Akkermansia Muciniphila Potentiates the Antitumor Efficacy of FOLFOX in Colon Cancer

Abstract

FOLFOX (oxaliplatin, fluorouracil and calcium folinate) is the first-line chemotherapy regimen for colon cancer therapy in the clinic. It provides superior efficacy than oxaliplatin alone, but the underlying mechanism remains unclear. In the present study, pharmacomicrobiomics integrated with metabolomics was conducted to uncover the role of the gut microbiome behind this. First, in vivo study demonstrated that FOLFOX exhibited better efficacy than oxaliplatin alone in colon cancer animal models. Second, 16S rDNA gene sequencing analysis showed that the abundance of Akkermansia muciniphila (A. muciniphila) remarkably increased in the FOLFOX treated individuals and positively correlated with the therapeutic effect. Third, further exploration confirmed A. muciniphila colonization significantly enhanced the anti-cancer efficacy of FOLFOX. Last, metabolomics analysis suggested dipeptides containing branched-chain amino acid (BCAA) might be responsible for gut bacteria mediated FOLFOX efficacy. In conclusion, our study revealed the key role of A. muciniphila in mediating FOLFOX efficacy, and manipulating A. muciniphila might serve as a novel strategy for colon cancer therapy.

Commentary: Intermittent Fasting and Akkermansia Muciniphila Potentiate the Antitumor Efficacy of FOLFOX in Colon Cancer

“…These data would fit well recent data that fasting per se decreases the propensity to contract colorectal cancer (Weng et al, 2020). Thus in conjunction with the data presented by Hou et al (2021) it would thus be rational to propose that intermittent fasting for patients who are taking medications such as FOLFOX or patients at risk for colorectal cancer (e.g., patients with inflammatory bowel with a history of neoplasms) would benefit from intermittent fasting.…”

“…Unfortunately, the earlier studies by Hou et al (2021) and Wang et al (2020) do not address this point directly and further work is necessary to exploit the potential of this bacterium in increasing the efficacy of. FOLFOX.…”

Presence of Akkermansiaceae in gut microbiome and immunotherapy effectiveness in patients with advanced non-small cell lung cancer

“…In colorectal cancer patients, it is described as one of the possible causes of this disease, due to its ability to degrade mucin in the intestine, causing inflammation and subsequent cancer (Weir et al 2013 ; Sanapareddy et al 2013 ). On the other hand, positive effect of its presence on the treatment of patients with colorectal cancer (CRC) is reported (Hou et al 2021 ). Next generation sequencing (NGS) of 16S rRNA gene (V3-V4 regions) showed that the abundance of Akkermansia muciniphila is remarkably increased in the FOLFOX (fluorouracil and leucovorin with oxaliplatin) treated individuals and positively correlates with the therapeutic effect of chemotherapy (Zackular et al 2013 ; Hou et al 2021 ).…”

“…On the other hand, positive effect of its presence on the treatment of patients with colorectal cancer (CRC) is reported (Hou et al 2021 ). Next generation sequencing (NGS) of 16S rRNA gene (V3-V4 regions) showed that the abundance of Akkermansia muciniphila is remarkably increased in the FOLFOX (fluorouracil and leucovorin with oxaliplatin) treated individuals and positively correlates with the therapeutic effect of chemotherapy (Zackular et al 2013 ; Hou et al 2021 ). In NSCLC and in renal cell carcinoma patients treated with anti-PD-1 antibodies, A. muciniphila seems to be enriched in responders compared to non-responders (Routy et al 2018 ).…”

Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm

“…Some drugs, such as streptomycin and methyldopate, are clinically applicable but have frequent or severe side effects after long-term application 21 , 22 . Calcium folinate is a clinical act as the first-line chemotherapy regimen for colon cancer therapy 23 . Among the others, the naturally occurring grapefruit flavonoid naringenin (NGN) exhibited a significant correlation with doxycycline ( R = 0.24, P < 2.2e−16) and has previously recognized lipid-lowering, anti-atherosclerotic, anti-hypertensive, and anti-inflammatory properties 24 – 27 .…”