Gut microbiotas and immune checkpoint inhibitor therapy response: a causal or coincidental relationship?

Abstract

As the largest immune organ, human gut microbiome could influence the efficacy of immune checkpoint inhibitor therapy (ICI). However, identifying contributory microbes from over 35,000 species is virtually impossible and the identified microbes are not consistent among studies. The reason for the disparity may be that the microbes found in feces are markers of other factors that link immune response and microbiotas. Notably, gut microbiome is influenced by stool consistency, diet and other lifestyle factors. Therefore, the ICI and microbiotas relationship must be adjusted for potential confounders and analyzed longitudinally. Moreover, a recent study where 11 low-abundance commensal bacteria induced interferon-γ-producing CD8 T cells, challenges the validity of the abundance-oriented microbiotas investigations. This study also confirmed the hierarchy in immunogenic roles among microbiotas. Fecal transplantation trials in germ-free mice provided “the proof of principle” that germ-free mice reproduce the donor’s microbiome and corresponding ICI efficacy. However, species-specific biological differences prevent direct extrapolation between the results in murine and human models. Fecal transplantation or supplementation with microbes found in ICI responders requires caution due to potential adverse events.

Commensals can become pathobionts

“…The authors speculated that Akkermansia may be used as an adjunctive treatment for periodontal disease.We are writing this letter to caution the readers that there are no harmless commensals because under certain conditions most commensals are capable of becoming pathobionts. As we have stated in our previous review, A. muciniphila prefers euglycemia and a high-fibre diet (Janket et al, 2019b), not causing any harm most of the time.However, A. muciniphila spp. are mucin-degrading microbes (Janket et al, 2019b) and their overgrowth can erode the protective mucin layer and damage the mucosa, which will allow pathobionts for easy access causing lethal colitis in murine models (Desai et al, 2016).Moreover, in genetically susceptible hosts, or when dietary fibre is deficient, Akkermansia can become a pathobiont and express proinflammatory responses.…”

“…As we have stated in our previous review, A. muciniphila prefers euglycemia and a high-fibre diet (Janket et al, 2019b), not causing any harm most of the time.However, A. muciniphila spp. are mucin-degrading microbes (Janket et al, 2019b) and their overgrowth can erode the protective mucin layer and damage the mucosa, which will allow pathobionts for easy access causing lethal colitis in murine models (Desai et al, 2016).Moreover, in genetically susceptible hosts, or when dietary fibre is deficient, Akkermansia can become a pathobiont and express proinflammatory responses. It has been reported that enrichment of Akkermansia caused intestinal inflammation and colitis (Seregin et al, 2017).…”

Modulation of Gut Microbiota to Enhance Effect of Checkpoint Inhibitor Immunotherapy

“…Another 12-year prospective clinical study showed that long-term intake of high-dose yogurt (containing Streptococcus thermophilus and Lactobacillus bulgaricus ) has a significantly reduced risk of colorectal cancer ( 79 ). However, although probiotics were proved to be beneficial with antitumor effects, probiotic supplementation with ICIs might generate conflicting results ( 80 ). Probiotic use after ATBs could have opposite effect and delay restoration of the gut microbiota ( 81 ).…”

Do Prevotella copri and Blastocystis promote euglycaemia?

“…1 This study corroborated our view that faecal microbiota reflect lifestyle factors such as diet, exercise, medicine intake, and other factors. 2 The long-term intake of healthy plant-based foods was associated with improved cardiometabolic markers. This finding is consistent with our previous report 3 that fruit and vegetable intake is predictive of risk of diabetes.…”