The gut microbiota improves nonalcoholic steatohepatitis aggravated by smoking by degrading nicotine

Tobacco use is the leading preventable cause
of disease and death globally.
China's direct smoking population exceeds 300 million, and the number of people passively exposed to the smoke environment is even more difficult to count
.
As we all know, smoking is not only an important pathogenic factor of lung cancer, but also closely related
to cardiovascular diseases, diabetes and other metabolic diseases.
In recent years, a number of epidemiological evidence have shown that long-term smoking is closely related to the progression of nonalcoholic steatohepatitis (NASH), but there are still gaps
in its molecular mechanism and intervention strategy.
Therefore, it is of great significance
to analyze the main components, action sites, molecular mechanisms and potential regulatory modes of smoking aggravating NASH to deepen the understanding of the harm of smoking and develop corresponding targeted interventions.

On October 20, 2022, the international academic journal Nature published a research paper by the team and collaborators of Professor Jiang Changtao, School of Basic Medicine of Peking University Health Science Center/Peking University Third Hospital Institute of Medical Innovation, "Gut bacteria alleviate smoking-related NASH by degrading gut nicotine"
.
This paper reveals a novel molecular mechanism
by which nicotine accumulates in the intestine during tobacco ingestion and promotes the progression of NASH through gut-liver interaction.
The team discovered for the first time the degradation of intestinal nicotine by human intestinal flora, and revealed the key intestinal commensal bacteria, Bacteroides xylanisolvens and the novel nicotine metabolism enzyme NicX: Bacteroides degrades intestinal nicotine through NicX, effectively alleviating NASH
aggravated by smoking 。 The study found that nicotine accumulates in the intestine during smoking, elucidates its promoting effect and molecular mechanism on NASH, reveals the key protective role of intestinal commensal bacteria in the pathogenesis of nicotine-related NASH, and provides new targets and strategies
for basic research and clinical intervention of smoking-related metabolic diseases.

Figure 1.
Intestinal commensal bacteria degrade nicotine and improve the aggravating effect of intestinal nicotine accumulation on NASH during smoking

In order to more comprehensively and accurately explore the distribution and function of nicotine in different tissues, researchers used metabolomics to accurately determine nicotine content in different tissues in smoking people and a variety of nicotine-exposed mouse models, and accidentally found that nicotine accumulated
in the intestine during smoking or nicotine exposure.
More notably, after nicotine treatment, the concentration of nicotine in the ileum and its contents of sterile (GF) mice was significantly higher than that of normal SPF mice, suggesting that the intestinal flora has the potential to
degrade intestinal nicotine in vivo 。 Through metagenomic analysis of fecal samples from smoking people, combined with a series of in vivo and in vitro experiments, synthetic biology methods, and chromatography and spectroscopic techniques, the researchers found that the enteric commensal bacterium Bacteroides xylanisolvens can efficiently degrade intestinal nicotine to 4-hydroxy-1-(3-pyridine)-1-butanone (HPB)
through the nicotine metabolism enzyme NicX 。 Through experiments in NASH mouse models of Bacillus lycan (wild-type and NicX knockout strains) stacked with nicotine on a high-fat, high-fructose and high-cholesterol diet (HFHFrC), the researchers confirmed that Xylanoides can alleviate nicotine-facilitated NASH progression
in a NicX-dependent manner.

Figure 2.
Smoking causes intestinal accumulation of nicotine, which can be efficiently degraded by intestinal commensal bacteria

Using multi-omics techniques such as phosphoproteomics and lipidomics and multiple intestinal epithelial cell-specific knockout mouse models, the researchers found that intestinal nicotine accumulation significantly activated AMPKα1 signaling in intestinal epithelial cells and promoted the secretion
of intestinal ceramide by upregulating the phosphorylation level of phosphingomyidyl phosphodilipase 3 (SMPD3).
Further, the researchers determined that AMPKα1 can directly bind SMPD3 and phosphorylate the S208 (S209) site, inhibit ubiquitination at the K103 site, thereby inhibiting the SMPD3 proteasome degradation pathway, and ultimately increasing SMPD3 activity
.
This discovery links AMPK signaling for the first time to sphingomyidylceramide metabolism, revealing new important functions
of AMPK.

Figure 3.
Nicotine promotes the production of intestinal ceramide through the intestinal AMPKα-SMPD3 axis

The researchers recruited 83 patients with NAFLD confirmed by liver biopsy and used their stool samples for metagenomic, metabolomic testing, and association analysis
.
The results showed that nicotine levels in smokers' feces were positively correlated with the severity of the NAFLD-NASH process, while B.
The abundance of xylanisolvens and the degradation product HPB of nicotine were negatively correlated
with the NASH process.
The above findings provide a new strategy
for targeting specific gut microbiota and its metabolic enzymes to treat nicotine-related NASH progression.

Figure 4.
B.
xylanisolvens-mediated nicotine degradation is negatively correlated with NASH progression in smokers

The School of Basic Medicine of Peking University Health Science Center is the first completion of the paper, and Jiang Changtao, Frank Gonzalez, researcher of the National Institutes of Health, Professor Yu Zhaohui of the First Affiliated Hospital of Zhejiang University School of Medicine, Li Yang, researcher of Fudan University School of Basic Medicine, and Professor Zheng Minghua of the First Affiliated Hospital of Wenzhou Medical University are the co-corresponding authors
of this result 。 Chen Bo, a 2013 basic eight-year basic student at the School of Basic Medicine of Peking University Health Science Center, Sun Lulu, a postdoctoral fellow at the National Institutes of Health, Zeng Guangyi, a doctoral student at the School of Basic Medicine of Peking University, Professor Shen Zhe from the First Affiliated Hospital of Zhejiang University School of Medicine, Wang Kai, a postdoctoral fellow at the School of Basic Medicine of Peking University, and Yin Limin, a doctoral student at the School of Basic Medicine of Fudan University, are the co-first authors
of this paper.
This research was supported
by the National Natural Science Foundation of China "Spatio-temporal Network Regulation of Glycolipid Metabolism", the National Science Foundation for Outstanding Young Scholars, and the National Key Research and Development Program.

About the author:

Jiang Changtao is a permanent professor and distinguished professor of liberal arts at Peking University, and vice dean
of the School of Basic Medicine of Peking University.

Mainly engaged in the pathogenesis and translational medicine research of metabolic diseases, focusing on the role of
intestinal microecology.
In the past 5 years, he has published more than 20 SCI papers as a corresponding author in journals such as Nature, Nature Medicine (3), Cell Metabolism (3), Journal of Clinical Investigation and Diabetes (2), and has been authorized 4 invention patents
。 He was selected as a winner of the National Science Foundation for Outstanding Young Scholars, a young Changjiang scholar of the Ministry of Education, and a national "10,000 people plan" for young top-notch talents; He won the 16th China Youth Science and Technology Award, the 8th Shulan Medical Youth Award, the 6th North American Chinese Diabetes Association (CADA) Young Scientist Award and other awards; He has presided over more than 10 funds such as key projects, major research plans and national key research and development programs of the National Natural Science Foundation of China, and won the National Natural Science Foundation of China Innovative Research Group Project as a PI; As the chairman of the conference, he hosted the 295th Young Scientists Forum "Frontier Meeting of Metabolic Regulation and Target Discovery" of the Chinese Association for Science and Technology, the 2021 China Intestinal Conference, and served as the secretary general of the Intestinal Microbiota Branch of the Chinese Biophysical Society, the chairman of the Physiology Professional Committee of the Beijing Physiological Society, the deputy editor of the journal "Heredity", and the editorial board member of Science Bulletin magazine
.