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Probiotic supplementation may lead to impaired immunotherapy efficacy
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Probiotic supplementation may lead to impaired immunotherapy efficacy.
“Science”: Cancer patients must not mess with probiotics! Scientists find that low dietary fiber and probiotic supplementation may lead to impaired immunotherapy efficacy
With dietary fiber and probiotics, Singularity Cake just wants to ask whose weight loss DNA is moving again!
We all know that dietary fiber and probiotics can regulate the balance of intestinal flora, promote gastrointestinal motility and nutrient absorption.
Singularity Cake has also witnessed the powerful functions of dietary fiber such as lowering blood pressure, improving cognition, and helping immunity with you before [1- 3], however, probiotics, which are also intestinal bacteria regulators, seem to have not 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 a major research result in the journal Science .
The researchers found that melanoma patients did not respond equally to immune checkpoint inhibitor (ICI) therapy after consuming dietary fiber and probiotics, with high dietary fiber intake associated with significantly improved progression-free survival compared with probiotic use. However, there is a phenomenon of impaired anti-tumor immunity.
While immune checkpoint inhibitors have successfully reached the top of the field of cancer treatment, scientists have also mastered some clues that the intestinal flora affects the effect of ICI treatment, which was quickly confirmed in many human cohorts and preclinical models [5- 7], but whether such factors that modulate 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 .
overall programme of study
Most of these patients were receiving systemic therapy, and 158 patients with advanced melanoma received ICI therapy, most commonly anti-PD-1 therapy, and 293 patients had an evaluable response to treatment.
Researchers responders entire cohort (n = 193, R) and non-responders (n = 100, NR) gut microflora was evaluated, we found cure treatment responders intestine Ruminococcus significant abundance Section higher than non-responders , but there was no difference in the overall composition of gut bacteria.
Volcano plot comparing the relative abundance of gut microbiota in responders and non-responders
Enterobacteriaceae can affect the effect of immunotherapy, so what is the impact of probiotics known for regulating enterobacteria?
According to statistics, 31% of patients receiving ICI treatment reported probiotic supplementation in the past month, the researchers evaluated the relationship between the use of probiotics and the effect of ICI treatment, but unfortunately, whether it was progression-free survival or No statistically significant differences were observed in treatment response rates.
Comparison of progression-free survival in patients with and without probiotics
Such results were not unexpected for the researchers, who quickly reinvested in their later review, considering possible patient size limitations and the heterogeneity of probiotic supplementation.
New research work – Exploring the effect of probiotic use 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 to germ-free mice, and then administered Bifidobacterium longum or Lactobacillus rhamnosus orally to the mice, with sterile water as a control group. Mice were inoculated subcutaneously with melanoma some time later and treated with anti-PD-L1 therapy.
The researchers found that the tumors in mice given the probiotic were significantly larger.
Tumor growth curve of mice under different feeding methods
However, it would be premature to judge the effect of probiotic use on the efficacy of ICI treatment only by tumor volume, so the researchers then analyzed the tumor immune infiltration of each group of mice.
Compared with the control group, the infiltration ratio of interferon-γ (IFN-γ)-positive CD8+ T cells in the tumors of mice treated with probiotics was significantly reduced ;
in addition, although the three groups of mice had no IFN-γ-positive CD4+ T cells statistically However, the proportion in the probiotic supplemented group showed a decreasing trend;
flow analysis also confirmed that the proportion of cytotoxic T cells in the mice in the probiotic group was reduced .
The data from these studies 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 under different feeding methods
In addition, during the study, the scientists also discovered an interesting phenomenon. From the cohort of responders, they identified higher abundance of gut microbiota species related to starch degradation and fiber fermentation , so they assessed dietary fiber intake. Effects on response to ICI therapy.
The results showed that about 30% of patients reached the set threshold for adequate intake, and their progression-free survival was significantly improved compared with patients with insufficient intake .
Thus, adequate dietary fiber intake has a positive effect on the therapeutic effect of ICI.
Effects of dietary fiber intake on progression-free survival in patients receiving ICI therapy
Considering the potential association between probiotics and dietary fiber, the researchers investigated the combined effects of dietary fiber and probiotics on the efficacy of ICI treatment, and further confirmed the above by comparing the potential additive effects of combined variables in the four groups of patients.
The results of the study were that patients who consumed adequate dietary fiber and did not receive probiotic supplementation had a higher response to ICI treatment and longer progression-free survival .
Even though the clinical results have supported the researchers’ conclusions, in line with rigorous principles, the researchers also established preclinical models to continue to explore, respectively, to provide enriched fiber (17.6%) to germ-free mice receiving anti-PD-1 treatment. or a low-fiber (2%) diet.
The study found that the tumor growth 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 speculated that the effect of this dietary intervention on immunotherapy may depend on the intestinal tract. tract flora.
Effects of dietary fiber intake on tumor growth in germ-free mice during treatment period
Further analysis of the intestinal flora, tumor immune infiltration and small molecule metabolites in mice showed that Ruminococcus may produce a series of small molecule metabolites such as short-chain fatty acids and propionate by fermenting dietary fiber, and the latter will directly affect The infiltration ratio and activation pathways of T cells are the intrinsic mechanisms by which high dietary fiber intake improves the response to immunotherapy.
In fact, studies on the regulation of immunotherapy by small molecule metabolites in the gut microbiota have long been reported [5, 8-9], and Singularity Cake has also been shared with current events, but this research is by no means unnecessary duplication of work.
We can see that there are too many unknown confounding factors in human cohorts, and although it is difficult to draw a clear causal relationship, the results of preclinical models are still instructive for the treatment of clinical cancer patients.
First, patients receiving ICI therapy should carefully consider dietary nutrition ratios and probiotic supplementation to avoid damaging the effect of immunotherapy;
in addition, when evaluating clinical treatment strategies, doctors should have a deep understanding of the butterfly effect of factors such as intestinal flora, and timely Tailored treatment plans.
1. Seidelmann SB, Claggett B, Cheng S, et al. Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis[J]. The Lancet Public Health, 2018, 3(9): e419-e428. doi: 10.1016/S2468-2667(18)30135-X
2. Kaye DM, Shihata WA, Jama HA, et al. Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease. Circulation. 2020;141(17):1393-1403. doi:10.1161/CIRCULATIONAHA .119.043081
3. 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. Microbiome. 2021;9(1):223. Published 2021 Nov 11. doi: 10.1186/s40168-021-01172-0.
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
5. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97.
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. Cell. 2021;184(21):5338-5356.e21. doi:10.1016/j .cell.2021.09.019
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. Nat Biomed Eng. 2021;5(11):1377-1388. doi: 10.1038/s41551-021-00749-2
Probiotic supplementation may lead to impaired immunotherapy efficacy
(source:internet, reference only)