Randomized double-blind, placebo-controlled multicenter phase III study of prevention of irinotecan-induced diarrhea by a probiotic mixture containing Bifidobacterium BB-12®Lactobacillus rhamnosus LGG® in colorectal cancer patients.

Background: The incidence of irinotecan-induced diarrhea varies between 60-90%, by which the incidence of severe diarrhea is 20-40%. The objective of this phase III trial was to determine the effectiveness of the probiotic mixture containing Bifidobacterium, BB-12® and Lactobacillus rhamnosus, LGG® in the prophylaxis of irinotecan-induced diarrhea in metastatic colorectal cancer patients due to a reduction in the activity of intestinal beta-D-glucuronidase. Methods: From March 2016 to May 2022, a total of 242 patients with colorectal cancer starting a new line of irinotecan-based therapy were registered to the study in 11 cancer centers in Slovakia. Patients were randomized in a ratio 1:1 to probiotic formula vs. placebo that was administered for 6 weeks. Each capsule of Probio-Tec® BG-Vcap-6.5 contained 2.7x109 colony-forming units (CFU) of 2 lyophilized probiotic strains Bifidobacterium, BB-12® (50%) and Lactobacillus rhamnosus GG, LGG® (50%). Results: Administration of probiotics compared to placebo was not associated with a significant reduction of grade 3/4 diarrhea (placebo arm 11.8% vs. probiotic arm 7.9%, p=0.38). Neither the overall incidence of diarrhea (46.2% vs. 41.2%, p=0.51) nor the incidence of enterocolitis (3.4% vs. 0.9%, p=0.37) was different in the placebo vs. probiotic arm. Subgroup analysis revealed that patients with colostomy had higher incidence of any diarrhea and grade 3/4 diarrhea in the placebo arm compared to the probiotic arm (48.5% vs. 22.2%, p=0.06 and 15.2% vs. 0%, p=0.06, respectively). Moreover, patients on probiotic arm had significantly better diarrhea-free survival (HR = 0.41, 95%CI 0.18 - 0.95, p=0.05) and needed less loperamide (p=0.01) compared to patients on placebo arm. We did not observe any infection caused by probiotic strains used in this study. Conclusion: This study failed to achieve its primary endpoint, and results suggest a lack of benefit of administered probiotic formula for the prevention of irinotecan-induced diarrhea. However, subgroup analysis suggests a possible benefit in patients with colostomy.

Orally Administered Probiotics in the Prevention of Chemotherapy (± Radiotherapy)-Induced Gastrointestinal Toxicity: A Systematic Review With Meta-Analysis of Randomized Trials.

BACKGROUND: Chemoradiotherapy-induced gastrointestinal toxicity may lead to a significant impairment of the oncological patient's quality of life, as well as to reduced adherence to the treatment, which may have a negative impact on survival and mortality rates. OBJECTIVE: The aim of this review was to investigate whether oral probiotic administration prevents chemotherapy (± radiotherapy)-induced gastrointestinal toxicity, particularly diarrhea. METHODS: We searched the MEDLINE, Web of Science, and SCOPUS databases for randomized controlled trials in English published between 1990 and 2020. We conducted statistical data analyses expressing the treatment effect size as a risk ratio (RR) together with a 95% confidence interval (CI). Implications are based on trials rated as having a low risk of bias (RoB). RESULTS: We included 8 trials (n = 697 participants), from which 3 studies rated as low RoB contained primary endpoint data; the risk of developing grade 3/4 diarrhea in patients receiving probiotics was reduced by 78% compared to the control group (RR = 0.22 [95% CI 0.05-1.08]; P = .06; n = 114 participants). Probiotics showed preventive effects in patients treated with chemotherapy alone (RR = 0.34 [0.12-0.94]; P = .04, n = 121 participants) and in patients with colorectal cancer (RR = 0.56 [0.34-0.92]; P = .02; n = 208 participants). The reduction in the incidence of overall diarrhea was not significant. CONCLUSIONS: Probiotics failed to prove a preventive effect of statistical significance against the development of severe and overall diarrhea in cancer patients treated with chemotherapy (± radiotherapy). However, we cannot rule out that the effects of probiotics are clinically relevant, especially in certain subgroups of patients. This needs to be clarified in further well-performed studies.

Travellers' diarrhoea - prevention, trends and role of microbiome.

OBJECTIVES: In this review, we present a contemporary look at the management of travellers' diarrhoea (TD), and we discuss the potential role of a microbiome as well as the administration of live microorganisms in order to prevent TD. METHODS: We performed a comprehensive search using the PubMed and Web of Science databases for the period 2014-2021, looking for original and review articles on travellers' diarrhoea. RESULTS: TD belongs among the most frequent illnesses experienced by travellers. For the most part, it is manifested as an acute yet self limiting condition, and only in a few cases proceeds to a prolonged form. Epidemiological analyses have shown that the majority of TD cases are caused by bacterial infections. In practice, pharmacological therapy is often used in the prevention and treatment of TD, since patients naturally seek preventive measures against the development of its severe course and its impact on planned activities. Bismuth salicylate is a strongly recommended TD prophylaxis but is not available on all European Union markets. Although the antibiotic prophylaxis is not generally recommended in guidelines, some antibiotic or chemotherapeutic agents are accessible over-the-counter in certain countries, and travellers are routinely encouraged to use them preventively. This routine can alter the microbiome of the traveller and promote the spread of drug resistant bacteria in their place of residence. Probiotic administration is considered safe, although the quality of evidence in favour of its prophylactic use in TD is currently low. CONCLUSIONS: The challenge for public health authorities is to educate personnel that can directly influence the behaviour of travellers through safe and effective pharmacological alternatives to antibiotics. Manipulation of the gut microbiome using specific probiotic strains can represent a safe and promising intervention.

Histamine Intolerance-The More We Know the Less We Know. A Review.

The intake of food may be an initiator of adverse reactions. Food intolerance is an abnormal non-immunological response of the organism to the ingestion of food or its components in a dosage normally tolerated. Despite the fact that food intolerance is spread throughout the world, its diagnosing is still difficult. Histamine intolerance (HIT) is the term for that type of food intolerance which includes a set of undesirable reactions as a result of accumulated or ingested histamine. Manifestations may be caused by various pathophysiological mechanisms or a combination of them. The problem with a "diagnosis" of HIT is precisely the inconstancy and variety of the manifestations in the same individual following similar stimuli. The diagnosing of HIT therefore requires a complex time-demanding multidisciplinary approach, including the systematic elimination of disorders with a similar manifestation of symptoms. Among therapeutic approaches, the gold standard is a low-histamine diet. A good response to such a diet is considered to be confirmation of HIT. Alongside the dietary measures, DAO supplementation supporting the degradation of ingested histamine may be considered as subsidiary treatment for individuals with intestinal DAO deficiency. If antihistamines are indicated, the treatment should be conscious and time-limited, while 2nd or 3rd generation of H1 antihistamines should take precedence.