Xylitol Is It Good for You?

The digestion and absorption of nutrients in the diet depends on one of the most important systems of the human body - the digestive system. Foods are digested and absorbed in the intestines through oral chewing, gastric decomposition, and intestinal digestion to provide the body with the energy and nutrients it needs on a daily basis. People consume a wide variety of foods, and many foods that are not digested and absorbed by the gastrointestinal tract, such as complex dietary fibers, polysaccharides, and structurally altered proteins, basically rely on intestinal microorganisms to solve the problem.

Therefore, the large intestinal microbial community is known as the human body's independent organ or the second genome, plays an important role in food digestion, nutritional intake and maintenance of the host's health, etc. The intestinal flora disorders can cause metabolic diseases, such as obesity, diabetes, insulin resistance, and so on. As a low-calorie functional sweetener, only a small amount of xylitol is directly absorbed by the human body, and only 5% of it is excreted. A large amount of xylitol is digested by intestinal microorganisms, and its role in the intestinal tract through microorganisms should not be underestimated.

1 Overview

Xylitol is a very soluble in water pentahydroxy sugar alcohol, usually white or colorless solid, chemical formula for C5 H12 O5. Natural xylitol is widely available in fruits, vegetables, cereals, but the content is very low. People initially extracted xylitol from plant materials, but as the global market's top rare sugar alcohols, the extraction of natural xylitol is far from meeting market demand, so the industry commonly used chemical methods nickel-catalyzed hydrolysis of xylose to get a large amount of xylitol. Nowadays, metabolically engineered bacteria such as Saccharomyces cerevisiae, Pseudohyphalotropic yeast and other biotechnological methods to improve production[1] .

Based on its natural properties, xylitol has been used with great success in biomedical, food and other applications. Xylitol dissolves in the mouth and absorbs heat, often with a slight cooling sensation, and is therefore often used as a substitute for food sweeteners and as a novel cooling agent[2] . Xylitol does not need insulin to promote the cell membrane, for cellular nutrients and energy, and will not cause an increase in blood glucose, but also to eliminate the diabetic after taking the three symptoms (more food, drink, more urine), is the most suitable for diabetic patients to consume the nutritional sugar substitutes. Xylitol has a comparable sweetness to common sugar, and also has the advantage of being low in calories - 1 g of xylitol contains only 2.4 calories, which is 40% less than most other carbohydrates, and thus xylitol can be used in a variety of weight-loss foods as a substitute for high-calorie white sugar[3] .

Although xylitol has a wide range of applications in food, its application level in China is still relatively low. According to China's per capita consumption of sugar 8 kg per year, if 0.1% of the sugar is replaced by xylitol, then the food industry should need more than 10,000 tons of xylitol, the cumulative annual demand of the pharmaceutical industry (14,000 t) and the light chemical industry (0.2 million t) is expected to be, China's annual demand for xylitol in the more than 26,000 t. However, in fact, China's xylitol products have been used as a substitute for high-calorie white sugar[3]. In fact, the application quantity of xylitol products in China (below 2.7 million t) is less than 30% of the total output (below 90,000 t) [4-5]. Therefore, xylitol still has a lot of space for application in China.

2 Biological metabolism of xylitol

2.1 Metabolism of xylitol in the human body

Xylitol is an intermediate in human metabolism, and normal adults can synthesize about 15 g of xylitol per day, with a mass concentration of 0.03 ~ 0.06 mg/100 mL in normal human blood. xylitol has very important physiological and biological properties, and will have a positive impact on various functions of the human body. Xylitol can participate in the physiological synthesis of nucleic acids and detoxification process, correct abnormal metabolism of protein, fat and steroid, and has a strong anti-ketogenesis, so it can be used as a regulator and nutrient for diabetic patients with abnormal metabolism, auxiliary treatment of liver disease, and energy supplementation before and after surgery.

The metabolism of xylitol in the human body is quite fast, a healthy person weighing 70 kg can metabolize 500~600 g of xylitol per day, which is about 0.7 g per kg of body weight per hour, and each gram of xylitol is metabolized to produce 4.06 calories. The results of the study showed that xylitol was absorbed orally through the intestinal tract and was not affected by phasic inhibitors such as rhizopyranoside and 2,4-dinitrophenol. Whether administered orally or intravenously, approximately 85% of xylitol entering the body is metabolized by the liver, 10% by the kidneys, and a small portion is utilized by blood cells, the adrenal cortex, and other tissues. The capacity of human liver to metabolize xylitol is about 0.37~0.5 g/kg body weight.

According to the 13 C tracer atom experiment, within 12 h after taking xylitol, 50% ~ 60% of the xylitol ingested becomes CO2, which is exhaled through the lungs, and 2% ~ 10% is excreted in the urine and feces, and 20% ~ 30% is converted into glycogen or other intermediates stored in the cells, which has a fairly good bioavailability[6] .

Commercially available xylitol is D-xylitol, exogenous xylitol enters the body and is quickly converted to D-xylulose in the cytoplasm of the cell by the enzyme Eduardtol dehydrogenase, a process that does not require insulin to promote and passes through the cell membrane, with no effect on blood glucose. This is the basis for the use of xylitol in the treatment of diabetes. As shown in Figure 1, xylitol is mainly involved in the glucuronic acid-xylulose cycle in the body, which consists of 6-carbon glucuronic acid converted to L-guluronic acid, then converted to L-xylulose by 3-keto L-guluronic acid, and then converted to D-xylulose by xylitol, and the conversion of xylitol to D-xylulose in the body then reacts to produce 5-phosphate xylulose, which is converted to 5-phosphate ketone sugar, and so on. The glucuronide-xylulose branch is then fully linked to pentose phosphate and the normal pathway of sugar metabolism.

After the production of fructose 6-phosphate, it enters the glycolytic pathway and is metabolized to pyruvate, which finally enters the tricarboxylic acid cycle to provide energy for the body or is converted to other substances such as ribose and succinate for use by the body[7] . The glucuronic acid-xylulose cycle recycles glucuronic acid, which cannot be used in synthetic and biochemical reactions, into xylitol through a series of reactions, which is connected to the pentose phosphate pathway and recycled back into glucose metabolism. Part of the xylitol can be metabolized into D-xylose, and then after a series of reactions to generate pyruvate, linked to the citric acid cycle, but also to ribitol, L-arabinose conversion.

2.2 Microbial metabolism of xylitol

Microbial xylitol metabolic pathway is similar to the human body, mainly directly or indirectly into xylulose into the pentose phosphate pathway is metabolized. Many microorganisms such as Escherichia coli, yeast, etc. are excellent strains for the production of xylitol from xylose as raw material in industry, and microorganisms in the intestine, in addition to generating energy to maintain their own metabolic activities or those of other microorganisms, also produce secondary metabolites that are beneficial to the intestine. It is known that pyruvate is an important intermediate in the metabolism of carbohydrates to short-chain fatty acids, so the main metabolic pathway of xylitol metabolized by microorganisms to short-chain fatty acids is shown in Figure 2. Xylitol dehydrogenase (EC 1. 1. 1. 14) and xylitol oxygenase (EC 1. 1. 3. 41), xylitol reductase (EC 1. 1. 1. 21) and xylose isomerase (EC 5. 3. 1. 5) are the transducing enzymes in the two pathways for the conversion of D-xylitol to D-xylulose, xylitone kinase (EC 2. 7. 1. 17) and xylitone phosphate isomerase (EC 5. 1. 1. 3. 1. 5), respectively. Xylulose kinase (EC 2. 7. 1. 17) and xylulose phosphate isomerase (EC 5. 1. 3. 1) are two important enzymes in the pathway of xylulose to pentose phosphate.

Existing studies have not found that xylitol has its own transport system, and it has been reported that xylitol may share the carbohydrate phosphotransferase system with glucose[9 -10] , and KENTACHE et al[11] confirmed this possibility by inserting a transposon into the gene encoding the membrane protein EIIC in the phosphotransferase system of Listeria monocytogenes, which prevented arabitol and xylitol from being utilized. Confirmed this possibility.

3 xylitol on the role of microorganisms

3.1 Intestinal microorganisms

Colon living in 1013 ~ 1014 microorganisms, nearly 100 times the total number of all human cells, so the gut microbes are also known as the body's independent organs or the second genome. The gut microflora has many basic functions, one of the most important of which is energy acquisition. Gut microorganisms play an important role in food digestion, for example, several polysaccharide-degrading enzymes in the walls of plant cells are not encoded by the host cell, but are specifically expressed by certain bacterial genes in the gut. Part of the ingested food is broken down by microorganisms before it can be absorbed by intestinal cells, providing nutrients and energy to the host and affecting the physiological health of the host[12] .

Gut microorganisms have also been reported to be involved in the inhibition of pathogenic bacterial infections, enhancement of the immune system, and vitamin synthesis, and have been implicated in gastrointestinal disorders such as gastritis, inflammatory bowel disease, irritable bowel syndrome, and celiac disease, metabolic disorders such as obesity, diabetes, and insulin resistance, and even neurological disorders such as Alzheimer's disease, autism spectrum disorders, Parkinson's disease, and clinical depression, via the brain-gut axis[13 -14] . The brain-gut axis is also involved in metabolic disorders. At the same time, a sick organism can, in turn, further exacerbate the dysbiosis of the intestinal flora.

The dialog between host and gut microbes affects human health, but it is not only when the organism is in trouble that the gut microbes communicate with the host. In a healthy host, the trillions of microorganisms living in the colon are also working diligently to maintain their own balance and at the same time, to promote the host's intake of energy and nutrients, to improve and maintain the host's health, and to prevent the occurrence of various diseases. Therefore, in recent years, intestinal flora has become a hot research topic in the field of food digestion and biomedicine.

3.2 Effects of xylitol on intestinal flora

As a class of indigestible carbohydrates, xylitol and some prebiotics similar to the nature of the scientists aroused curiosity, through a series of experiments to explore xylitol and intestinal microorganisms, metabolic markers of the relationship between. For example, feeding rats a high-fat diet with high doses of xylitol [1.5-4.0 g/(kg -d)] promoted lipid metabolism. Supplementation with low and medium doses of xylitol [40 and 194 mg/(kg -d)] significantly altered the composition of the gut microflora of rats, but lipid metabolism was not significantly altered, and it was hypothesized that the gut microflora inhibited lipid accumulation through short-chain fatty acids derived from dietary fiber[15] . The combination of dextran and xylitol increased the concentration of all short-chain fatty acids, especially acetate and propionate, and decreased the level of branched-chain fatty acids, while the level of biogenic amines remained essentially unchanged[16] .

Xylitol also affected the intestinal microbiota and the secretion of isoflavones in the urine of mice. The dietary addition of xylitol to two groups of male mice fed with soybean sapogenins significantly reduced plasma cholesterol concentration, increased the amount of isoflavones in the urine, and significantly increased the content of lipids in the feces, compared with that of the control group. These results suggest that xylitol may affect the metabolism of soy glycosides through intestinal microorganisms or intestinal metabolic activities[17] . Xylitol and sorbitol significantly promoted butyrate production through in vitro fecal slurry fermentation, which may be related to the increased abundance of microorganisms associated with the metabolism of Anaerostipes hadrus or Anaerostipes caccae. There are 12 typical butyrate-producing organisms in the human colon, and only two of them produced butyrate from sorbitol and xylitol, but further studies have shown that xylitol may affect the metabolism of soybean glycosides through gut metabolic activities[17] . Butyrate production by only two of these species was derived from sorbose and xylitol, but further studies found that A. hadrus DSM 3319 could not utilize xylitol in vitro in pure culture [18]. Other studies have found that xylitol can increase the growth of beneficial intestinal microorganisms such as Bifidobacterium and Lactobacillus in mice.

In addition, xylitol has an inhibitory effect on many pathogenic bacteria, such as Streptococcus pyogenes in the oral cavity, it can affect its cell structure, reduce the level of lipopolysaccharide on the cell membrane, and reduce the adhesion of bacteria on the teeth so as to reduce dental plaque, and play a role in the prevention and treatment of dental caries [19 -20]; it can also inhibit the growth of Streptococcus pneumoniae, so as to prevent the occurrence of acute otitis media in infants and young children [21]. FERREIRA et al[22] speculated that xylitol inhibits microbial growth by inhibiting the formation of microbial membranes, and then through anti-adhesion. Many studies have also confirmed the inhibitory effect of xylitol on the formation of biofilm of pathogenic bacteria.

4 Research tools

4.1 In vivo experiments

In vivo experiments usually refer to the testing of the effects of various substances on the whole of a living organism, rather than a part or a dead organism. Therefore, animal testing and clinical trials are the main components of in vivo research. In vivo experiments are usually conducted on animals or human subjects. Animal experiments usually use the mouse as a model. Currently, the mouse model is still the preferred choice for most microbiome studies. Mice are fed xylitol at various doses in the diet, and their feces and cecum are collected to measure changes in the intestinal flora. The mouse experiment can be used as a preliminary study to investigate the changes in intestinal microbial composition, short-chain fatty acids, microbial metabolism, and the physiological health of mice.

Wei Tao et al[23] used 1-month-old male mice as experimental subjects and studied the effects of xylitol on the gastrointestinal flora by gavage with a certain dose per day.UEBANSO et al[15] used pair-feeding to control xylitol intake in mice. Xylitol concentration was calculated based on daily water intake and body weight, and the concentration of xylitol in drinking water was adjusted every 1~2 days to regulate xylitol consumption. The effects of low or moderate doses of xylitol on intestinal flora and lipid metabolism have been investigated in mice. However, no experiments have been conducted to investigate the role of xylitol in the causal relationship between microorganisms and related diseases by administering xylitol to a mouse model of intestinal microbial transplantation.

However, the composition of gut microorganisms in mice and humans is significantly different, and it is not possible to extrapolate the results of the mouse model to humans. In vivo experiments with xylitol in healthy volunteers can provide a more accurate assessment of the effects of xylitol on the composition and metabolism of human gut microorganisms, and Salminen et al.[24] investigated the effects of xylitol on the quantity and quality of fecal microflora in healthy human volunteers. Healthy volunteers who were not exposed to dietary xylitol supplementation were exposed to xylitol solution orally after an overnight fast, and fecal samples were collected for testing. The effects of xylitol on human fecal microorganisms were investigated. However, the results are subject to error due to individual differences in the subjects and their dietary habits.

In vivo experiments present difficulties in terms of ethical constraints, sampling in different areas of the gut, long trial periods, and the fact that in vivo studies rely heavily on endpoint data, usually from fecal samples, means that dynamic monitoring of the gut microbiota along the gastrointestinal tract is difficult to achieve, making it difficult to determine where specific interventions are working. However, in vivo experiments are often better suited than in vitro experiments to observe the overall effects of in vivo experiments and better reflect the effects of xylitol on the gut flora.

4.2 In vitro experiments

An in vitro assay is an in vitro study using components of an organism isolated from its usual biological environment. An in vitro gut model is an in vitro model used to investigate changes in the growth and metabolism of human intestinal flora following disease states, dietary interventions, and pharmacological treatments.

In vitro gut modeling systems provide a rapid, simple, and cost-effective way to study the gut microbiota in one or more intestinal segments, or along the entire gastrointestinal tract. The static fermentation model and the dynamic in vitro continuous culture system are two commonly used in vitro fermentation models. The static fermentation model is limited by nutrients and bacterial metabolites and does not reflect the entire gut flora. The dynamic continuous fermentation model can simulate individual regions of the colon or the entire colon, and its stable control state is similar to that of the human intestine.SATO et al [8] investigated the effects of xylitol and sorbose on the intestinal flora in human fecal cultures in vitro.

XU Yuanyuan et al. [25] simulated the changes of microflora and their metabolites under xylitol supplementation by cultivating human fecal flora in a single-phase continuous fermentation model, and MAKE-LAINEN et al. [16] used a semi-continuous anaerobic culture system with four sequentially connected glass containers (representing the ascending, transverse, descending, and rectal terminals, respectively) to more accurately mimic the human colon to evaluate the effect of xylitol supplementation on human intestinal microflora and its metabolites. The beneficial characteristics of the prebiotics chrysoglucose and xylitol were evaluated, and evidence was provided for their prebiotic properties. Generally speaking, there are few research results on simulating the beneficial functions of xylitol and its mechanism by in vitro experiments, and the development of in vitro experimental techniques is needed to enrich and improve the related research.

Compared with in vivo experiments, in vitro experiments utilize the whole organism, which enables simpler, more convenient and more detailed analyses, and is free from the ethical and moral constraints of in vivo experiments. In vitro work simplifies the system under study, so researchers can focus on a few components to explore basic biological functions. In contrast to human and mouse experiments, in vitro gut models can monitor changes in the microbiota that can be attributed to specific diseases, substrates, or inhibitors based on microbial populations and metabolic activity. Just as whole animal studies are replacing human studies, in vitro studies are replacing whole animal studies. However, all in vitro intestinal models have limitations, mainly related to reduced physiological relevance. Such systems also do not always provide an accurate model of in vivo occurrence because they lack epithelial mucosal, host-immune interactions and neuroendocrine system function[26] . Extrapolating the results of in vitro experiments to the biology of whole organisms is also challenging. Researchers conducting in vitro experiments must be careful to avoid over-interpretation of their results, which may lead to erroneous conclusions about organismal and systems biology.

5 Implications for the direction of research

According to the various studies conducted on xylitol in recent years, xylitol has been shown to be beneficial to dental health, reduce fat accumulation, promote bone health, and enhance immunity, etc. Therefore, xylitol can be used as a functional sweetener. Therefore, xylitol, as a functional sweetener, is widely used in various foods and is an excellent sugar substitute for diabetics and obese patients. However, most of the xylitol ingested in the diet is digested by intestinal microorganisms. Xylitol, like dietary fiber, polysaccharides and other prebiotics, can be selectively utilized by microorganisms to produce beneficial metabolites for the human body. Existing studies on xylitol on intestinal microorganisms show that xylitol has a favorable impact on the regulation of intestinal flora and human health, especially for the treatment and prevention of certain diseases to play a complementary role, but its in-depth probiotic mechanism and effect of the lack of research. Therefore, the key to the study of xylitol is to explore the beneficial effects, sites and modes of action of xylitol by means of modern biological techniques. The study of its beneficial mechanism and the exploration of its more beneficial effects are conducive to further expanding its application space and giving full play to its great potential.

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