The journal Nature published the important research results of Professor Jiang Changtao's team

Link to the article: https://doi.
org/10.
1038/s41586-022-05299-4

On October 20, 2022, the international academic journal Nature published the team of Professor Jiang Changtao, School of Basic Medicine of Peking University Health Science Center and Institute of Medical Innovation, Peking University Third Hospital and co-author research paper "Gut bacteria alleviate smoking-related NASH by degrading gut nicotine"
.
The paper reveals that nicotine accumulation in the intestine during tobacco intake is promoted through the regulation of the gut-liver interaction Novel molecular mechanisms
of NASH progression.
For the first time, the team discovered 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: xylanoides degrade 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, and reveals that intestinal commensal bacteria are associated with nicotine The key protective role in the pathogenesis of NASH provides a new target for basic research and clinical intervention of smoking-related metabolic diseases New policy
.

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

Previous nicotine-related research has focused on its impact on organs such as the lungs and brain, and in order to more comprehensively and accurately explore the distribution and function of nicotine in different tissues, researchers use metabolomics Precise determination of nicotine content in different tissues in smokers and various nicotine-exposed mouse models unexpectedly found that nicotine accumulates in the intestines
during smoking or nicotine exposure.
What's more, after nicotine treatment, the concentration of nicotine in the ileum and its contents of bacteria-free (GF) mice was significantly higher than that of normal SPF mice, suggesting that the gut microbiota has the potential to
degrade intestinal nicotine in vivo.
Through the metagenomic analysis of fecal samples from smoking people, a series of in vivo and in vitro experiments, synthetic biology methods, and chromatography and spectroscopy techniques are combined The researchers found that the enteric commensal bacterium Bacteroides xylanisolvens can efficiently degrade intestinal nicotine to 4-hydroxyl group through the nicotine metabolization enzyme NicX -1-(3-Pyridine)-1-butanone (HPB).

Xylarinolytic bacteroides (wild-type and NicX knockout strains) are stacked with nicotine on a high-fat, high-fructose and high-cholesterol diet (HFHFrC).
In a colonization experiment in a mouse model of NASH, the researchers confirmed that Bacteroides lycan alleviate nicotine-promoted 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 phosphorylated proteomics and lipidomics, as well as multiple intestinal epithelial cell-specific gene knockout mouse models, the researchers found that intestinal nicotine accumulation significantly activated the intestinal epithelium Cell AMPKα1 signaling via upregulation of sphingomyelin phosphodilipase 3 (SMPD3).
Phosphorylation level, which promotes the secretion
of enterogenic ceramide.
Further, the researchers determined that AMPKα1 can directly bind SMPD3 and phosphorylate S208 (S209 ) site, inhibiting 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 with sphingolipid neuromide metabolism, revealing AMPK new important features
.

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

The researchers then 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 the abundance of B.
xylanisolvens and the degradation product HPB of nicotine were associated with The NASH process is negatively correlated
.
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 to complete the thesis, Professor Jiang Changtao, School of Basic Medicine of Peking University Health Science Center/Peking University Third Hospital Institute of Medical Innovation Frank Gonzalez researcher of the National Institutes of Health, Professor Yu Zhaohui of the First Affiliated Hospital of Zhejiang University School of Medicine, and researcher Li Yang of the School of Basic Medicine of Fudan University and Professor Zheng Minghua of the First Affiliated Hospital of Wenzhou Medical University is the co-corresponding author
of this achievement.
Chen Bo, 2013 basic eight-year basic eight-year program of the School of Basic Medicine of Peking University Health Science Center, and Sun Lulu, postdoctoral fellow of the National Institutes of Health Zeng Guangyi, doctoral research student at Peking University School of Basic Medicine, Professor Shen Zhe from the First Affiliated Hospital of Zhejiang University School of Medicine, and postdoctoral fellow at Peking University School of Basic Medical Sciences Wang Kai 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 been a corresponding author in Nature, Nature Medicine (3 articles), and Cell Metabolism (3), Journal of Clinical Investigation, and Diabetes (2 papers) and other journals published more than 20 SCI papers, and 4 authorized 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 presided over more than ten funds such as key projects, major research plans and national key research and development plans of the National Natural Science Foundation of China, and won the National Natural Science Foundation of China Innovation Research Group Project as a PI; As the chairman of the conference, he hosted the 295th Young Scientists Forum "Frontier Conference of Metabolic Regulation and Target Discovery" of the Chinese Association for Science and Technology, and the 2021 China Intestinal Conference.
He also serves 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 Genetics, and the editorial board member of the journal Science Bulletin
.

(School of Basic Medicine, Peking University)