Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel

Han, Kai; Nam, Jutaek; Xu, Jin; Sun, Xiaoqi; Huang, Xuehui; Animasahun, Olamide; Achreja, Abhinav; Jeon, Jin Heon; Pursley, Benjamin; Kamada, Nobuhiko; Chen, Grace Y.; Nagrath, Deepak; Moon, James J.

doi:10.1038/s41551-021-00749-2

Cited by 128 publications

(109 citation statements)

References 40 publications

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“…Tumor transplantation was conducted at day 0, and all mice were subcutaneously injected with 5 × 10 5 CT26 cells. For ICB therapy, mice from MC and CT groups were intraperitoneally injected with 100 μg anti-mouse PD-1 monoclonal antibody (Clone RMP1-14, BioXCell, USA), while mice from PA and NC groups were intraperitoneally injected with 100 μg rat immunoglobulin (Ig)G2a (Clone 2A3, BioXCell, USA) as isotype control ( 17 , 26 ). The injections were administered every 3 or 4 days from day 10, and the mice were sacrificed at day 24.…”

Section: Methodsmentioning

confidence: 99%

Adjunctive Probiotic Lactobacillus rhamnosus Probio-M9 Administration Enhances the Effect of Anti-PD-1 Antitumor Therapy via Restoring Antibiotic-Disrupted Gut Microbiota

Gao

Zou

et al. 2021

Front. Immunol.

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Emerging evidence supports that the efficacy of immune checkpoint blockade (ICB) therapy is associated with the host’s gut microbiota, as prior antibiotic intake often leads to poor outcome and low responsiveness toward ICB treatment. Therefore, we hypothesized that the efficacy of ICB therapy like anti-programmed cell death protein-1 (PD-1) treatment required an intact host gut microbiota, and it was established that probiotics could enhance the recovery of gut microbiota disruption by external stimuli. Thus, the present study aimed to evaluate the effect of the probiotics, Lactobacillus rhamnosus Probio-M9, on recovering antibiotic-disrupted gut microbiota and its impact on the outcome of ICB therapy in tumor-bearing mice. We first disrupted the mouse microbiota by antibiotics and then remediated the gut microbiota by probiotics or naturally. Tumor transplantation was then performed, followed by anti-PD-1-based antitumor therapy. Changes in the fecal metagenomes and the tumor suppression effect were monitored during different stages of the experiment. Our results showed that Probio-M9 synergized with ICB therapy, significantly improving tumor inhibition compared with groups not receiving the probiotic treatment (P < 0.05 at most time points). The synergistic effect was accompanied by effective restoration of antibiotic-disrupted fecal microbiome that was characterized by a drastically reduced Shannon diversity value and shifted composition of dominating taxa. Moreover, probiotic administration significantly increased the relative abundance of beneficial bacteria (e.g., Bifidobacterium pseudolongum, Parabacteroides distasonis, and some Bacteroides species; 0.0001 < P < 0.05). The gut microbiome changes were accompanied by mild reshaping of the functional metagenomes characterized by enrichment in sugar degradation and vitamin and amino acid synthesis pathways. Collectively, this study supported that probiotic administration could enhance the efficacy and responsiveness of anti-PD-1-based immunotherapy, and Probio-M9 could be a potential candidate of microbe-based synergistic tumor therapeutics. The preclinical data obtained here would support the design of future human clinical trials for further consolidating the current findings and for safety assessment of probiotic adjunctive treatment in ICB therapy.

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Section: Methodsmentioning

confidence: 99%

Adjunctive Probiotic Lactobacillus rhamnosus Probio-M9 Administration Enhances the Effect of Anti-PD-1 Antitumor Therapy via Restoring Antibiotic-Disrupted Gut Microbiota

Gao

Zou

et al. 2021

Front. Immunol.

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“…The reprogramming increases the production of effector molecules such as CD25, IFN-γ, and TNF-α that significantly enhanced the antitumor activity of antigen-specific CTL and CAR-T in cancer models ( 113 ). In addition, after oral administration of inulin, which eventually increases the concentration of SCFAs, the antitumor adaptive immune phenotypes including circulating antigen-specific CD8+ T cells and CD44+CD62L+CD8+ memory T cells were significantly increased, further confirming the existence of a long-term memory response ( 146 ).…”

Section: Gut Microbiota Regulates Adaptive Immunity Under Tumor Patho...mentioning

confidence: 88%

“…found that paclitaxel induced the increase of intestinal permeability and triggered the immune system to aggravate neuroinflammation ( 144 ). They preliminarily found that the decreased cognitive performance occurred in parallel with reduced microglial immunoreactivity and transient increases in pro-inflammatory cytokine/chemokine (Il-1β, Tnfα, Il-6, and Cxcl1) gene expression in the brain, which may be mediated by the brain–gut–microbiota axis ( 145 , 146 ). More studies like this may be helpful for decreasing the side effects of chemotherapy.…”

Section: Gut Microbiota Regulates Adaptive Immunity Under Tumor Patho...mentioning

confidence: 99%

Effects of Gut Microbiota on Host Adaptive Immunity Under Immune Homeostasis and Tumor Pathology State

Zhu³

et al. 2022

Front. Immunol.

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Gut microbiota stimulate and shape the body’s adaptive immune response through bacterial components and its active metabolites, which orchestrates the formation and maintenance of the body’s immune homeostasis. In addition, the imbalances in microbiota-adaptive immunity contribute to the development of tumor and the antitumor efficiency of a series of antitumor therapies at the preclinical and clinical levels. Regardless of significant results, the regulation of gut microbiota on adaptive immunity in immune homeostasis and tumors needs a more thorough understanding. Herein, we highlighted the comprehensive knowledge, status, and limitations in the mechanism of microbiome interaction with adaptive immunity and put forward the prospect of how to translate these insights in inhibiting tumor progression and enhancing the efficacy of antitumor interventions.

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“…Recent work showed that gut immunity can be greatly influenced by the commensal bacteria in the gut. Interestingly, the microbiome and its metabolites were identified as critical factors that directly affect the activity of surrounding immune cells [85] . In addition, the effectiveness of oral vaccines was reported to be lowered by regulatory T cells induced under an abnormal intestinal environment, such as those associated with chronic malnutrition or environmental enteric dysfunction [86] .…”

Section: Impact Of the Delivery Routes On The In Vivo Fates Of Vaccinesmentioning

confidence: 99%

In vivo fate and intracellular trafficking of vaccine delivery systems

Lee

Kim

Byun

et al. 2022

Advanced Drug Delivery Reviews

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Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel

Cited by 128 publications

References 40 publications

Adjunctive Probiotic Lactobacillus rhamnosus Probio-M9 Administration Enhances the Effect of Anti-PD-1 Antitumor Therapy via Restoring Antibiotic-Disrupted Gut Microbiota

Adjunctive Probiotic Lactobacillus rhamnosus Probio-M9 Administration Enhances the Effect of Anti-PD-1 Antitumor Therapy via Restoring Antibiotic-Disrupted Gut Microbiota

Effects of Gut Microbiota on Host Adaptive Immunity Under Immune Homeostasis and Tumor Pathology State

In vivo fate and intracellular trafficking of vaccine delivery systems

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