Cancer patients should never use probiotics indiscriminately!

We all know that dietary fiber and probiotics can regulate the balance of intestinal flora, promote gastrointestinal motility and absorption of nutrients
.

However, probiotics, as modulators of gut bacteria, do not seem to have been carefully studied…

Recently, the team of Jennifer A.
Wargo and Carrie R.
Daniel from the University of Texas MD Anderson Cancer Center and the team of Giorgio Trinchieri of the National Institutes of Health published an important study in the journal Science
.

The researchers found that melanoma patients did not respond equally to immune checkpoint inhibitor (ICI) treatment after consuming dietary fiber and probiotics, with high dietary fiber intake associated with significant improvement without progression compared with use of probiotics survival related
.

However, there is a phenomenon of impaired anti-tumor immune function

 

While immunosuppressant checkpoints have successfully reached the summit of the cancer treatment arena, scientists also have some clues that the gut microbiota influences ICI's impact on therapy, which was soon confirmed in many human cells and preclinical models [5-7] , but whether these factors modulating the gut microbiota, such as dietary fiber and probiotics, also influence the response of cancer patients to ICI therapy is inconclusive
.

To do this, the researchers analyzed the fecal microbes of 438 melanoma patients and assessed their gut microbiota profile, dietary habits and probiotic use in relation to prognosis
.

 

 

Most of these patients received systemic therapy, 158 patients with advanced melanoma received ICI therapy, most commonly anti-PD-1 therapy, and 293 patients had an evaluable response to therapy
.

The gut microbiota of responders (n = 193, R) and non-responders (n = 100, NR) were assessed, and we found that the gut Ruminococcus was significantly more abundant in curative treatment responders than non-responders, But there were no differences in the overall composition of gut bacteria
.

 

 

Escherichia coli can affect the efficacy of immunotherapy, so what is the known effect of probiotics on regulating Enterobacteriaceae?

According to statistics, 31% of patients receiving ICI treatment reported supplementation with probiotics in the past month.

The researchers evaluated the relationship between the use of probiotics and the effect of ICI treatment, but unfortunately, whether without There was no statistical difference in progression survival or treatment response rate

 

Comparison of progression-free survival in patients with and without probiotics

 

Such results were not surprising to the researchers, who quickly reinvested in a later review given possible patient size limitations and heterogeneity of probiotic supplementation
.

New research work - Exploring the effect of the use of probiotics on the efficacy of ICI treatment in a preclinical model

 

Protocol design for preclinical models

 

First, the researchers transplanted the feces of patients with anti-PD-1 antibody responses into germ-free mice, then gave the mice orally Bifidobacterium longum or Lactobacillus rhamnosus, and the control group was sterile water
.

After a period of time, the mice were subcutaneously inoculated with melanoma and treated with anti-PD-L1

The researchers found that the tumors in the mice given the probiotics were significantly larger
.

 

Tumor growth curve of mice under different feeding methods

 

However, it is too early to judge the effect of probiotic use on the efficacy of ICI treatment from tumor volume alone, so the researchers then analyzed tumor immune infiltration in each group of mice
.

Compared with the control group, the infiltration rate of interferon-γ (IFN-γ)-positive CD8+ T cells in the tumors of the mice in the probiotic group was significantly reduced;

Furthermore, although none of the three groups of mice were statistically free of IFN-γ-positive CD4+ T cells, the proportion in the probiotic-supplemented group showed a decreasing trend;

Flow analysis also confirmed a decreased proportion of cytotoxic T cells in the mice in the probiotic group
.

The data from these studies all point to the same conclusion: the use of probiotics can lead to impaired ICI treatment effect

 

Analysis of tumor immune infiltration in tumor-bearing mice with different feeding methods

 

In addition, during the research, the scientists also discovered an interesting phenomenon
.

From the cohort of responders, they found a greater diversity of gut microbiota related to starch degradation and fiber fermentation, so they assessed dietary fiber intake

The results showed that about 30% of patients reached the set threshold for adequate intake, and their progression-free survival was significantly improved compared to patients with insufficient intake
.

Therefore, an adequate intake of dietary fiber has a positive impact on the therapeutic effect of ICI
.

 

Influence of dietary fiber intake on progression-free survival in ICI-treated patients

 

Considering the potential association between probiotics and dietary fiber, the researchers examined the effect of the combined effect of dietary fiber and probiotics on the treatment effect of ICI, and further confirmed this by comparing the potential additive effect of the combined variable in the four groups of patients.

a little

The results of the study were that patients who consumed adequate dietary fiber and were not supplemented with probiotics had a higher response to ICI treatment and longer progression-free survival
.

Although the clinical results support the researchers' conclusions, according to strict principles, the researchers also established a preclinical model to continue the exploration, respectively, to provide abundant fiber (17.

6%) in germ-free mice receiving anti-PD-1 treatment
.
Or a low-fiber diet (2%)
.

The study found that the tumor growth rate of mice in the high dietary fiber group was slower
.
In addition, the two diets had no significant effect on the treatment response of germ-free mice
.

The researchers speculate that the impact of this dietary intervention on immunotherapy may depend on the gut
.

 

Effects of dietary fiber intake during treatment on tumor growth in germ-free mice

 

Further analysis of the intestinal flora, tumor immune infiltration and small-molecule metabolites in mice showed that Ruminococcus produces a series of small-molecule metabolites such as short-chain fatty acids and propionic acid by fermenting dietary fiber, and the latter will directly affect the growth of T cells.
Infiltration rates and activated pathways are intrinsic mechanisms by which high dietary fiber intake enhances immunotherapy response
.

In fact, studies on the modulation of immunotherapy by small-molecule metabolites in the gut microbiota have long been reported [5,8-9], and we can see that there are too many unknown confounding factors in the human cohort, although it is difficult to draw a definitive causality, but the results from preclinical models remain instructive for the treatment of clinical cancer patients
.

First, patients receiving ICI therapy should seriously consider dietary nutrition ratios and probiotic supplementation to avoid compromising the effect of immunotherapy;

In addition, when evaluating clinical treatment strategies, physicians should have an in-depth understanding of the impact of factors such as intestinal flora on the butterfly effect, and timely formulate targeted treatment plans
.

references:

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Seidelmann SB, Claggett B, Cheng S, et al.
Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis[J].
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Kaye DM, Shihata WA, Jama HA, et al.
Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease.
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Shi H, Ge X, Ma X, et al.
A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites.
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4.
Spencer CN, McQuade JL, Gopalakrishnan V, et al.
Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.
Science.
2021;374(6575):1632-1640.
doi:10.
1126/science.
aaz7015

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Routy B, Le Chatelier E, Derosa L, et al.
Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.
Science.
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6.
Matson V, Fessler J, Bao R, et al.
The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.
Science.
2018;359(6371):104-108.
doi:10.
1126/science.
aao3290

7.
Andrews MC, Duong CPM, Gopalakrishnan V, et al.
Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.
Nat Med.
2021;27(8):1432-1441.
doi:10.
1038/ s41591-021-01406-6

8.
Lam KC, Araya RE, Huang A, et al.
Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment.
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9.
Han K, Nam J, Xu J, et al.
Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel.
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