Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer

Ryu, Tae Young; Kim, Kwang‐Ho; Han, Tae-Su; Lee, Mi‐Ok; Lee, Jinkwon; Choi, Jinhyeon; Jung, Kwang Bo; Jeong, Eun-Jeong; An, Da Mi; Jung, Cho‐Rok; Jung, Jaeeun; Park, Kunhyang; Kim, Miyoung; Oh, Soo Jin; Hur, Keun; Hamamoto, Ryuji; Park, Doo-Sang; Kim, Dae‐Soo; Son, Mi‐Young; Cho, Hyun Soo

doi:10.1038/s41396-021-01119-1

“…Major SCFAs include acetate, butyrate, and propionate. Butyrate could inhibit the motility of colorectal cancer cells by deactivating Akt/ERK signaling ( Li et al, 2017 ); acetate was shown to promote the expression of anti-inflammatory cytokines and reduce the generation of pro-inflammatory factors and NF-κB pathway activation in CRC cells ( Tedelind et al, 2007 ); and propionate suppressed CRC growth by promoting the proteasomal degradation of euchromatic histone-lysine N-methyltransferase 2 (EHMT2) through HECT domain E3 ubiquitin protein ligase 2 (HECTD2) upregulation ( Ryu et al, 2022 ). Secondary bile acids, lactate, trimethylamine N-oxide (TMAO), N-nitroso compounds, acetaldehyde, 4-hydroxyphenylacetic acid, phenylacetic acid, and phenol are related to CRC ( Mohseni et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Alterations of the Gut Microbiome and Fecal Metabolome in Colorectal Cancer: Implication of Intestinal Metabolism for Tumorigenesis

Du

¹

,

Li

²

,

Tang

³

et al. 2022

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Objective: The gut microbiota and its metabolites are important for host physiological homeostasis, while dysbiosis is related to diseases including the development of cancers such as colorectal cancer (CRC). In this study, we characterized the relationship of an altered gut microbiome with the fecal metabolome in CRC patients in comparison with volunteers having a normal colorectal mucous membrane (NC).Methods: The richness and composition of the microbiota in fecal samples of 30 CRC patients and 36 NC controls were analyzed through 16S rRNA gene sequencing, and the metabolome was determined by ultra-performance liquid chromatography coupled to tandem mass spectrometry. Spearman correlation analysis was to determine the correlation between the gut microbiome and fecal metabolome in CRC patients.Results: There were significant alterations in the gut microbiome and fecal metabolome in CRC patients compared with NC controls. Bacteroidetes, Firmicutes, Actinobacteriota, and Proteobacteria dominated the gut microbial communities at the phylum level in both groups. Compared with NC controls, CRC patients had a lower frequency of Blautia and Lachnospiracaea but a higher abundance of Bacteroides fragilis and Prevotella. Regarding the fecal metabolome, twenty-nine metabolites were identified as having significantly changed, showing increased levels of adrenic acid, decanoic acid, arachidonic acid, and tryptophan but a reduction in various monosaccharides in the fecal samples of CRC patients. Moreover, increased abundance of Bacteroides fragilis was strongly associated with decreased levels of monosaccharides, while Blautia was positively associated with the production of monosaccharides in the fecal samples.Conclusion: These results highlight alterations of gut microbiota in association with certain metabolites in CRC progression, implying potential diagnostic and intervention potential for CRC.

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“…A wide range of commensal bacterial species have been reported to be associated with the enhanced efficacy of ICIs, including B. thetaiotaomicron (23), B. fragilis (24), B. cellulosilyticus (25), Parabacteroides distasonis (26), B. salyersiae (27), and B. uniformis (13). In this study, our metagenomic analysis showed that FMT significantly upregulated the abundance of those potentially beneficial species, particularly those species from Bacteroides genus (Figures 2C, E).…”

Section: Discussionmentioning

confidence: 99%

“…the expression of IL-10) and mediate intestinal homeostasis (29). B. thetaiotaomicron is also able to inhibit the growth of CRC cells via its metabolite propionate (23). Another Bacteroides species B. fragilis is associated with the favorable clinical outcome of CTLA-4 inhibitors (24) via inducing regulatory T cells to secrete IL-10 through the immunomodulatory molecule polysaccharide A (PSA) of B. fragilis (30).…”

Section: Discussionmentioning

confidence: 99%

Metagenomic and metabolomic analyses reveal synergistic effects of fecal microbiota transplantation and anti-PD-1 therapy on treating colorectal cancer

Huang

¹

,

Zheng

²

,

Kang

³

et al. 2022

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Anti-PD-1 immunotherapy has saved numerous lives of cancer patients; however, it only exerts efficacy in 10-15% of patients with colorectal cancer. Fecal microbiota transplantation (FMT) is a potential approach to improving the efficacy of anti-PD-1 therapy, whereas the detailed mechanisms and the applicability of this combination therapy remain unclear. In this study, we evaluated the synergistic effect of FMT with anti-PD-1 in curing colorectal tumor-bearing mice using a multi-omics approach. Mice treated with the combination therapy showed superior survival rate and tumor control, compared to the mice received anti-PD-1 therapy or FMT alone. Metagenomic analysis showed that composition of gut microbiota in tumor-bearing mice treated with anti-PD-1 therapy was remarkably altered through receiving FMT. Particularly, Bacteroides genus, including FMT-increased B. thetaiotaomicron, B. fragilis, and FMT-decreased B. ovatus might contribute to the enhanced efficacy of anti-PD-1 therapy. Furthermore, metabolomic analysis upon mouse plasma revealed several potential metabolites that upregulated after FMT, including punicic acid and aspirin, might promote the response to anti-PD-1 therapy via their immunomodulatory functions. This work broadens our understanding of the mechanism by which FMT improves the efficacy of anti-PD-1 therapy, which may contribute to the development of novel microbiota-based anti-cancer therapies.

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“…A wide range of commensal bacterial species have been reported to enhance the efficacy of ICIs, including B. thetaiotaomicron (23), B. fragilis (24), B. cellulosilyticus (25), Parabacteroides distasonis (26), B. salyersiae (27), and B. uniformis (13). In this study, our metagenomic analysis showed that FMT significantly upregulated the abundance of those aforementioned species, particularly those species from Bacteroides genus ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Metagenomic and Metabolomic Analyses Reveal Synergistic Effects of Fecal Microbiota Transplantation and Anti-PD-1 Therapy on Treating Colorectal Cancer

Huang

¹

,

Zheng

²

,

Kang

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

Anti-PD-1 immunotherapy has saved numerous lives of cancer patients; however, it only exerts efficacy in 10-15% of patients with colorectal cancer. Fecal microbiota transplantation (FMT) is a potential approach to improving the efficacy of anti-PD-1 therapy, whereas the detailed mechanisms and the applicability of this combination therapy remain unclear. In this study, we evaluated the synergistic effect of FMT with anti-PD-1 in curing colorectal tumor-bearing mice using a multi-omics approach. Mice treated with the combination therapy showed superior survival rate and tumor control, compared to the mice received anti-PD-1 therapy or FMT alone. Metagenomic analysis showed that composition of gut microbiota in tumor-bearing mice treated with anti-PD-1 therapy was remarkably altered through receiving FMT. Particularly, Bacteroides genus, including FMT-increased B. thetaiotaomicron, B. fragilis, and FMT-decreased B. ovatus might contribute to the enhanced efficacy of anti-PD-1 therapy. Furthermore, metabolomic analysis upon mouse plasma revealed several potential metabolites that upregulated after FMT, including punicic acid and aspirin, might promote the response to anti-PD-1 therapy via their immunomodulatory functions. This work broadens our understanding of the mechanism by which FMT improves the efficacy of anti-PD-1 therapy, which may contribute to the development of novel microbiota-based anti-cancer therapies.

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Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer

Cited by 61 publications

References 47 publications

Alterations of the Gut Microbiome and Fecal Metabolome in Colorectal Cancer: Implication of Intestinal Metabolism for Tumorigenesis

Alterations of the Gut Microbiome and Fecal Metabolome in Colorectal Cancer: Implication of Intestinal Metabolism for Tumorigenesis

Metagenomic and metabolomic analyses reveal synergistic effects of fecal microbiota transplantation and anti-PD-1 therapy on treating colorectal cancer

Metagenomic and Metabolomic Analyses Reveal Synergistic Effects of Fecal Microbiota Transplantation and Anti-PD-1 Therapy on Treating Colorectal Cancer

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