Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models

Abstract

Background/aims: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods: BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Results: Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. Conclusion: A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients.

Fasting and engineered diets as powerful tool in the medical practice: an old approach in the new era

“…A further strategy to decrease glucose levels has been the development of engineered diets replacing corn starch with resistant starch, which is not digestible by the intestinal enzymes thus not releasing glucose. This approach has turned out to slow pancreatic cancer growth in a mouse model, without causing weight loss (16). Consistently, a number of previous studies on rat models of colon cancer revealed a protective role for resistant starch against carcinogenesis (17)(18)(19)(20), even upon high-protein diets (19,20).…”

“…It has been demonstrated that certain types of foods selectively enhance some microbial groups which in turn can shape the profile of the whole gut microbiota thus affecting the onset and the progression of several diseases, including cancer. Fiber-rich food regimens significantly decrease pro-inflammatory microorganisms such as Bacteroides acidifaciens, Escherichia coli, Ruminococcus gnavus and Clostridium cocleatum (16), supporting the indication that engineered diets able to perturb gut microbial community can be synergistically used together with the current chemotherapeutic approaches. Administration of probiotics and prebiotics represents the most common measure to shape gut microbiota in order to slow cancer progression, improve response to therapy or limit toxic side effects (22).…”

“…Moreover, in very recent years, a growing body of evidence has been produced highlighting the prominent role of the diet in shaping gut microbiota composition, which in turn plays a major role in the pathogenesis of several diseases (16,21). These studies suggest that not only the calories intake is important but also the type of dietary compounds.…”

Pancreatic Cancer, Gut Microbiota, and Therapeutic Efficacy

“…A considerable proportion of nonantibiotics also influence the growth of bacterial species [18]. A resistant starch diet promoted a decrease in tumor progression in PDAC xenograft mice, which was associated with a reduction in proinflammatory fecal microbiota [19].…”

Production of frozen probiotic fermented milk enriched with green banana biomass: The effects of freezing, acid stress conditions and bile salts on Lactobacillus paracasei subsp paracasei LBC 81 viability

“…In this case, the environment becomes undesirable for pathogenic microorganisms, and consequently reduces the risk of cancer cell formation (Khalili & Amini, 2015). Some studies have shown that resistant starch can prevent colorectal cancer (Panebianco et al, 2017;Yin & Zhao, 2017).…”