Reference
Maher S, Elmeligy HA, Aboushousha T, et al. Synergistic immunomodulatory effect of synbiotics pre- and postoperative resection of pancreatic ductal adenocarcinoma: a randomized controlled study. Cancer Immunol Immunother. 2024;73(6):109.
Study Objective
To assess the synergistic effect of synbiotics (a combination of probiotics and prebiotics) compared to probiotics alone in providing a significant antitumor, immunomodulating effect in pancreatic ductal adenocarcinoma patients, as well as synbiotics’ impact on postoperative complications and outcomes
Key Takeaway
The study provided evidence of a significant immunomodulatory impact from supplementation with synbiotics vs probiotics alone as well as the former’s contribution in reducing postoperative complications in pancreatic cancer patients.
Design
Single-blind, randomized study
Participants
Investigators enrolled and randomized 90 patients diagnosed with pancreatic ductal adenocarcinoma at the Theodor Bilharz Research Institute in Egypt. The demographic characteristics of the patients were as follows: They were equally divided between those aged younger than 50 years and those aged older than 50 years; 62 of the participants were male, and 28 were female; 78 of the patients had no significant medical history, whereas 5 of the patients had a history of diabetes and 7 had a history of hypertension. The mean body mass index (BMI) for the patients was 22.47. The patients were scheduled to undergo pancreatoduodenectomy. The inclusion criteria included patients with primary pancreatic ductal adenocarcinoma without distant metastasis or any treatments before surgery. The exclusion criteria included patients diagnosed with other cancers or other diseases, patients with lack of pathological and follow-up data or distant metastases before the surgery, and those recently infected with Covid-19 or vaccinated with Covid-19 vaccines. The patients were randomly assigned to 1 of 3 arms (probiotic, synbiotic, or placebo), and the patients were blinded as to which arm.
Interventions
The 3 arms of the study included those receiving a probiotic supplement, synbiotic supplement, or placebo.
The probiotic group received 25 billion colony-forming units (CFUs; NOW brand), composed of 10 strains of bacteria (Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus plantarum, Lactobacillus paracasei, Bifidobacterium breve, Streptococcus thermophilus, Lactobacillus salivarius, and Bifidobacterium longum). Patients took 2 capsules once daily for 2 weeks (oral route) before the surgery and continued postoperatively for 1 month (on the first day postoperative, the capsules were diluted in 50-mL sterile water and given through feeding jejunostomy tube). For the synbiotic group, patients took the same probiotic supplement in addition to taking 1,000 mg inulin (Herbamama brand), 2 capsules once daily. For the placebo group, the same regimen was applied using a placebo.
Study Parameters Assessed
Investigators determined serum concentrations of inflammatory cytokines interleukin 10 (IL-10), IL-6, and IL-1β using enzyme-linked immunosorbent assay (ELISA) at baseline, 14 days before surgery, on the surgery day, and 14 days and 30 days postoperatively. They assessed tumor-tissue infiltration of CD8+ T cells and the expression of interferon gamma (IFN-γ) through immunohistochemistry (IHC) using patients’ pancreatic tumor samples. Investigators also followed up with patients after the surgery to assess postoperative short-term outcomes.
Primary Outcome
Impact of probiotics, synbiotics, or placebo on serum concentrations of inflammatory cytokines, immune response in tumor tissue, and postoperative short-term outcomes
Key Findings
The results showed a significant elevation of CD8+ T cell proportion and IFN-γ expression in the synbiotics group compared to the probiotics group (P=0.049, P=0.013, respectively). Inflammatory cytokines showed a significant gradual decrease in the synbiotics group compared to placebo- and probiotics-treated groups (P=0.000 for both). Administration of synbiotics and probiotics significantly decreased the rate of postoperative complications including anastomotic leakage, diarrhea, and abdominal distension (P=0.032, P=0.044, P=0.042, respectively), with a reduction in bacteremia in the synbiotics group (P=0.047).
Transparency
Open-access funding was provided by the Science, Technology & Innovation Funding Authority in cooperation with the Egyptian Knowledge Bank. The authors declared that they received no funds, grants, or other support.
Practice Implications & Limitations
Pancreatic cancer has the highest mortality rate of all major cancers.1 It is currently the 3rd leading cause of cancer-related death in the US after lung and colon cancer and is expected to become the 2nd leading cause of cancer-related death by 2030.1 Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer and has a highly immunosuppressive tumor microenvironment.2 This microenvironment facilitates tumor evolution, which begins when a single cell in the normal tissue transforms and expands to form a tumor mass. During this complex process, clonal lineages diverge and form distinct subpopulations, which result in heterogeneity within the tumor.3 Tumor evolution plays a role in resistance to treatment as well as the cancer cells becoming more aggressive and metastatic.4 Surgical resection represents the only chance for cure,5 followed by adjuvant therapy, however, with limited long-term effectiveness.3
There has been research recently on pancreatic cancer and the gut microbiota.5 Pancreatic ductal adenocarcinoma has been found to harbor a more abundant microbiome as compared to the normal pancreas,8 and these endogenous microbiota promote the immune-suppression characteristics of pancreatic cancer.8
Probiotics, in the field of cancer research, have demonstrated the ability to improve immune response by attracting diverse immune cells and regulating inflammation.6
Prebiotics have been shown to play a beneficial role in reducing inflammation and exhibiting antitumor effects.7 In the context of cancer therapy, synbiotics, encompassing probiotics plus prebiotics, potentially have a synergistic effect, contributing to immunomodulation.8 Tumor biopsies from long-term survivors of pancreatic cancer are more likely to be infiltrated by cytotoxic T cells and certain species of bacteria that activate T cells. These observations suggest that T-cell activation is essential for antitumor immunity in pancreatic cancers.9 This study showed a significant elevation of CD8+ T-cell proportion and IFN-γ expression in the synbiotics group compared to the probiotics group.3
The results of this study have clinically useful practice implications, especially since it utilized 2 commercially available products: Herbamama’s inulin, 1,000 mg (which is now 1,200 mg), and Now Foods’ Probiotic-10TM 25 Billion, with 10 probiotic strains. The dosing is very achievable in this patient population, albeit the administration in the immediate postoperative period may be challenging and will require approval from the surgical oncologist and administration via the hospital pharmacy and nursing staff. However, since consuming synbiotics and probiotics for 2 weeks pre-operatively and for 4 weeks postoperatively significantly improved the immune response in the treated group as compared to the placebo group,3 even if a patient were unable to ingest the synbiotics as an inpatient, there would likely still be significant benefit conferred.
These observations suggest that T-cell activation is essential for antitumor immunity in pancreatic cancers.
Numerous studies have been conducted on colorectal cancer, exploring the role of synbiotics. A recent meta-analysis of 24 randomized, controlled trials (RCTs) showed that the administration of pre-, pro-, or synbiotics improved surgical outcomes, including the incidence of infectious and noninfectious postoperative complications, return to normal gut function, hospital length of stay, and antibiotic usage. In addition, pre-, pro-, and synbiotics alleviated diarrhea from chemotherapy and radiation.10
This study provides useful clinical decision-making guidance for the support of pancreatic cancer patients in the perioperative phase of the treatment. In light of the outcomes from this study, recommending synbiotics pre- and postoperatively is likely to yield significant benefits and is a very reasonable approach from both a cost-effectiveness and practicality standpoint.
Conflict of Interest Disclosure
The author discloses no conflict of interest.
