Indigenous microbes and digestive features
The term “holobiont” unites the host organism and its indigenous microbes (indibiome), the aggregate of genetic material in the host – microbe system provides a more accurate description of the complex system and, due to the possibilities of directional change of the microbiota, makes it possible to correct states characterized as distress.
Lactose intolerance is a set of symptoms that manifest as discomfort, flatulence, diarrhea and diarrhea when drinking milk or products containing lactose. Symptoms are associated with the active growth of bacteria in the lower intestines, if lactose is not digested by the enzyme (lactase) of our body in the upper sections.
The study of the effect of lactose intolerance (NL) led to reflections on the evolution of digestion, revealed the presence of contradictions in the description by experts and suggested some solutions for improving the health of the geek. In many respects, NL is not a good model for other types of reactions to products, which does not prevent us from building very plausible hypotheses on the basis of the material below about the interaction of the genes of our body and the genes of the microbes that inhabit our intestines.
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Digestion 101
The process of digesting food in the human body begins in the mouth with the enzyme amylase, which breaks down complex carbohydrates (starch) to simpler sugars, then pepsin and other enzymes break down proteins in the stomach, then pancreatic enzymes break down fats in the duodenum. proteins, carbohydrates and nucleic acids in the next section, the small intestine, enzymes are secreted by the intestinal cells themselves and are responsible for the breakdown of the remaining sugars and fats, and finally, in the large intestine, bacteria digest complex polysaccharides (dietary fibers). Evolutionarily, many different bacteria in the intestines are used to break up a huge number of link options in polysaccharides. In the database of enzymes for working with polysaccharides ( CaZymes ), bacteria lead, they have 12,743 different enzymes, and eukaryotes contain only 243 enzymes. The simple interpretation is as follows: plants build their cell walls in thousands of different ways, and it’s not at all profitable for the macro-organism to evolve and to have a new gene for each plant, it’s much more economical to carry around an arsenal of bacteria whose capacity of the genome exceeds ours by orders of magnitude and more , bacteria can quickly divide, and therefore mutate and exchange genetic material horizontally .
Lactose intolerance
Mammals lose their ability to digest lactose when they reach a certain age, due to the end of breastfeeding. One of the most important events in the development of society of pastoralists was the acquisition and spread of a genetic mutation conducive to the digestion of lactose in adulthood. The genetics of Europeans has been studied quite well, it has been shown that there is a characteristic genetic mutation in the European population, in the presence of which the lactase gene, the enzyme responsible for digesting lactose in the small intestine, is also expressed in adulthood. According to available data, lactose intolerance may be associated with comorbidity of a wide range of diseases: from osteoporosis associated with calcium deficiency to inflammatory bowel disease (IBD), since it is assumed that systemic irritation of the intestine increases the risk of IBD.
Intestinal bacteria are the main factor creating symptoms, it is assumed that the composition of the microbiota is associated with the severity of NL, or, on the contrary, a certain composition can level the effects of lactose. Preliminary data from epidemiological studies have identified associations of bacterial species with the presence of symptoms. In this regard, the concept of indigenous microbes (see indigenous microbes ) takes on new dimensions of meaning.
Field for data analysis
One of the publications (see. Indigenous microbes of the vagina ) caused a heated discussion on the relevance of such articles on Habr, I suggest to colleagues who are interested in data analysis to join the research topic. Interestingly, the systematic issue of lactose intolerance has not been studied, since LN is not a disease and for the most part ordinary doctors fall into the same category as allergies to certain products.
It is possible to systematically approach the issue from the data point of view: conduct text mining literature (over 3000 articles), select all known human genetic polymorphisms associated with lactose tolerance (estimated at least several dozen), compile a database of mutation frequencies in different ethnic groups, make using text-mining approaches, a map of the field of knowledge where diseases, genotypes, NL testing methods, microbial taxa and symptoms will be linked. The genomes of intestinal bacteria and metagenomic data can be analyzed to create the orthology of beta-galactosidases and their occurrence in intestinal bacteria.
An estimate of the economic burden of food allergies and intolerances in the United States is $ 25 billion per year ( link ), and this is only for children under the age of 16. It is necessary to distinguish between allergies and intolerances, allergies imply that the food component becomes an antigen and with an increase in the dose or frequency of allergen exposure, the developing immune system response can be fatal, the most common allergens are nuts and seafood. Food intolerance manifests itself in the absence of a significant reaction from the immune system, but as a result of incomplete or incorrect digestion, components of the products cause symptoms such as nausea, diarrhea, gas formation. It is believed that the intolerance of individual components is much more common and dose-dependent: up to a certain amount, the body is able to absorb the food component, and symptoms appear above a certain threshold. The most common example of food intolerance is lactose intolerance (LL).
In an adult who is well assimilating milk, the enzyme responsible for digesting lactose (lactase) is found in the villi of enterocytes of the small intestine; in the case of NL, the enzyme is determined only in rare enterocytes inside the same villus. The ability to digest lactose is mainly determined by the level of gene expression, and therefore is determined genetically.
Genetics of lactose intolerance
The frequency of NL and the age of its manifestation depends on the ethnic group (Heyman, 2006; Swallow, 2003). Among Spaniards, the frequency is up to 8 percent, Ashkenazi 60-80%, Asians and American Indians up to 100%. The opposite situation has developed among the North European ethnoses (Johnson, 1981), where the NL occurs in 2%. In most works, the same polymorphism is found responsible for maintaining a high level of lactase (C / T-13910). This polymorphism located above the lactase gene in the genome at 13.9 thousand base pairs explains the majority of cases of lactose tolerance in the European population (Enattah et al., 2007). To date, at least 8 unique nucleotide polymorphisms characteristic of a particular race are known, associated with lactose intolerance (Torniainen et al., 2009).
Despite the fact that the symptoms themselves disappear when they refuse to use milk, the American Society of Gastroenterologists believes that the obtained indicators of comorbidity indicate the importance of research on the issue of NL.
There is some evidence of NL association and diseases, in particular osteoporosis, depression, abdominal pain, irritable bowel syndrome and fructose intolerance (Schiffner et al., 2016).
Clinical methods for determining lactose intolerance include the following methods:
The role of microbiota
The role of microbiota in the development and severity of symptoms is not fully elucidated. Undigested lactose is supposed to come from the small intestine into the fat fermented by the intestinal microbiota. In the process of fermentation, short-chain fatty acids, hydrogen, methane and carbon dioxide are formed, thereby increasing the intestinal pressure and intestinal transit time. Acidification of the contents of the colon and an increase in osmotic load leads to an increase in the secretion of electrolytes and fluids, which causes liquid stools and diarrhea.
There are studies that show an increase in fecal waters cytotoxicity in individuals with NL (Windey et al., 2015). The Campbell Group in the UK is developing a theory about specific bacterial toxins (Campbell et al., 2010), suggesting that a certain microflora composition, when exposed to such a high energy resource like lactose, leads to the production of low or high molecular weight bacterial toxins that cause .
The first epidemiological studies revealed (Kurilshikov et. Al 2016) a link between genetic polymorphism, microbiota composition, and symptoms. However, in general, the question of the influence of the composition of the microbiota as a factor in the manifestation of symptoms of NL has not been studied.
Dairy products
Interesting in terms of the influence of indigenous microbes is an explanation of the possibilities of people with NL to digest dairy products. The majority of fermented milk products (kefir, yogurt) do not differ much from milk in terms of the amount of lactose, however, their use even in the presence of NL does not cause symptoms.
Again. Microbes from fermented foods give us their enzymes, bringing them to the upper intestines in their bodies. In the small intestine, bacterial enzymes help us digest lactose, and it does not enter the large intestine, and therefore there are no symptoms of NL.
The same reasoning applies to many fermented products, for which during the development of mankind fermentation conditions were selected. Most often plant foods can be fermented by indibiom living right on the leaves, such as sauerkraut. Fermentation is external (in relation to human) digestion, and more fermented foods contain a mixture of enzymes for the best absorption of foods inside our intestines.
Another observation: bacteria are a factor that can affect food intolerance, both positively and negatively. And apparently, there is an optimal combination of intestinal microbiome and product microbiome, in which negative reactions will be absent.
The problem described above was largely not given due attention, since officially NL is not considered a disease, and data on the economic burden, comorbidity and disease statistics are rather fragmented. While many issues are being addressed today by national or international societies or consortia - the issue of lactose intolerance remains unaddressed. A related fact is the disconnection of researchers and research: different assessment technologies are used, or NL assessment protocols, separate polymorphisms are considered, there is no standardized validated questionnaire and coordination in the direction of epidemiological studies.
The ability to use milk for food is considered to be a powerful evolutionary impetus in the development of mankind, the emergence of a mutation that allows digesting lactose according to calculations (Bersaglieri, T. et al. 2004) increased the number of healthy offspring by 19% from its owners. So far there is no data, but it is obvious that the microbial part of the holobiont also co-evolved with human digestion, possibly also compensating for the lack of lactase in an individual with NL. Deciphering the mechanisms of microbial adaptation in the case of NL would allow to proceed to the study of the processes of coevolution.
Data on comorbidity also speaks about the significance of LN in the pathogenesis of multifactorial diseases, here microbial compensation and correct control of the state of intolerance would lead to direct economic consequences - an increase in the working-age population.
The study of fermented products will potentially allow for the adjustment of the microbiota without the use of drugs or food additives. Working with food intolerances using fermented products is undoubtedly in the sphere of interests not only of health care, but also of pharmaceuticals and food companies.
Lactose intolerance is a good model object for the study and resolution of food intolerance issues in general. Although the mechanisms may differ in case of other intolerances, the approach to researching the issue can be extended to other problems: detection of genetic dependencies, identification of mechanisms regulating the activity of enzymes, searching for links with the intestinal microbiota and correction of microbiota to reduce the negative effects of intolerance.
Lactose intolerance is a set of symptoms that manifest as discomfort, flatulence, diarrhea and diarrhea when drinking milk or products containing lactose. Symptoms are associated with the active growth of bacteria in the lower intestines, if lactose is not digested by the enzyme (lactase) of our body in the upper sections.
The study of the effect of lactose intolerance (NL) led to reflections on the evolution of digestion, revealed the presence of contradictions in the description by experts and suggested some solutions for improving the health of the geek. In many respects, NL is not a good model for other types of reactions to products, which does not prevent us from building very plausible hypotheses on the basis of the material below about the interaction of the genes of our body and the genes of the microbes that inhabit our intestines.
')
Digestion 101
The process of digesting food in the human body begins in the mouth with the enzyme amylase, which breaks down complex carbohydrates (starch) to simpler sugars, then pepsin and other enzymes break down proteins in the stomach, then pancreatic enzymes break down fats in the duodenum. proteins, carbohydrates and nucleic acids in the next section, the small intestine, enzymes are secreted by the intestinal cells themselves and are responsible for the breakdown of the remaining sugars and fats, and finally, in the large intestine, bacteria digest complex polysaccharides (dietary fibers). Evolutionarily, many different bacteria in the intestines are used to break up a huge number of link options in polysaccharides. In the database of enzymes for working with polysaccharides ( CaZymes ), bacteria lead, they have 12,743 different enzymes, and eukaryotes contain only 243 enzymes. The simple interpretation is as follows: plants build their cell walls in thousands of different ways, and it’s not at all profitable for the macro-organism to evolve and to have a new gene for each plant, it’s much more economical to carry around an arsenal of bacteria whose capacity of the genome exceeds ours by orders of magnitude and more , bacteria can quickly divide, and therefore mutate and exchange genetic material horizontally .
Lactose intolerance
Mammals lose their ability to digest lactose when they reach a certain age, due to the end of breastfeeding. One of the most important events in the development of society of pastoralists was the acquisition and spread of a genetic mutation conducive to the digestion of lactose in adulthood. The genetics of Europeans has been studied quite well, it has been shown that there is a characteristic genetic mutation in the European population, in the presence of which the lactase gene, the enzyme responsible for digesting lactose in the small intestine, is also expressed in adulthood. According to available data, lactose intolerance may be associated with comorbidity of a wide range of diseases: from osteoporosis associated with calcium deficiency to inflammatory bowel disease (IBD), since it is assumed that systemic irritation of the intestine increases the risk of IBD.
Intestinal bacteria are the main factor creating symptoms, it is assumed that the composition of the microbiota is associated with the severity of NL, or, on the contrary, a certain composition can level the effects of lactose. Preliminary data from epidemiological studies have identified associations of bacterial species with the presence of symptoms. In this regard, the concept of indigenous microbes (see indigenous microbes ) takes on new dimensions of meaning.
Field for data analysis
One of the publications (see. Indigenous microbes of the vagina ) caused a heated discussion on the relevance of such articles on Habr, I suggest to colleagues who are interested in data analysis to join the research topic. Interestingly, the systematic issue of lactose intolerance has not been studied, since LN is not a disease and for the most part ordinary doctors fall into the same category as allergies to certain products.
It is possible to systematically approach the issue from the data point of view: conduct text mining literature (over 3000 articles), select all known human genetic polymorphisms associated with lactose tolerance (estimated at least several dozen), compile a database of mutation frequencies in different ethnic groups, make using text-mining approaches, a map of the field of knowledge where diseases, genotypes, NL testing methods, microbial taxa and symptoms will be linked. The genomes of intestinal bacteria and metagenomic data can be analyzed to create the orthology of beta-galactosidases and their occurrence in intestinal bacteria.
Food Allergies and Intolerances
An estimate of the economic burden of food allergies and intolerances in the United States is $ 25 billion per year ( link ), and this is only for children under the age of 16. It is necessary to distinguish between allergies and intolerances, allergies imply that the food component becomes an antigen and with an increase in the dose or frequency of allergen exposure, the developing immune system response can be fatal, the most common allergens are nuts and seafood. Food intolerance manifests itself in the absence of a significant reaction from the immune system, but as a result of incomplete or incorrect digestion, components of the products cause symptoms such as nausea, diarrhea, gas formation. It is believed that the intolerance of individual components is much more common and dose-dependent: up to a certain amount, the body is able to absorb the food component, and symptoms appear above a certain threshold. The most common example of food intolerance is lactose intolerance (LL).
In an adult who is well assimilating milk, the enzyme responsible for digesting lactose (lactase) is found in the villi of enterocytes of the small intestine; in the case of NL, the enzyme is determined only in rare enterocytes inside the same villus. The ability to digest lactose is mainly determined by the level of gene expression, and therefore is determined genetically.
Genetics of lactose intolerance
The frequency of NL and the age of its manifestation depends on the ethnic group (Heyman, 2006; Swallow, 2003). Among Spaniards, the frequency is up to 8 percent, Ashkenazi 60-80%, Asians and American Indians up to 100%. The opposite situation has developed among the North European ethnoses (Johnson, 1981), where the NL occurs in 2%. In most works, the same polymorphism is found responsible for maintaining a high level of lactase (C / T-13910). This polymorphism located above the lactase gene in the genome at 13.9 thousand base pairs explains the majority of cases of lactose tolerance in the European population (Enattah et al., 2007). To date, at least 8 unique nucleotide polymorphisms characteristic of a particular race are known, associated with lactose intolerance (Torniainen et al., 2009).
Despite the fact that the symptoms themselves disappear when they refuse to use milk, the American Society of Gastroenterologists believes that the obtained indicators of comorbidity indicate the importance of research on the issue of NL.
There is some evidence of NL association and diseases, in particular osteoporosis, depression, abdominal pain, irritable bowel syndrome and fructose intolerance (Schiffner et al., 2016).
Determination of lactose intolerance
Clinical methods for determining lactose intolerance include the following methods:
- Lactose intolerance test. Measurement of blood glucose is carried out two hours after drinking a lactose beverage. If the glucose level has not increased, then lactose has not been digested.
- Hydrogen breath test. After consuming the lactose beverage, the concentration of hydrogen in the exhaled air is measured. In case of intolerance, its levels will be increased, because lactose will be metabolized in the colon to hydrogen, which is then eliminated through respiration.
- The 13C test is a test for the concentration of modified carbon, carried out after drinking a drink with 13C-labeled lactose. In the case of its digestion in the small intestine, 13C-labeled glucose can be detected in the blood.
- Acid test for feces. For children who can not pass the above tests due to a very young age, the test for acidity of feces is used. Lactose fermentation in the colon leads to acidification of feces (due to lactic acid).
The role of microbiota
The role of microbiota in the development and severity of symptoms is not fully elucidated. Undigested lactose is supposed to come from the small intestine into the fat fermented by the intestinal microbiota. In the process of fermentation, short-chain fatty acids, hydrogen, methane and carbon dioxide are formed, thereby increasing the intestinal pressure and intestinal transit time. Acidification of the contents of the colon and an increase in osmotic load leads to an increase in the secretion of electrolytes and fluids, which causes liquid stools and diarrhea.
There are studies that show an increase in fecal waters cytotoxicity in individuals with NL (Windey et al., 2015). The Campbell Group in the UK is developing a theory about specific bacterial toxins (Campbell et al., 2010), suggesting that a certain microflora composition, when exposed to such a high energy resource like lactose, leads to the production of low or high molecular weight bacterial toxins that cause .
The first epidemiological studies revealed (Kurilshikov et. Al 2016) a link between genetic polymorphism, microbiota composition, and symptoms. However, in general, the question of the influence of the composition of the microbiota as a factor in the manifestation of symptoms of NL has not been studied.
Dairy products
Interesting in terms of the influence of indigenous microbes is an explanation of the possibilities of people with NL to digest dairy products. The majority of fermented milk products (kefir, yogurt) do not differ much from milk in terms of the amount of lactose, however, their use even in the presence of NL does not cause symptoms.
Important note.Honestly, I myself was surprised that there is so much lactose in fermented milk products. The more interesting it was to understand the details. The work (de Verse et al., 2001) reveals the mechanism according to which microbial beta-galactosidase contained in fermented dairy products avoids digestion in the stomach, since it is located in the cell membrane of bacteria and hydrolyses lactose at the time it enters the upper intestine.
Since the topic is not discussed in textbooks, colleagues often make unsubstantiated statements, without evidence, believing that only the absence of lactose makes it possible to drink kefir.
For example, in the magazine “Chemistry and Life” www.hij.ru/read/articles/all/5394 it is stated that there is no lactose in kefir. Moreover, the respected magazine also trolls Malyshev (we already have a common past with her on Habr ( link )).
In principle, asking the question “Dr. Google” can be met by various interpretations, most of the colleagues apparently think that since kefir does not cause a reaction, there is no lactose in it.
Actually there is.
Original article with measurement (milk 5 g. Lactose, kefir 3.7 g.) ( Link )
Most of the work refers to Renner and Renz-Schaven, 1986 or Hallé et al., 1994, where 100 g of kefir 4 g of lactose.
Conclusion : lactose is enough in kefir.
Again. Microbes from fermented foods give us their enzymes, bringing them to the upper intestines in their bodies. In the small intestine, bacterial enzymes help us digest lactose, and it does not enter the large intestine, and therefore there are no symptoms of NL.
Reasoning
The same reasoning applies to many fermented products, for which during the development of mankind fermentation conditions were selected. Most often plant foods can be fermented by indibiom living right on the leaves, such as sauerkraut. Fermentation is external (in relation to human) digestion, and more fermented foods contain a mixture of enzymes for the best absorption of foods inside our intestines.
Another observation: bacteria are a factor that can affect food intolerance, both positively and negatively. And apparently, there is an optimal combination of intestinal microbiome and product microbiome, in which negative reactions will be absent.
Conclusion
The problem described above was largely not given due attention, since officially NL is not considered a disease, and data on the economic burden, comorbidity and disease statistics are rather fragmented. While many issues are being addressed today by national or international societies or consortia - the issue of lactose intolerance remains unaddressed. A related fact is the disconnection of researchers and research: different assessment technologies are used, or NL assessment protocols, separate polymorphisms are considered, there is no standardized validated questionnaire and coordination in the direction of epidemiological studies.
Why is it important
The ability to use milk for food is considered to be a powerful evolutionary impetus in the development of mankind, the emergence of a mutation that allows digesting lactose according to calculations (Bersaglieri, T. et al. 2004) increased the number of healthy offspring by 19% from its owners. So far there is no data, but it is obvious that the microbial part of the holobiont also co-evolved with human digestion, possibly also compensating for the lack of lactase in an individual with NL. Deciphering the mechanisms of microbial adaptation in the case of NL would allow to proceed to the study of the processes of coevolution.
Data on comorbidity also speaks about the significance of LN in the pathogenesis of multifactorial diseases, here microbial compensation and correct control of the state of intolerance would lead to direct economic consequences - an increase in the working-age population.
The study of fermented products will potentially allow for the adjustment of the microbiota without the use of drugs or food additives. Working with food intolerances using fermented products is undoubtedly in the sphere of interests not only of health care, but also of pharmaceuticals and food companies.
Lactose intolerance is a good model object for the study and resolution of food intolerance issues in general. Although the mechanisms may differ in case of other intolerances, the approach to researching the issue can be extended to other problems: detection of genetic dependencies, identification of mechanisms regulating the activity of enzymes, searching for links with the intestinal microbiota and correction of microbiota to reduce the negative effects of intolerance.
Source: https://habr.com/ru/post/450080/
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