Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells

Abstract

Immune checkpoint blockade (ICB) immunotherapy increases antitumor immunity by blocking cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and displays robust clinical responses in various cancers. However, ICB immunotherapy also triggers severe inflammatory side effects, known as immune-related adverse effects (irAEs). One of the most common toxicities is immune checkpoint blockade-associated colitis (ICB associated colitis). The exact mechanism of ICB associated colitis remains to be explored. Here, we combined ICB (anti–CTLA-4 and anti-PD-1) treatment with a standard colitis model, in which a more severe form of colitis is induced in mice, to recapitulate the clinical observations in patients receiving combined ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy, during which colitis is the most frequent complication encountered. We found that the composition of the gut microbiota changed in ICB associated colitis. Principal component analysis of the gut microbiome showed an obvious reduction in the abundance of Lactobacillus in severe ICB associated colitis. Lactobacillus depletion completely by vancomycin augmented the immunopathology of ICB. Furthermore, we found that the ICB toxicity could be totally eliminated via the administration of a widely available probiotic Lactobacillus reuteri (L.reuteri) . Oral administration of L. reuteri therapeutically inhibited the development and progression of colitis, thus ameliorating the loss of body weight and inflammatory status induced by ICB treatment. Mechanistically, the protective effect of L. reuteri was associated with a decrease in the distribution of group 3 innate lymphocytes (ILC3s) induced by ICB associated colitis. In conclusion, our study highlights the immunomodulatory mechanism of the gut microbiota and suggests that manipulating the gut microbiota by administrating L. reuteri can mitigate the autoimmunity induced by ICB, thus allowing ICB immunotherapy to stimulate the desired immune response without an apparent immunopathology.

Intestinal Flora and Disease Mutually Shape the Regional Immune System in the Intestinal Tract

“…The use of certain probiotics, such as Lactobacillus reuteri, can also alleviate immune checkpoint inhibitor-associated colitis caused by immunotherapy. The ability of L. reuteri (a 3-day treatment) to protect the colon is primarily associated with its ability to lower serum levels of anti-inflammatory factors, such as TNF-α, IFN-γ, and IL-6, as well as the ability to suppress serum levels of ILC3, IL-23, and IL-17, effectively relieving colitis induced by immunotherapy (115).…”

A Tool for the Treatment of Gastrointestinal Tumors: Micro- Ecological Immunotherapy

“…The effects of oral administration of Bifidobacteria alone on tumors were the same as those of PD-L1-specific antibody treatment, and combination therapy almost eliminated tumor growth [71]. When Wang T et al administered Lactobacillus reuteri to regulate intestinal microbiota, it alleviated PD-1 antibodyinduced autoimmunity, thereby enabling immunotherapy to produce the desired immune response without significant immunopathology [72]. This suggests that the resistance of PD-1-deficient mice to colitis depends on their intestinal microbiota.…”

Recognition and management of the gastrointestinal and hepatic immune‐related adverse events

“…Further, an increased proportion of Bacteroides phylum can exempt patients from ipilimumab‐induced colitis . Oral administration of Lactobacillus reuteri therapeutically inhibited the development and progression of ICI‐related colitis, by decreasing the distribution of group 3 innate lymphocytes (ILC3s) . These data suggest the prospect of further improving the efficacy of ICIs while avoiding irAEs.…”