Amazing! Intestinal flora can actually metabolize nicotine???

Author: Zhao Bei

Smoking is harmful to health, but quitting smoking is harder than climbing to the sky. Is there any other way to reduce the harm of smoking to human health? Just in October this year, Professor Jiang Changtao's team from the Department of Basic Medicine of Peking University published an exciting study proving that a xylanogenic Bacteroides in our intestines can degrade nicotine. It takes a thousand days to cultivate bacteria, but only a moment to use them. Are our own intestinal flora finally going to make a contribution? Don't worry, let's see what's going on.

1. Where does the inhaled nicotine go?

Whether you smoke regular cigarettes, e-cigarettes, or even secondhand smoke, you cannot escape the harm of nicotine. Nicotine is not polite at all after entering the body. It can not only enter the blood circulation through the capillaries of the lungs, but can even easily cross the blood-brain barrier and reach the central nervous system. The whole process can be completed within 10 seconds. No wonder the pleasure of smoking comes so quickly.

The reason why nicotine that enters the body can affect a variety of physiological reactions is because nicotine receptors are widely present in our bodies. Nicotine is highly compatible with the nicotinic acetylcholine receptors on the surface of central nervous cells. After binding with them, it can increase the amount of neurotransmitters, and the neurons in the reward center of the brain secrete dopamine. The binding time is very long, which keeps the brain neurons excited.

**In addition to brain neurons, nicotine receptors exist on the surfaces of lung epithelial cells, intestinal epithelial cells, lymphocytes and other cells. After nicotine binds to them, it affects the cell's signal transduction, metabolic state and even induces cell apoptosis, **therefore it will have a long-term impact on all organs in our body.

So how is nicotine excreted from our body? Nicotine is mainly metabolized in the liver and broken down by cytochrome enzymes expressed by stem cells. 90% of nicotine is excreted through the kidneys, but some of it adheres to blood vessels, lung cilia, and fat cells.

2. Bacteria that can degrade nicotine exist naturally in nature

Although it is unexpected to find bacteria that can metabolize nicotine in the intestine, it is also reasonable. In the soil where tobacco grows, there are naturally present microorganisms that metabolize nicotine. For example, a bacterium called Pseudomonas putida can express nicotine oxidoreductase ( NicA2 ) , which successfully breaks down nicotine and uses it as its own carbon and nitrogen source [1].

This time, Professor Jiang Changtao's team discovered that the xylanobacterium in the intestine can express a nicotine metabolism protein called NicX , whose core structure is very similar to NicA2 carried by Pseudomonas aeruginosa.** It can metabolize nicotine into 4-hydroxy-1-(3-pyridyl)-1-butanone, which is excreted in the feces. Smokers with xylanobacterium in their intestines have lower nicotine levels in the small intestine, blood and feces, and have milder symptoms of non-alcoholic fatty liver disease **[2] .

Interestingly, when researchers added nicotine to the culture medium in which Bacteroides xylanicum was growing, Bacteroides xylanicum did not grow better or replicate faster, and it seems that metabolizing nicotine does not benefit Bacteroides xylanicum. It is one thing for Bacteroides xylanicum to be able to metabolize nicotine, but it is another thing for it to be willing to metabolize nicotine in the intestine. As for why Bacteroides xylanicum is so "selfless", researchers have not yet found the reason.

3. Smoking changes the intestinal environment and flora composition

A small cigarette can actually cause a turmoil in the intestines. Smoking can change the oxygen concentration, ion concentration, immune cell function, and biofilm integrity in the intestines. These changes in the microenvironment can affect the composition of the intestinal flora. In addition, some of the thousands of compounds contained in cigarettes can directly affect the growth and metabolism of certain microorganisms. For example, nicotine can change the metabolism of certain vitamins or coenzymes [3]. Scientists compared the intestinal flora of smokers and non-smokers and found that smoking caused a decrease in the diversity of intestinal flora, a decrease in the proportion of Firmicutes, and an increase in the proportion of Bacteroidetes, which is usually a sign of intestinal flora disorder.

However, the intestinal flora does not passively accept the environmental changes brought by cigarettes. They will also actively adapt, and even affect the activity of nerve cells through the gut-brain axis, participating in the interaction between cigarettes and the nervous system. The xylanophila Bacteroides activates the expression of NicX protein and actively metabolizes nicotine, which may also be a proactive attack in the face of pressure. In the end, it is not only the host that benefits, but also themselves.

Accelerating the decomposition of nicotine in the body or blocking the contact between nicotine and neurons is an important means to reduce the harm of smoking besides quitting smoking . In addition to the decomposition of nicotine by intestinal flora introduced in this article, scientists have also tried and developed nicotine vaccines [4]. The principle of this method is to allow the vaccine and nicotine to combine in the blood to block nicotine from entering the brain. However, this attempt failed in the Phase III clinical trial. In addition, there is also a method of directly accelerating the metabolism of nicotine by injecting nicotine oxidoreductase ( NicA2 ) into the blood, reducing the amount of nicotine entering the brain or other tissues. This study has obtained relatively good results in mouse models and is expected to be launched in clinical trials[5].

Professor Jiang Changtao's discovery this time has brought new hope to smokers with non-alcoholic fatty liver disease. Although the proportion of people with Bacteroides xylans is not high (about 20%), and its abundance in the intestine is also low (about only 1%) [6], Bacteroides xylans is a certified harmless intestinal bacteria and can be used as a dietary supplement, which makes it more likely to be taken by patients in the form of probiotics. Of course, whether Bacteroides xylans is easy to colonize in the population and how good the clinical effect is after taking it still requires more experiments and data support. After all, the best way to stay healthy is to stay away from cigarettes and not poison yourself or those around you.

1. Tang H, Wang L, Wang W,Yu H, Zhang K, Yao Y, Xu P, Systematic unraveling of the unsolved pathway ofnicotine degradation in Pseudomonas. PLoS Genet. 2013;9(10):e1003923.

2. Chen, B., Sun, L., Zeng, G. et al. Gut bacteria alleviatesmoking-related NASH by degrading gut nicotine. Nature 610, 562–568 (2022).

3. Anna K Whitehead, Margaret C Meyers, Christopher M Taylor, et al., Sex-Dependent Effects of Inhaled Nicotine on the Gut Microbiome, Nicotine & Tobacco Research, Volume 24, Issue 9, September 2022, Pages 1363–1370.

4. Pentel PR., LeSage MG.,New directions in nicotine vaccine design and use. Adv Pharmacol. 2014;69:553–80.

5. Onno CP van Schayck, Bovan Engelen, Thisted T. and Kalnik M., Nicotine degradation in smokers: will anew and potent enzymatic approach work where nicotine vaccines have failed? PrevMed Commun Health , 2018, Volume 1(4): 1-4

6. Kollarcikova M., Faldynova M., Matiasovicova J., et al., Different Bacteroides Species ColoniseHuman and Chicken Intestinal Tract. Microorganisms. 2020;8(10):1483.

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