Probiotic and synbiotic safety in infants under two years of age

In this study, we systematically evaluated safety aspects in clinical trials with probiotics and synbiotics in young infants (0-2 years of age). This study is an update of earlier reports and covers the recent literature from 2008-2013. The safety evaluation is performed along the Common Terminology Clinical Adverse Events (CTCAE) version 4.0 scale, hereby also providing guidance for future studies. Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. The results show a deficiency in the precise reporting and classification of adverse events in most studies. Analysis of 57 clinical trials with probiotics and synbiotics in combination with eight follow-up studies indicate that probiotic administration to infants between 0 and 24 months is safe with regard to the evaluated strains in infants with a particular health status or susceptibility. Most adverse events and serious adverse events were considered unrelated to the study product, and there were no major safety concerns. Almost all studies concluded that none of the adverse effects were related to the study product; the study products are generally well tolerated. Finally, inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes, greatly limit the generalizability of conclusions and argue convincingly for obligatory and standardised behaviour on adverse events (CTCAE) reporting in 'food' studies

Safety of probiotics and synbiotics in children under 18 years of age

This study aimed to systematically evaluate safety of probiotics and synbiotics in children ageing 0-18 years. This study is the third and final part in a safety trilogy and an update is provided using the most recent available clinical data (2008-2013) by means of the Common Terminology Clinical Adverse Events (CTCAE version 4.0) classification. Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. Analysis of 74 clinical studies indicated that probiotic and/or synbiotic administration in children is safe with regard to the specific evaluated strains, dosages and duration. The population of children include healthy, immune compromised and obese subjects, as well as subjects with intestinal disorders, infections and inflammatory disorders. This study revealed no major safety concerns, as the adverse events (AEs) were unrelated, or not suspected to be related, to the probiotic or synbiotic product. In general the study products were well tolerated. Overall, AEs occurred more frequent in the control arm compared to children receiving probiotics and/or synbiotics. Furthermore, the results indicate inadequate reporting and classification of AEs in the majority of the studies. In addition, generalizability of conclusions are greatly limited by the inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes

Lactobacillus plantarum WCFS1 and its host interaction : a dozen years after the genome

Lactobacillus plantarum WCFS1 is one of the best studied Lactobacilli, notably as its genome was unravelled over 12years ago. L.plantarum WCFS1 can be grown to high densities, is amenable to genetic transformation and highly robust with a relatively high survival rate during the gastrointestinal passage. In this review, we present and discuss the main insights provided by the functional genomics research on L.plantarum WCFS1 with specific attention for the molecular mechanisms related to its interaction with the human host and its potential to modify the immune system, and induce other health-related benefits. Whereas most insight has been gained in mouse and other model studies, onlyfive human studies have been reported with L.plantarum WCFS1. Hence NCIMB 8826 (the parental strain of L.plantarum WCFS1) in human trials as to capitalize on the wealth of knowledge that is summarized here.Peer reviewe

A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance

Cancer cells make extensive use of the folate cycle to sustain increased anabolic metabolism. Multiple chemotherapeutic drugs interfere with the folate cycle, including methotrexate and 5-fluorouracil that are commonly applied for the treatment of leukemia and colorectal cancer (CRC), respectively. Despite high success rates, therapy-induced resistance causes relapse at later disease stages. Depletion of folylpolyglutamate synthetase (FPGS), which normally promotes intracellular accumulation and activity of natural folates and methotrexate, is linked to methotrexate and 5-fluorouracil resistance and its association with relapse illustrates the need for improved intervention strategies. Here, we describe a novel antifolate (C1) that, like methotrexate, potently inhibits dihydrofolate reductase and downstream one-carbon metabolism. Contrary to methotrexate, C1 displays optimal efficacy in FPGS-deficient contexts, due to decreased competition with intracellular folates for interaction with dihydrofolate reductase. We show that FPGS-deficient patient-derived CRC organoids display enhanced sensitivity to C1, whereas FPGS-high CRC organoids are more sensitive to methotrexate. Our results argue that polyglutamylation-independent antifolates can be applied to exert selective pressure on FPGS-deficient cells during chemotherapy, using a vulnerability created by polyglutamylation deficiency

Dealing with the remaining controversies of probiotic safety

A clear safety profile of probiotics in clinical practice is essential in decision-making for all stakeholders and regulators. Probiotics have been investigated in different target populations, conditions and age groups. This also includes the use of probiotics in critically ill patients. Despite promising results reported with the use of probiotics and synbiotics, there is still a lively discussion regarding the proper and safe use of probiotics among physicians, researchers and regulators. This doubt and debate was sparked by the high incidence in mortality reported in a study with critically ill patients. Whereas no causal relationship has been established since, safety of probiotic has been questioned. In response, an overwhelming body of evidence suggesting that probiotics are safe has been compiled. Moreover, data indicates that probiotics reduce the number of adverse events compared to the control. However, due to a lack of standardised safety reporting in clinical studies, a strong evidence base on probiotic safety remains to be established. Here, we will discuss: (1) the rationale for using probiotics in the critically ill; (2) what happened during the Dutch Pancreatitis trial; (3) what are the known safety risks of probiotics based on the available data; and finally (4) how standardisation in safety reporting can drive probiotic innovation. Building a strong safety profile for probiotic strains will solidify its use in individuals that can benefit the most from microbial modulation

Patient needs and research priorities in probiotics: A quantitative KOL prioritization analysis with emphasis on infants and children

Due to broad application of probiotics, research efforts are diluted, thus contributing to rejection of health claims. This study aimed to systematically prioritize the unmet needs and research opportunities in infants, children, adults and elderly for probiotics according to their relative importance from a key-opinion-leader (KOL) perspective. In addition, it reveals potential probiotic product characteristics that need improvement from both a patient or consumer and a KOL perspective. Moreover, KOL involvement in the probiotic research & development (R&D) process was assessed. Data was collected by conducting semi-structured interviews and subsequent online questionnaires. The three clinical indications requiring the highest research attention for infants were (infectious) diarrhoea, antibiotic-associated diarrhoea (AAD) and necrotizing enterocolitis (NEC); for children, obesity, AAD and diarrhoea and for adults, AAD, irritable bowel syndrome (IBS) and Alzheimer's disease. From both a KOL as well as a patient or consumer perspective, clinical evidence needs to be improved for probiotic products. Although the majority of the KOLs consult for and perform research with probiotic companies, they are (surprisingly) not able to sufficiently influence industry research agendas. This study incorporates the insights of KOLs and provides direction in the R&D of probiotics to fulfil unmet medical needs in patients

Safety of probiotics in infants and children

Item does not contain fulltextSince the PROPATRIA-trial in 2008, probiotics have been placed under scrutiny and concerns have been raised regarding the safety of administration of live microorganisms. When probiotics are administered to immune-incompetent or immune-deficient individuals, probiotic strains can potentially cause systemic infections. As probiotic intake and gut modulation might be most effective early in life, no uncertainties should remain regarding safety administration of probiotics during the perinatal period and childhood. This chapter provides a comprehensive overview of the safety of probiotics based on data from clinical trials up to 2016. These studies indicate that probiotics are safe for infants and children, even in frail preterm infants