The Effects of Probiotics on Intestinal Permeability in Gastrointestinal Cancer Patients in Chemotherapy

The aim of this study is to test the hypothesis that adjuvant administration of probiotics in cancer patients undergoing chemotherapy can reduce a chemo-induced increased intestinal permeability. Furthermore, we hypothesize that the use of probiotics may reduce the occurrence of gastrointestinal side effects such as diarrhea, abdominal pains, bacterial translocation and infections following chemotherapy.

Study Overview

• Status: Completed
• Conditions: Mucositis; Intestinal Permeability; Gastrointestinal Irritation
• Intervention / Treatment: Dietary supplement: Probiotic

Detailed Description

Treatment of most cancer patients involves radiation and/or chemotherapy which often leads to gastrointestinal toxicity. Cytotoxic chemotherapy in particular often induces several intestinal abnormalities such as mucositis including destruction of intestinal villi, alterations in the gut microbiota, modulation of tight junctions, leading to an increased intestinal permeability. These toxic effects have been observed in several types of chemotherapy and different methods of administering chemotherapy.

The intestinal permeability is regulated and protected by a number factors, including a mucus layer covering the surface of the epithelium. This mucus layer is partly regulated by intestinal bacteria. Therefore it is hypothesized that chemoinduced changes in the intestinal microbiota may possibly affect intestinal permeability. Changes in the intestinal microbiota are seen after only one or a few cycles of chemotherapy treatment in different types of cancers, and could possibly be a contributing factor in the development of mucositis.

It is possible that probiotics may interfere with the ability of pathogenic bacteria to bind to the surface of the intestinal epithelial lining. In vitro studies have shown that probiotics may reduce a post-infective (Escherichia coli) increased intestinal permeability, or increased permeability due to incubation with pro-inflammatory cytokines. VSL#3 is a probiotic formula containing a mixture of 9x10^10 CFU/g Lactobacilli strains (Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, and Lactobacillus bulgaricus), 8x10^10 CFU/g Bifidum strains (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis) and 20x10^10 CFU/g Streptococcus thermophilus. In vitro and ex vivo studies have suggested that the probiotic bacteria found in VSL#3 may have a reducing effect on intestinal permeability as well as a positive modulating effect on tight junction protein expression. Escherichia coli Nissle 1917 is another bacterial strain that has been shown to be able to mediate the modulation of tight junction proteins and thus intestinal permeability. The precise mechanisms behind the effects of probiotics on intestinal epithelial permeability are not yet clear, but some mechanisms have been proposed, including a reduction in bacterial secretion of proinflammatory cytokines as well as other secreted products from probiotic microbial metabolism.

It is not known whether all probiotic strains exert a similar effect on intestinal permeability, as only very limited clinical research has addressed this relation. However, it is very likely that the specific choice of probiotic bacterial species may play a crucial role. We are only familiar with one clinical trial examining the effect of probiotics on intestinal permeability in adults with cancer undergoing treatment in the form of colectomy, but no adjuvant chemotherapy. Probiotics in the form of Lactobacillus plantarum, Lactobacillus acidophilus and Bifidobacterium longum was administered perioperative and postoperative to patients undergoing colectomy, and the study showed that probiotics improved the integrity of the small intestinal mucosal barrier, induced modulation of the intestinal microbiome as well as a reduction in the postoperative rate of infections.The same researchers also measured serum zonulin in the same subjects, and found that the treatment with probiotics also reduced the concentration of postoperative serum zonulin, and thus inhibited the same increase in intestinal permeability as was the case in the control group.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100 OE
    • Departmen of Oncology, Rigshospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• GI cancer (all types) patients undergoing chemotherapy in oncologic department at Rigshospitalet in Copenhagen
• Age >18 years
• Patients with at least three planned chemo therapy sessions left

Exclusion Criteria:

• Pregnant
• Patients who don't speak, write or understand Danish
• Known inflammatory bowel diseases or malabsorption
• Chronic kidney disease (2 x upper limit plasma creatinine)
• Neutropenia (< 1.5 x 109/L neutrophilic granulocytes in peripheral blood)
• Use of antibiotics
• Use of lactulose (laxative) and not able to discontinue three days prior to urin collection (lactulose/mannitol test)
• Use of probiotics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: probiotic treatment; Probiotic: VSL#3 is a probiotic formula containing a mixture of 9x10^10 CFU/g Lactobacilli strains (Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, and Lactobacillus bulgaricus), 8x10^10 CFU/g Bifidum strains (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis) and 20x10^10 CFU/g Streptococcus thermophilus. Administred orally

Dietary supplement: Probiotic; Probiotics (beneficial microorganisms) VSL#3 is a probiotic formula containing a mixture of 9x10^10 CFU/g Lactobacilli strains (Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, and Lactobacillus bulgaricus), 8x10^10 CFU/g Bifidum strains (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis) and 20x10^10 CFU/g Streptococcus thermophilus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intestinal permeability	Urinary lactulose-mannitol test	4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastrointestinal adverse events	Diarrhea, abdominal pain, abdominal cramps, constipation, etc.	1 week

Collaborators and Investigators

• Sponsor: University of Copenhagen
• Collaborators: Nutricia, Inc.; Actial Farmaceutica S.r.l.
• Investigators: Principal Investigator: Jens R Andersen, MD,MPA, University of Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Actual): February 1, 2019
• Study Completion (Actual): February 1, 2019

Study Registration Dates

• First Submitted: October 10, 2018
• First Submitted That Met QC Criteria: October 10, 2018
• First Posted (Actual): October 15, 2018

Study Record Updates

• Last Update Posted (Actual): April 18, 2019
• Last Update Submitted That Met QC Criteria: April 17, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Gastrointestinal Diseases; Gastroenteritis; Stomatognathic Diseases; Mouth Diseases; Gastrointestinal Neoplasms; Mucositis
• Other Study ID Numbers: H-18010425

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No