Biostimulating Gut Microbiome with Bilberry Anthocyanin Combo to Enhance Anti-PD-L1 Efficiency against Murine Colon Cancer.

Xuerun Liu,Nan Jing,Guoqiang Jiang,Zheng Liu,Luoyang Wang

doi:10.3390/microorganisms8020175

Abstract

Recent advances have revealed the essential role of gut microbiomes in the therapeutic efficiency of immune checkpoint inhibitors (ICIs). Inspired by biostimulation, a method using nutrients to accelerate the growth of soil microorganisms and the recovery of soil microbial consortia, here we propose a bilberry anthocyanin combo containing chitosan and low molecular citrus pectin (LCP), in which LCP–chitosan is used to encapsulate anthocyanins so to enhance its digestive stability and, moreover, modulate the microbiome more favorable for the PD-L1 blockade treatment. Using murine MC38 colon cancer as a model system, we examined the effects of the combo on modulating the gut microbiome and therapeutic efficiency of PD-L1 blockade treatment. It was shown that bilberry anthocyanins enriched the subdominant species, increased both the concentration and the proportion of butyrate in feces and enhanced intratumoral CD8+ T cell infiltrations. The application of the bilberry anthocyanin combo restored the species diversity of gut microbiome decreased by LCP–chitosan and achieved the best control of tumor growth. These preliminary results indicated unprecedented opportunities of probiotics combo in improving the therapeutic efficiency of immune checkpoint inhibitor through manipulating gut microbiome.

Highlights

While immunotherapy through targeting immune checkpoints to unleash the adaptive immune response has rekindled hopes for millions of cancer patients, the response rates are below 30% for immune checkpoint inhibitors (ICIs), such as anti-programmed death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1), in some tumor types [1,2,3,4]
It is noted that chitosan is soluble in simulated gastric fluid (SGF) but dissoluble in simulated intestinal fluid (SIF)
It is anticipated that chitosan will form precipitate encapsulating anthocyanins when the pH increases from simulated gastric fluid to simulated intestinal fluid

Summary

Introduction

While immunotherapy through targeting immune checkpoints to unleash the adaptive immune response has rekindled hopes for millions of cancer patients, the response rates are below 30% for immune checkpoint inhibitors (ICIs), such as anti-programmed death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1), in some tumor types [1,2,3,4]. The prebiotic function of anthocyanins has attracted growing attention Both in vitro fermentation of anthocyanins by human fecal microbiome [15] and in vivo dietary intervention in mice [16,17] have demonstrated that anthocyanins can improve the diversity of the gut microbiome, promote growth of the beneficial bacterial groups while inhibit the potentially harmful bacterial groups, and increase the concentration of fecal short-chain fatty acids (SCFAs) [16,18]. All these indicate a high potential of anthocyanins in enhancing therapeutic efficiency of α-PD-L1. The observation of the low recovery (below 27%) in ileal effluent [19,20] suggests the poor availability of anthocyanins in the colon and the need to enhance the digestive stability of anthocyanin products used for oral administration

Methods

Results

Discussion

Conclusion