PNAS: Probiotics work! Wang Feng's team reported that Bifidobacteria can alleviate the side effects of cancer immunotherapy.

As an effective method of tumor immunotherapy, immune checkpoint blocking has made a breakthrough in clinical application in recent years.
But inhibitors targeting immuno checkpoints such as CTLA-4 and PD-1 improve anti-tumor effectiveness while also breaking the immune balance and triggering a variety of even life-threatening autoimmune responses, of which diarrhea and colitis are among the most common and serious diseases.
Bifidobacterium is one of the most common probiotics in food, in recent years has been frequently used by major businesses as a buying point, past research has found that Bifidobacteria has the role of regulating intestinal function, enhance immunity, so Bifidobacteria may also play an active role in immuno-checkpoint inhibitor-induced enteritis? On October 19, 2020, the Wang Feng team from Shanghai Jiaobi University School of Medicine published a research paper on PNAS entitled: Bifidobacterium alters the gut microbiota and modulates the meta-functionalism of T regulatory cells in context of the immune checkpoint.
the study found that Bifidobacteria can optimize the composition of symblotic bacteria under the condition of CTLA-4 blocking at the immuno checkpoint, and enhance the function and metabolism of intestinal regulatory T-cells (Treg), thereby alleviating anti-CTLA-4 antibody-induced intestinal inflammation.
authors' previous studies have found that the regulatory role of Bifidobacteria in CTLA-4-induced immunopathological responses requires the involvement of Treg cells, so the authors first explore whether Treg cells directly affect the composition of gut microorganisms.
the authors first treated mice with a mixture of Bifidobacteria, and found that not only did the abundance of Bifidobacteria increase in the intestinal bacteria in mice, but the abundance of a variety of bacteria, such as Lactobacillus lactobacillus, also increased significantly.
in mice with Treg cell loss, however, Bifidobacteria was unable to colonise and increase the levels of other probiotics.
this reveals that the intestinal immune status determines the transmission relationship between Bifidobacteria and other symbic bacteria, and ultimately contributes to the maintenance of intestinal stability.
Next, the authors tested the effects of each of the four Bifidobacteria strains from a mixture of four Bifidobacteria used in previous experiments, and found that only short Bifidobacteria could alleviate symptoms in mice with colitis.
Because the author found that the abundance of Bifidobacteria and Lactobacillus was related at the genus level, the author experimented with different strains of Lactobacillus lactobacillus, and found that lactobacillus saccharide reduced symptoms in mice with colitis.
, the authors studied the effects of Bifidobacteria on intestinal Treg cells.
the authors analyzed the gene expression patterns of Treg cells in the colon in mice treated with Bifidobacteria and PBS, and found that Bifidobacteria treatment increased the expression of inflammatory-related genes such as Il10r alpha, Cxcr5, and Il17r alpha.
further confirmed an increase in the expression of IL-10R alpha and IL-10 in Treg cells in the inherent layer of the colon after Bifidobacteria treatment.
IL-22 is also one of the cytokines in the IL-10 family and play an important role in maintaining intestinal stability, so the authors also studied the role of IL-22.
mice showed more severe enteritis after knocking out the Il-10 gene or using IL-22 median antibodies.
In mice that knocked out the Il-10 gene while blocking IL-22, the remission effect of Bifidobacteria on enteritis completely disappeared, indicating that IL-22 and IL-10 were necessary for Bifidobacteria to function as an improved intestinal immunopathy.
, how does Bifidobacteria affect the function of Treg cells? After analyzing the serum of mice based on mass spectrometry, the authors found that the levels of serum nicotic acid increased significantly in mice in the Bifidobacteria treatment group, which can react with mitochondrial activity.
rich analysis of the expression spectrum data of Treg cells, and it was also found that Bifidobacteria treatment can significantly affect metabolic-related path pathfage.
to see if Bifidobacteria affects the volume and function of Treg cell mitochondrials, the authors used fluorescence probes to stain cells to detect the volume and membrane prototyping of mitochondrials.
results of current cytomegi showed an increase in the mitochondrial volume and mitochondrial stress of Treg cells in the Treg cell treatment group.
, the authors also found that Bifidobacteria treatment significantly increased the expression of multiple genes in Treg cells associated with mitochondrial function or structure.
these results suggest that Bifidobacteria regulates metabolic processes in the gut Treg and enhances mitochondrial activity.
this work revealed the enhanced function of Bifidobacteria on intestinal Treg cells through symblotic bacteria under CTLA-4 immune checkpoint blocking conditions.
study found that introducing Bifidobacteria into mice significantly altered their gut microbiome, suggesting that gut microbes are a dynamic and interconnected ecosystem.
Bifidobacteria also increases the expression of IL-10Ra and IL-10 in intestinal Treg cells, thereby enhancing the immunosuppressive effects of Treg cells to alleviate the side effects of intestinal immunity caused by CTLA-4 blocking.
Bifidobacteria significantly reduces the side effects of immuno-checkpoint blocking tumor immunotherapy and enhances the characteristics of the combined therapeutic effect of various immuno-checkpoint antibodies, which will help optimize the relevant clinical immunotherapy program, and lay a solid theoretical foundation for improving the structure of the intestinal bacteriology and improving the comprehensive effect of tumor immunotherapy by using probiotic strains.
, the authors are Wang Feng, a researcher at the Shanghai Institute of Immunology at Shanghai Jiaojiao University School of Medicine, and Mark Davis, a professor at Stanford University School of Medicine.
co-authors of this article are Master's student Sun Shan, Assistant Researcher Luo Lingjie and PhD student Liang Wenhua.
, the study has received strong support from many domestic and foreign partners, including Professor Michel Fischbach of Stanford University and Professor Justin Sonnenburg.
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