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iNature
As one of the most common unhealthy behaviors in humans, the World Health Organization ranks smoking as the leading cause of
preventable death worldwide.
Quitting smoking is the most effective way to prolong life, but this is not easy to achieve due to
nicotine's powerful addictive and withdrawal symptoms.
Nicotine degradation has recently been recognized as a strategy
to block nicotine-induced pathology.
A positive association between smoking and non-alcoholic fatty liver disease (NAFLD) has been demonstrated, but the underlying mechanism of this association is unclear
.
On October 19, 2022, the team of Jiang Changtao of the School of Basic Medicine of Peking University Health Science Center, the team of Jiang Changtao of the Institute of Medical Innovation of Peking University Third Hospital, the team of Frank Gonzalez of the National Institutes of Health, the team of Yu Zhaohui of the First Affiliated Hospital of Zhejiang University School of Medicine, the team of Li Yang of the School of Basic Medicine of Fudan University, and the team of Zheng Minghua of the First Affiliated Hospital of Wenzhou Medical University published an online publication in Nature magazine Gut bacteria alleviate smoking-related NASH by degrading gut nicotine", which for the first time revealed the key mechanism
by which nicotine accumulates in the gut during smoking and activates the intestinal epithelial AMPKα-SMPD3-ceramide axis, which in turn promotes NASH.
Not only that, the study is the first to identify the intestinal bacterium Bacteriolycan (B.
lycanoides.
xylanisolvens) is a potent nicotine degrader
.
Together, this study identifies the role of intestinal nicotine accumulation in NAFLD progression and reveals an endogenous bacterium with the ability to
metabolize nicotine in the human gut.
These findings provide a possible pathway
to reduce the progression of NAFLD exacerbated by smoking.
NAFLD encompasses a wide range of pathologies, often progressing from simple steatosis (defined as nonalcoholic fatty liver disease (NAFL)) to NASH and, in some cases, to cirrhosis and hepatocellular carcinoma
.
Since intestinal metabolites play a key role in NAFLD progression through the gut-liver axis, establishing a relationship between intestinal nicotine accumulation, gut-derived metabolites, and NAFLD progression could provide new ideas
for studying smoking-related liver diseases.
In this study, the researchers found that nicotine accumulates in the gut during smoking and accelerates the progression of
NAFLD.
High levels of nicotine
were found in the ileal mucosal tissue, the ileum, and its contents of different mouse models were found to be high levels in the ileal mucosal tissue, the ileum and its contents of different mouse models, using a liquid chromatography-mass spectrometry-based method.
Interestingly, after nicotine exposure, the concentration of nicotine in the ileum and its contents was higher in sterile (GF) mice than in SPF mice, suggesting that the gut microbiota has the potential to
degrade intestinal nicotine.
Figure 1.
Tissue nicotine concentrations in SPF and GF mice in a nicotine drinking model (Figure from Nature) Although some natural nicotine-degrading bacteria have been proposed — implying a bacteria-based approach to lowering nicotine levels — the nicotine-degrading properties of mammalian gut microbiota have yet to be proven
.
The study found that the gut microbiome xylolycan bacteroides (B.
lyticulans) xylanisolvens) increases the potential of
the gut to degrade nicotine.
By B.
Xylanisolvens colonization reduces intestinal nicotine concentrations in nicotine-exposed mice and improves NAFLD progression
in nicotine-aggravated mice.
Further studies found that nicotine accumulation in the intestine significantly activates intestinal epithelial cell AMPKα1 signaling
.
In a mouse model, intestinal epithelial cell-specific knockout of AMPKα1 can significantly improve nicotine-aggravated NASH, suggesting that intestinal AMPKα1 plays a key role
in nicotine aggravation NASH progression.
By identifying SMPD3, the phosphorylated substrate of AMPK, this is the first link from nicotine-activated AMPK to ceramide metabolism, a pathway that could also explain cigarette smoke promoting ceramide levels
in serum and other tissues such as the lung, liver, and abdominal aorta 。 AMPKα mechanically promotes phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter, thereby increasing the formation of intestinal ceramides, which contributes to the progression of NAFLD to non-alcoholic steatohepatitis (NASH).
Figure 2.
Role of microbial nicotine degradation in ceramide regulation and NAFL-NASH progression (Figure from Nature) Overall, the study is the first to find that nicotine accumulates in the intestine during smoking and accelerates the progression of NAFLD, but it can be effectively degraded
by ethyl xylan, a human commenite 。 These findings address the pathological effects of intestinal nicotine accumulation and identify an endogenous nicotine-degrading gut bacterium, suggesting that other targeted interventions based on the intestinal AMPK α-SMPD3-ceramide axis have potential value
for the prevention and treatment of NASH in smokers.
Original link: —END—content is [iNature].
