmed its dose-specific response for immune homeostasis. Further, safety of LF was also confirmed by insignificant changes in release of FITC-dextran (4 kDa) in blood on its consumption than control group where only saline was given orally. Moreover, significantly (p ≤ 0.05) increased mRNA expression of claudin-1 and MUC-2 in intestinal epithelial cells on feeding L. fermentum further supported FITC-dextran permeability data which otherwise showed increased flux of FITC-dextran in blood on consumption of E. coli (109 cfu/animal/day) due to intestinal damage. Thus, in vivo results confirmed that Lactobacillus fermentum MTCC 5898 is safe and non-toxic to weanling mice and may be considered for functional food application after clinical testing.

Food 4 Health - He Oranga Kai: Assessing the efficacy, acceptability and economic implications of Lactobacillus rhamnosus HN001 and ß-glucan to improve glycated haemoglobin, metabolic health, and general well-being in adults with pre-diabetes: study protocol for a 2 × 2 factorial design, parallel group, placebo-controlled randomized controlled trial, with embedded qualitative study and economic analysis.

BACKGROUND: The rates of pre-diabetes and type 2 diabetes mellitus are increasing worldwide, producing significant burdens for individuals, families, and healthcare systems. In New Zealand, type 2 diabetes mellitus and pre-diabetes disproportionally affect Maori, Pacific, and South Asian peoples. This research evaluates the efficacy, acceptability, and economic impact of a probiotic capsule and a prebiotic cereal intervention in adults with pre-diabetes on metabolic and mental health and well-being outcomes. METHODS: Eligible adults (n = 152) aged 18-80 years with pre-diabetes (glycated haemoglobin 41-49 mmol/mol) will be enrolled in a 2 × 2 factorial design, randomised, parallel-group, placebo-controlled trial. Computer-generated block randomization will be performed independently. Interventions are capsulated Lactobacillus rhamnosus HN001 (6 × 109 colony-forming units/day) (A) and cereal containing 4 g ß-glucan (B), placebo capsules (O1), and calorie-matched control cereal (O2). Eligible participants will receive 6 months intervention in the following groups: AB, AO1, BO2, and O1O2. The primary outcome is glycated haemoglobin after 6 months. Follow-up at 9 months will assess the durability of response. Secondary outcomes are glycated haemoglobin after 3 and 9 months, fasting glucose, insulin resistance, blood pressure, body weight, body mass index, and blood lipid levels. General well-being and quality of life will be measured by the Short-Form Health Survey 36 and Depression Anxiety Stress Scale 21 at 6 and 9 months. Outcome assessors will be blind to capsule allocation. An accompanying qualitative study will include 24 face-to-face semistructured interviews with an ethnically balanced sample from the ß-glucan arms at 2 months, participant focus groups at 6 months, and three health professional focus groups. These will explore how interventions are adopted, their acceptability, and elicit factors that may support the uptake of interventions. A simulation model of the pre-diabetic New Zealand population will be used to estimate the likely impact in quality-adjusted life years and health system costs of the interventions if rolled out in New Zealand. DISCUSSION: This study will examine the efficacy of interventions in a population with pre-diabetes. Qualitative components provide rich description of views on the interventions. When combined with the economic analysis, the study will provide insights into how to translate the interventions into practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617000990325. Prospectively registered on 10 July 2017.

Adherence capability and safety assessment of an indigenous probiotic strain Lactobacillus rhamnosus MTCC-5897.

With the growing interest in probiotic microorganisms based on their well established immense health benefits, the present investigation was aimed to assess the adhesion potential and safety of probiotic Lactobacillus rhamnosus MTCC- 5897 (LR) before it can be put into a probiotic formulations. L. rhamnosus showed an adhesion index of 166.7 ±â€¯11, which was further confirmed by scanning electron microscopy and relative expression of mucus binding protein (Mub) and mucus adhesion promoting protein (Map-A) genes. In vitro safety assessment by tetrazolium dye reduction, neutral red and lactate dehydrogenase (LDH) release assays revealed unchanged metabolic activity of Caco-2 cells even when incubated with L. rhamnosus ranged between 106-1010 cfu/mL for 24 h. Similarly, a moderate increase in bile salt hydrolase (bsh) expression (6.84 ±â€¯0.73 and 3.42 ±â€¯0.39 folds in 1% and 3% bile medium respectively) further proved its safety towards normal lipid digestion and absorption. Moreover, L. rhamnosus feeding to mice (107, 109, 1011 and 1013 cfu/animal/d) repetitively for 28 days revealed no adverse effects on parameters of general animal health status including body weight, organ indices, plasma glucose, liver malondialdehyde (MDA), serum aspartate amino transaminase (AST), cholesterol, triglycerides, high-density lipoprotein (HDL). Similarly, significant (p ≤ 0.05) reduced activities of serum alanine amino transaminase (ALT) and LDH on continuous probiotic feeding were also indicative of normal liver/kidney functions as they were in normal range for mice. Further, insignificant changes in macrophage chemoattractant protein (MCP-1) in intestinal fluid irrespective of bacterial dose fed along with significant reduction (p ≤ 0.05) of tumor necrosis factor-α (TNF-α) at much higher dose (1013 cfu/animal/d) also confirmed safe response of probotic L.rhamnosus against inflammation. To conclude, the results obtained under in vitro and in vivo studies has established the Lactobacillus rhamnosus as safe and non-toxic to weaning mice as well as human epithelial cells and thus may be used as a safe food additive.

Evaluation of Probiotic Potential and Safety Assessment of Lactobacillus pentosus MMP4 Isolated From Mare's Lactation.

Lactic acid bacteria isolated from indigenous milk of different animals were investigated for their efficacy, safety, and probiotic potential. The most potential isolate MMP4 was screened from mare's milk, which was further identified as Lactobacillus pentosus by using 16S rRNA gene sequencing and phylogeny. The probiotic potential of strain MMP4 was assessed by its ability to survive under acidic environment and in presence of bile salts along with the ability to inhibit food-borne as well as clinical pathogenic microorganisms such as Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Salmonella typhi. The phenol tolerance with cogent hydrophobicity to different hydrocarbons was demonstrated. Bile salt hydrolase activity of L. pentosus MMP4 was confirmed by detecting the Bsh gene by using colony PCR. The presence of Mub, Map, and EF-Tu genes involved in adhesion conferred the behavior of passage and adherence to gastrointestinal tract. Scanning electron microscopy of intestinal autopsy from albino mice revealed the attachment of bacterial cells on the mucus-lined intestinal walls against pathogens and further proved in vivo adhesion ability. The presence of intrinsic antibiotic resistance and lack of DNase, gelatinase, and hemolytic activity in MMP4 support its safety as probiotic traits. Thus, MMP4 bears an excellent and pragmatic properties for being used as probiotic and may be exploited in dairy industry.

Industry funding effect on positive results of probiotic use in the management of acute diarrhea: a systematized review.

Several investigations have found that industry-funded studies tend to inform results favoring the sponsored products. The pressure to demonstrate that a drug or a product causes a favorable outcome may result in investigation biases from industry-funded research. One example of this could be found in the probiotic research funded by the industry. The aim of this study was to assess the effect of industry funding on positive outcomes of the use of probiotics in the management of acute diarrhea. A systematized review of clinical trials on the use of probiotics in the management of acute diarrhea was performed. The associations between the source of funding, clinical outcomes, probiotic genus, and quality of the study were assessed using the χ-test and Fisher's exact test. Sixty-six clinical trials were included; 27 were industry funded, 18 were nonindustry funded, and 21 did not disclose their funding source. There were 48 positive and 30 negative clinical outcomes. There was no significant association between the source of funding and clinical outcomes (P=0.491). No association between the rest of the studied variables and outcomes was observed either (P>0.05). In clinical trials on the use of probiotics in the management of acute diarrhea, the source of funding has no influence on positive clinical outcomes.

Application of hydrolases and probiotic Pediococcus acidilactici BaltBio01 strain for cereal by-products conversion to bioproduct for food/feed.

The aim of this study was to apply the enzymatic treatment and fermentation by Pediococcus acidilactici BaltBio01 strain for industrial cereal by-products conversion to food/feed bioproducts with high amount of probiotic lactic acid bacteria (LAB). LAB propagated in potato media and spray-dried remained viable during 12 months (7.0 log10 cfu/g) of storage and was used as a starter for cereal by-products fermentation. The changes of microbial profile, biogenic amines (BAs), mycotoxins, lactic acid (L+/D-), lignans and alkylresorcinols (ARs) contents in fermented cereal by-product were analysed. Cereal by-products enzymatic hydrolysis before fermentation allows to obtain a higher count of LAB during fermentation. Fermentation with P. acidilactici reduce mycotoxins content in fermented cereal by-products. According to our results, P. acidilactici multiplied in potato juice could be used for cereal by-products fermentation, as a potential source to produce safer food/feed bioproduct with high amount of probiotic LAB for industrial production.

Safety Assessment of Bacteroides uniformis CECT 7771 Isolated from Stools of Healthy Breast-Fed Infants.

BACKGROUND: Bacteroides uniformis CECT 7771 is a potential probiotic strain, originally isolated from the stools of healthy breast-feed infants. The strain showed pre-clinical efficacy in a mouse obesity model. The objective of this study was to evaluate its potential toxicity and translocation ability after acute oral administration to mice. METHODS AND FINDINGS: A safety study was conducted in immunocompetent and immunosuppressed C57BL-6 mice. Both mouse groups (n = 10 per group) were fed orally 2 x 10(9) colony forming units (cfu)/day of B. uniformis CECT 7771 or placebo by gavage for 6 days. Throughout this time, feed and water intake and body weight were monitored. Afterwards, mice were sacrificed and biological samples were collected to analyze blood and urine biochemistry, inflammatory and immune markers; gut mucosal histology and bacterial translocation to peripheral tissues. The results demonstrated that acute ingestion of this Bacteroides strain had no adverse effects on the animals' general health status or food intake, nor did it affect biochemical indicators of liver, kidney and pancreatic function or gut mucosal histology. Findings also demonstrated that administration did not lead to bacterial translocation to blood, liver or mesenteric lymph nodes. B. uniformis CECT 7771 also downregulated gene and protein expression (iNOS and PPAR-γ) and inflammatory cytokines induced by immunosuppression. CONCLUSIONS: The findings indicate that the acute oral consumption of B. uniformis CECT 7771 does not raise safety concerns in mice. Further studies in humans should be conducted.

Review: The market of probiotics.

The advertising of probiotics in diary products on the market has claimed several health-improving properties, including prevention and treatment of obesity, cardiovascular diseases and cancer prophylaxis, osteoporosis and arthritis treatment, diabetes management and control of hypercholesterolemia. Therefore, it is reasonable to emphasize the perspective of a new self-care and integrative medicine season, where food industry is turned to research-oriented management with putative clinical goals to be achieved. We searched Pubmed/Medline using the terms "probiotics" and "market". Selected papers until 2013 were chosen on the basis of their content (clinical evidence-based quality). We performed an accurate investigation on the so-called "probiotic market", leading to better understanding the role of nutraceutical products in the human clinical nutrition physiology. As nutraceutical products are sold all over the world, information, provided by this review may be useful to evaluate their potential impact on human health.

[Probiotics: from the lab to the consumer]. / Probióticos: del laboratorio al consumidor.

INTRODUCTION: In the last years, the field of probiotics has grown notably. However, out of the thousands of strains isolated each year in the labs around the world, very few enter in a phase of industrial development and even a lower number go to the market. OBJECTIVE: In this article, the main aspects that have to be taken into account in the, usually, long and winding road that a strain must follow from isolation to the market are reviewed Results and conclusions: A probiotic microorganism has to be correctly identified at the species and strain levels. The genome sequence is the gold identification standard and provides valuable information on the safety, functionality and technological properties of a strain. The cases in which a link between a probiotic and an adverse effect has been established are scarce and have involved people with underlying pathologies. There is a wide variety of in vitro, ex vivo and animal model assays for the screening of probiotics, which provide useful information throughout the selection process; however, correctly designed clinical trials are the only way to obtain direct results on the safety and efficacy of a probiotic to the target population. Probiotic companies have the need to obtain a very high bacterial biomass in an economically viable manner while preserving the concentration of live bacteria required for exerting the expected beneficial effect until the end of the probiotic's shelf life. Finally, commercial aspects play a key role in the decision of starting an industrial development and, eventually, to place a probiotic in the market.

Introducción: En los últimos años, el campo de los probióticos ha experimentado un gran auge. Sin embargo, de los miles de cepas aisladas cada año por su potencial probiótico en los laboratorios de todo el mundo, muy pocas pasan a una fase de desarrollo industrial y menos aún son las que consiguen una vida comercial. Objetivo: En este artículo, se revisan los principales aspectos que se deben tener en cuenta en el, habitualmente, largo y tortuoso camino que debe seguir una cepa desde su aislamiento inicial hasta su comercialización. Resultados y conclusiones: Cualquier microorganismo probiótico debe estar correctamente identificado a nivel de especie y cepa. La secuencia del genoma es la mejor identificación posible, además de proporcionar información muy valiosa sobre su seguridad, funcionalidad y propiedades de interés tecnológico. Los casos en los que se ha podido establecer una relación entre un probiótico y un efecto adverso son muy escasos y han afectado a personas con patologías subyacentes. Globalmente, aunque las distintas pruebas in vitro, ex vivo y en modelos animales proporcionan información útil durante el proceso de selección de cepas, los únicos datos que permiten evaluar la seguridad y eficacia de un probiótico de una forma directa son los que se obtienen en el curso de ensayos clínicos correctamente diseñados y dirigidos específicamente a la población diana. Por otra parte, las empresas que comercializan probióticos tienen la necesidad de obtener una biomasa muy elevada de forma económicamente rentable y de que la concentración de bacterias viables necesaria para ejercer el efecto beneficioso se mantenga hasta el final de la vida útil del producto. Finalmente, los aspectos comerciales son determinantes en la decisión de afrontar el desarrollo industrial y la puesta en el mercado de un probiótico.

Probiotics in dietary guidelines and clinical recommendations outside the European Union.

Fermented foods have been consumed for centuries across many geographical locales and have traditionally been considered healthy foods, partly because of the live microbes contained in them. The concept of "probiotics" further requires that the microbes be defined and their health effects be demonstrated through human intervention studies or other suitable investigations before marketing with corresponding health messages. Here, we review recommendations for fermented foods and probiotics in several countries outside the EU, focusing on food-based dietary guidelines. We emphasize recommendations on yoghurt and probiotics made by expert bodies. We found that dietary guidelines commonly advocate the consumption of yoghurt or similar products, but specific comments on probiotics are rare. Further, we reviewed guidelines from clinical associations. In general, they acknowledge the beneficial effects of probiotics, but often suggest the need for further research. This is true despite good quality evidence supporting the role of probiotics for certain health effects, such as prevention of eczema in infants, management of side effects from antibiotics and alleviation of functional bowel symptoms. Additional research to support future dietary recommendations should focus on determining effect size, identifying responders and non-responders, clarifying strain-specificity of effects and confirming mechanisms.

Application of evidence on probiotics, prebiotics and synbiotics by food industry: a descriptive study.

BACKGROUND: This study assessed how the food industry applies the knowledge and evidence gained from synbiotics, probiotics or prebiotics research in infants, on the general paediatric population. This study also explored: what happens after the clinical trials using infant formula are completed, data is published or remains unpublished; the effectiveness and type of medium the formula manufacturers use to educate consumers on probiotic, prebiotic or synbiotic infant formula. FINDINGS: This was a descriptive study (a survey) that used a structured questionnaire. All listed companies that manufacture and / or market food products with added probiotics, prebiotics or synbiotics for infants were identified and invited to participate. People responsible for research and development were invited to participate in the survey. A letter of invitation was sent to selected participants and if they expressed willingness to take part in the study, a questionnaire with a written consent form was sent. Descriptive statistics and associations between categorical variables were to be tested using a Chi-square test, a p < 0.05 was statistically significant.A total of 25 major infant formulas, baby food manufacturers were identified, invited to participate in the survey. No company was willing to participate in the survey for different reasons: failure to take any action 5 (20%), decision to participate indefinitely delayed 2 (8%), sensitivity of requested information 3 (12%), company does not conduct clinical trials 1 (4%), company declined without further information 4 (16%), erroneous contact information 6 (24%), refusal by receptionists to forward telephone calls to appropriate staff 3 (12%), language barrier 3 (12%), company no longer agrees to market research 1 (4%). CONCLUSION: Due to a poor response rate in this study, no conclusion could be drawn on how the food industry applies evidence gained through probiotics, prebiotics or synbiotics research on infants for the benefit of the general paediatric population. More information and greater transparency is needed from the infant formula manufacturers on how they apply the evidence gained from the research on probiotics, prebiotics and synbiotics on infants.

The efficacy and safety of probiotics in people with cancer: a systematic review.

BACKGROUND: Probiotics are living microorganisms that are generally thought of as being beneficial to the recipient. They have been shown to be effective in people with acute infectious diarrhoea, and cost-effective in antibiotic-associated diarrhoea. Probiotics may have a role in people with cancer, as various cancer treatments often lead to diarrhoea. However, as people with cancer are often immunocompromised, it is important to assess for adverse events (AEs) such as infection, which could potentially be a consequence of deliberate ingestion of living microorganisms. DESIGN: A systematic review was carried out to collect, analyse and synthesise all available data on the efficacy and safety of probiotics in people with cancer (PROSPERO registration: CRD42012003454). Randomised, controlled trials, identified through screening multiple databases and grey literature, were included for analysing efficacy, while all studies were included for the analysis of safety of probiotics. Primary outcomes were the reduction in duration, severity and incidence of antibiotic-associated diarrhoea and chemotherapy-associated diarrhoea, and AEs, especially probiotic-associated infection. Where possible, data were combined for meta-analysis by a random-effects model, assessing causes of heterogeneity, including differences in strains, dosage and patient characteristics. RESULTS: Eleven studies (N = 1557 participants) were included for assessing efficacy. Results show that probiotics may reduce the severity and frequency of diarrhoea in patients with cancer and may reduce the requirement for anti-diarrhoeal medication, but more studies are needed to assess the true effect. For example comparing probiotic use to control 25 groups on effect on Common Toxicity Criteria ≥2 grade diarrhoea, odds ratio (OR) = 0.32 [95% confidence interval (CI) of 0.13-0.79; P = 0.01]. Seventeen studies (N = 1530) were included in the safety analysis. Five case reports showed probiotic-related bacteraemia/fungaemia/positive blood cultures. CONCLUSIONS: Probiotics may be a rare cause of sepsis. Further evidence needs to be collated to determine whether probiotics provide a significant overall benefit for people with cancer.

A high-dose preparation of lactobacilli and bifidobacteria in the prevention of antibiotic-associated and Clostridium difficile diarrhoea in older people admitted to hospital: a multicentre, randomised, double-blind, placebo-controlled, parallel arm trial (PLACIDE).

BACKGROUND: Antibiotic-associated diarrhoea (AAD) occurs most commonly in older people admitted to hospital and within 12 weeks of exposure to broad-spectrum antibiotics. Although usually a mild and self-limiting illness, the 15-39% of cases caused by Clostridium difficile infection [C. difficile diarrhoea (CDD)] may result in severe diarrhoea and death. Previous research has shown that probiotics, live microbial organisms that, when administered in adequate numbers, are beneficial to health, may be effective in preventing AAD and CDD. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of a high-dose, multistrain probiotic in the prevention of AAD and CDD in older people admitted to hospital. DESIGN: A multicentre, randomised, double-blind, placebo-controlled, parallel-arm trial. SETTING: Medical, surgical and elderly care inpatient wards in five NHS hospitals in the UK. PARTICIPANTS: Eligible patients were aged ≥ 65 years, were exposed to one or more oral or parenteral antibiotics and were without pre-existing diarrhoeal disorders, recent CDD or at risk of probiotic adverse effects. Out of 17,420 patients screened, 2981 (17.1%) were recruited. Participants were allocated sequentially according to a computer-generated random allocation sequence; 1493 (50.1%) were allocated to the probiotic and 1488 (49.9%) to the placebo arm. INTERVENTIONS: Vegetarian capsules containing two strains of lactobacilli and two strains of bifidobacteria (a total of 6 × 10(10) organisms per day) were taken daily for 21 days. The placebo was inert maltodextrin powder in identical capsules. MAIN OUTCOME MEASURES: The occurrence of AAD within 8 weeks and CDD within 12 weeks of recruitment was determined by participant follow-up and checking hospital laboratory records by research nurses who were blind to arm allocation. RESULTS: Analysis based on the treatment allocated included 2941 (98.7%) participants. Potential risk factors for AAD at baseline were similar in the two study arms. Frequency of AAD (including CDD) was similar in the probiotic (159/1470, 10.8%) and placebo arms [153/1471, 10.4%; relative risk (RR) 1.04; 95% confidence interval (CI) 0.84 to 1.28; p = 0.71]. CDD was an uncommon cause of AAD and occurred in 12/1470 (0.8%) participants in the probiotic and 17/1471 (1.2%) in the placebo arm (RR 0.71; 95% CI 0.34 to 1.47; p = 0.35). Duration and severity of diarrhoea, common gastrointestinal symptoms, serious adverse events and quality of life measures were also similar in the two arms. Total health-care costs per patient did not differ significantly between the probiotic (£8020; 95% CI £7620 to £8420) and placebo (£8010; 95% CI £7600 to £8420) arms. CONCLUSION: We found no evidence that probiotic administration was effective in preventing AAD. Although there was a trend towards reduced CDD in the probiotic arm, on balance, the administration of this probiotic seems unlikely to benefit older patients exposed to antibiotics. A better understanding of the pathogenesis of AAD and CDD and the strain-specific effects of probiotics is needed before further clinical trials of specific microbial preparations are undertaken. Evaluation of the effectiveness of other probiotics will be difficult where other measures, such as antibiotic stewardship, have reduced CDD rates. TRIAL REGISTRATION: This trial is registered as ISRCTN70017204. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 57. See the NIHR Journals Library website for further project information.

Association between funding source, methodological quality and research outcomes in randomized controlled trials of synbiotics, probiotics and prebiotics added to infant formula: a systematic review.

BACKGROUND: There is little or no information available on the impact of funding by the food industry on trial outcomes and methodological quality of synbiotics, probiotics and prebiotics research in infants. The objective of this study was to compare the methodological quality, outcomes of food industry sponsored trials versus non industry sponsored trials, with regards to supplementation of synbiotics, probiotics and prebiotics in infant formula. METHODS: A comprehensive search was conducted to identify published and unpublished randomized clinical trials (RCTs). Cochrane methodology was used to assess the risk of bias of included RCTs in the following domains: 1) sequence generation; 2) allocation concealment; 3) blinding; 4) incomplete outcome data; 5) selective outcome reporting; and 6) other bias. Clinical outcomes and authors' conclusions were reported in frequencies and percentages. The association between source of funding, risk of bias, clinical outcomes and conclusions were assessed using Pearson's Chi-square test and the Fisher's exact test. A p-value < 0.05 was statistically significant. RESULTS: Sixty seven completed and 3 on-going RCTs were included. Forty (59.7%) were funded by food industry, 11 (16.4%) by non-industry entities and 16 (23.9%) did not specify source of funding. Several risk of bias domains, especially sequence generation, allocation concealment and blinding, were not adequately reported. There was no significant association between the source of funding and sequence generation, allocation concealment, blinding and selective reporting, majority of reported clinical outcomes or authors' conclusions. On the other hand, source of funding was significantly associated with the domains of incomplete outcome data, free of other bias domains as well as reported antibiotic use and conclusions on weight gain. CONCLUSION: In RCTs on infants fed infant formula containing probiotics, prebiotics or synbiotics, the source of funding did not influence the majority of outcomes in favour of the sponsors' products. More non-industry funded research is needed to further assess the impact of funding on methodological quality, reported clinical outcomes and authors' conclusions.