Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites

Abstract

ObjectiveCigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and related metabolites.DesignAzoxymethane-treated C57BL/6 mice were exposed to cigarette smoke or clean air 2 hours per day for 28 weeks. Shotgun metagenomic sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Germ-free mice were transplanted with stools from smoke-exposed and smoke-free control mice.ResultsMice exposed to cigarette smoke had significantly increased tumour incidence and cellular proliferation compared with smoke-free control mice. Gut microbial dysbiosis was observed in smoke-exposed mice with significant differential abundance of bacterial species including the enrichment of Eggerthella lenta and depletion of Parabacteroides distasonis and Lactobacillus spp. Metabolomic analysis showed increased bile acid metabolites, especially taurodeoxycholic acid (TDCA) in the colon of smoke-exposed mice. We found that E. lenta had the most positive correlation with TDCA in smoke-exposed mice. Moreover, smoke-exposed mice manifested enhanced oncogenic MAPK/ERK (mitogen-activated protein kinase/extracellular signal‑regulated protein kinase 1/2) signalling (a downstream target of TDCA) and impaired gut barrier function. Furthermore, germ-free mice transplanted with stools from smoke-exposed mice (GF-AOMS) had increased colonocyte proliferation. Similarly, GF-AOMS showed increased abundances of gut E. lenta and TDCA, activated MAPK/ERK pathway and impaired gut barrier in colonic epithelium.ConclusionThe gut microbiota dysbiosis induced by cigarette smoke plays a protumourigenic role in CRC. The smoke-induced gut microbiota dysbiosis altered gut metabolites and impaired gut barrier function, which could activate oncogenic MAPK/ERK signalling in colonic epithelium.

Hesperidin inhibits tobacco smoke‑induced pulmonary cell proliferation and EMT in mouse lung tissues via the p38 signaling pathway

“…Carcinogens can stimulate abnormal cell proliferation and EMT, leading to lung cancer ( 10 – 12 ). TS-induced abnormal EMT and cell proliferation regulate early events in cancer ( 54 – 56 ). In the present study, the change in the expression levels of EMT and proliferation markers indicated abnormal EMT and cell proliferation in the lungs of mice exposed to TS.…”

Smoking-induced microbial dysbiosis in health and disease

“…Smoking is associated with genetic and epigenetic mutations leading to CRC, such as genetic microsatellite instability and mutations in oncogenes and tumor suppressor genes [ 103–105 ]. Gut dysbiosis was reported in CRC in both humans and rodent studies [ 106 , 107 ]. Recent studies suggested that gut microbial dysbiosis during CRC is associated with tumorigenesis, mutagenesis and epigenetic modifications related to CRC [ 108 , 109 ], and may potentially help in CRC detection [ 105 , 106 ].…”

“…Bai et al [ 107 ] recently showed that mice treated with the carcinogen azoxymethane for CRC induction and exposed to cigarette smoke developed an increased number of colorectal tumors and enhanced proliferation of colonic epithelial cells compared with cancer-induced mice exposed to air. Notably in this study, mice exposed to smoke exhibited gut microbial dysbiosis, which included significant enrichment of Eggerthella lenta and Staphylococcus capitis and reduction in Parabacteroides distasonis and Lactobacillus species.…”

“…Notably in this study, mice exposed to smoke exhibited gut microbial dysbiosis, which included significant enrichment of Eggerthella lenta and Staphylococcus capitis and reduction in Parabacteroides distasonis and Lactobacillus species. The smoking-induced microbial dysbiosis was accompanied with elevated fecal taurodeoxycholic acid (TDCA) and other bile acids in the colon, impaired barrier function, increased activation of ERK/MAPK signaling and inflammatory IL-17 and TNF signaling pathways in colonic epithelial cells [ 107 ] ( Figure 2 ). Germ-free mice colonized with fecal material from mice with CRC that were exposed to smoke exhibited similar gut microbial features as their corresponding donors, along with augmented proliferation of colonic epithelial cells, increased gut barrier dysfunction and elevated activation of ERK/MAPK signaling in the colon, in comparison with germ-free mice colonized with fecal material from control mice exposed to air [ 107 ].…”

“…Collectively, adaptation of such proposed approaches may reveal bacterial, viral, fungal members of the microbiome, and their respective metabolites that may impact smoking-associated disease pathophysiology. The contribution of bacterial metabolites to development of smoking-related disease can be assessed by administration of the candidate metabolite in mice model harboring smoking-associated disease such as COPD [ 83 ], lung cancer [ 158 ] and CRC [ 107 ]. These studies may pave the way toward incorporation of microbial interventions modifying the disease risk among smokers or optimizing their abstinence success rate.…”