Intestinal Dysbiosis
The effect of intestinal dysbiosis on human health.
Is it possible for a healthy diet to increase the endurance of our body? Is it possible for proper nutrition to help us to avoid allergies or inflammatory bowel disease? It seems that the underestimated microflora that colonizes our gut has a significant effect on our health. Factors such as diet and stress, shape the composition of the intestinal flora and its metabolic activity which in turn affect a number of normal processes in our body. Certain components of the diet, especially the use of food preservatives and overeating protein can cause carcinogenesis. Stress causes significant changes in the composition of the intestinal flora and promotes the growth of opportunistic bacterial species. Today, intestinal dysbiosis is believed to be a predisposing factor responsible for the development of diseases of modern civilization, such as obesity, cardiovascular disease, allergies, and inflammatory bowel diseases.
How much do you care about your gut bacteria? What will you choose to feed them?
The mucosal surfaces are the largest and most important connections between the external world and the internal environment of the human body. The gastrointestinal tract from the mouth to the anus is 9 meters long and its surface has an area of about 250-400 m2 forming a complex ecosystem that combines the intestinal epithelium, cells of the immune system, and the permanent symbiotic microflora. The permanent microflora of the gastrointestinal tract is compared to the liver due to its size (1-1.5 kg) and due to the number of biochemical reactions involved. However, in terms of systematic classification and metabolic processes, the microflora of the gastrointestinal tract is much more complex than the liver (1-4).
The normal microflora of the gastrointestinal tract
Due to adverse conditions, such as acidity, peristalsis, and the presence of proteolytic enzymes in the secretions of the pancreas and bile, both the stomach and small intestine are protected from colonization by a large number of bacteria. However, the terminal ileum and large intestine are colonized by a complex and diverse bacterial community consisting of approximately 1014 permanent and transient microbial cells in every 1 gr stool. This concentration is achieved under optimal in vitro culture conditions. The intestinal microflora consists of about 500-1000 different species of bacteria, which are 10 times more than the number of cells in the human body (4-6).
The intestinal epithelium is colonized with microorganisms immediately after birth and many factors can determine the composition and diversity of the microflora such as the type of infant's diet (breastfeeding or synthetic nutrition) or the presence of specific microorganisms in the environment depending on the location and country of birth of the infant (developing or developed countries). These precursor bacteria that colonize the infant's gut can alter gene expression in epithelial cells and thus create a more favorable environment for them, but hostile to other bacteria that are later introduced into the ecosystem (2).
Obligate anaerobes that colonize the intestine outnumber the facultative microaerophilic microbes by 100-1000 times. The predominant genera among them are Bacteroides, Bifidobacterium, Fusobacterium, Eubacterium, Clostridium, Peptococcus, Peptostreptococcus, and Ruminococcus. Among the facultative anaerobic genera, the most important are: Escherichia, Enterobacter, Klebsiella, Lactobacillus, and Proteus (3, 7). Interestingly, at least half of the bacteria that colonize the gut cannot be cultured in vitro and are known only on the basis of modern molecular analytical techniques such as 16S rRNA sequencing. Significant differences have been found in the composition of the intestinal microflora at the level of microbial genus and species between individuals, but even in the same individual, the composition of the microflora can be modified by lifestyle, diet, age, and other environmental factors (2, 3, 8, 9). Changes in the composition of the intestinal microflora and its metabolic activity are considered important factors that predispose to the development of diseases of modern civilization, such as irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD), rheumatoid arthritis, ankylosing spondylitis, allergies, obesity and diabetes (10-13).
From 400 BC, Hippocrates referred to the "Theory of Intestinal Toxemia" and expressed the view that "death is hidden in the intestine" and that "poor digestion is the root of all evil." The "Theory of Intestinal Toxemia" has evolved into the current hypothesis of Dysbiosis. Dysbiosis refers to the qualitative and quantitative changes that occur in the composition of the intestinal microflora, in its local distribution, and in its metabolic activity. According to the hypothesis of Dysbiosis, modern lifestyle, diet, use of antibiotics, and other factors that affect the normal intestinal microbiome play a role in the development of many chronic diseases (10).
The effect of normal intestinal flora on human health refers to the effect it has on metabolic processes, the development of villi and microvilli, blood circulation, and the development of the gut-associated lymphoid tissue (GALT). Also, the normal intestinal microflora stimulates the production of cells that secrete immunoglobulin A (IgA) and increases the levels of secretory IgA (sIgA), and affects the homeostasis of the mucosa and the maintenance of the functions of selectivity and protection of the epithelial cells (14-16).
The effect of intestinal microflora on metabolic processes
Many of the bacteria in the human gut contain enzymes that allow them to ferment carbohydrates such as starch, cellulose, hemicelluloses, pectin, and gum or oligosaccharides that have escaped digestion in the upper gastrointestinal tract. The main metabolic end products of carbohydrate fermentation are short-chain fatty acids (SCFAs): acetic, propionic, and butyric which play a nutritional role as a source of energy for the epithelial cells of the colon (7, 10, 17). In the epithelial cells of the colon, 60-70% of the energy they need comes from SCFAs. SCFAs play an important role in maintaining the integrity of the colon lining and preventing bacterial translocation. They also stimulate the proliferation of the intestinal epithelial cells. Butyric acid, used almost entirely by colon epithelial cells, is a potent inhibitor of cell growth, as well as a regulator of proliferation and differentiation of the colon epithelial cells. Facilitates the process of repairing damaged cells and promotes the return of neoplastic cells to non-neoplastic phenotypes. It has been documented that failure to oxidize butyrate in colon cells in genetically predisposed individuals leads to the development of ulcerative colitis and colorectal cancer. Oxidation of butyrate can also help increase glucose, sodium, magnesium, and iron uptake from the large intestine and increase mucus and lipid synthesis (10, 17). Acetic and propionic acid produced during bacterial fermentation are absorbed into the circulation and constitute substrates in the liver (mainly propionic acid), the heart muscle and skeletal muscle, and the brain (mainly acetic acid). In addition, they inhibit the oxidation and concentration of fatty acids in the blood and play a regulatory role in glucose metabolism. Absorption of acetate and propionate by the intestine reduces insulin secretion and inhibits hunger.
In addition, the intestinal microflora of the large intestine improves blood flow and plays an important role in the normal functioning of the intestine and the maintenance of the health of the host. In germ-free experimental animals, i.e., animals raised in a sterile environment, this beneficial effect of the intestinal microflora on the mucosal microcirculation is inhibited and its ability to absorb nutrients is affected (10, 18, 19). The inoculation of normal bacterial flora from healthy animals into the intestines of germ-free animals leads to an increase in body weight despite a reduction in food consumption.
Changes in the composition of the intestinal microflora can affect human body weight by altering the metabolic activity of intestinal bacteria. It has been shown that the number of Bacteroides in the large intestine of obese individuals is reduced and that the restriction of carbohydrates and fats in the diet is associated with an increase in the number of Bacteroides and weight loss (11). In addition, a diet high in fat and glucose has also been shown to affect the non-specific and specific immune response in obese individuals (12). The composition of the intestinal microflora also plays an important role in regulating the energy balance and the changes or disturbances in it which result in the appearance of certain diseases, e.g., obesity, increased risk of developing type 2 diabetes, non-alcoholic steatohepatitis (NASH) or cardiovascular disorders (12, 13).
The effect of intestinal microflora on immunity
The gut-associated lymphoid tissue (GALT) is considered to be the largest organ in the human immune system, as it contains the largest stock of immune cells and is the largest area of contact with microorganisms in the environment, so there is no exaggeration in the statement that the immune response in humans starts from the intestine. Various interactions between GALT and intestinal microflora provide continuous stimuli for the establishment of memory mechanisms of systemic immunity and tolerance to food allergens. Numerous studies in germ-free experimental animals have demonstrated the induction of immunity in the mucosa by the intestinal microflora.
Germ-free experimental animals lacking intestinal microflora have a reduced amount of GALT and its specialized structures, for example, smaller Peyer patches, fewer intraepithelial lymphocytes, and lower levels of circulating immunoglobulins. Exposing the intestinal mucosa of these animals to the normal gut microflora results in a rapid increase in circulating antibodies and an increase in the number of intraepithelial lymphocytes. This shows that the intestinal microflora is essential for the stimulation of the immune cells of the mucosa and thus affects the immune tolerance as well as homeostasis within the intestine (20, 21).
The protective barrier of the intestinal epithelium
The intestinal microflora plays a key role in preventing the colonization of the intestinal epithelium by pathogenic microorganisms. Several mechanisms are involved in this process including competition for nutrients or epithelial binding sites, and the production of polypeptide bacteriocins that inhibit the growth of antagonists (i.e., undesirable pathogens) (22, 23). In addition, the intestinal microflora contributes to the regulation of endothelial cells and epithelial structures, as well as to the maintenance of the intestinal mucosal barrier. So, the intestinal microflora has a significant impact on human health, but like any living cell, these beneficial bacteria need our care.
The effect of diet on the gastrointestinal microbiome
The intestinal microflora needs the right nutrients to grow and proliferate. Unfortunately, the modern diet full of food preservatives and dyes, on one hand, inhibits the growth of beneficial microorganisms by creating a hostile environment, and on the other hand, favors the growth of opportunistic microbes that can be harmful. The effect of diet on carcinogenesis has been documented for many years, but today much evidence suggests that the effect of dietary composition on the modulation of intestinal microflora metabolic activity may contribute to carcinogenesis (10).
In some individuals, depending on the geographical area and composition of the diet, the sulfur-reducing bacteria belonging to the genera Desulfovibrio (most), Desulfobulbus, Desulfobacter, and Desulfomonas may be found in the microflora of the large intestine. Sulfur-reducing bacteria reduce sulfites and sulfates to sulfides, which are involved in the production of potentially toxic hydrogen sulfide. This in turn is responsible for the destruction of the mucosa of the colon, due to the inhibition of the oxidation of butyrate, the primary source of energy for the cells of the colon. As sulfur-reducing bacteria compete with other microorganisms for the same nutrients, the presence of large amounts of sulfates derived from foods (e.g., food preservatives, packaged fruit juices, dried fruits, white bread, amino acids that contain sulfur found in eggs, cow's milk and cheese), promote their overgrowth and the production of large amounts of hydrogen sulfide. Endogenous sources of sulfates, e.g. chondroitin sulfate appears to have little or no effect on the levels of sulfur-reducing bacteria. Reduction of dietary sulfate intake has been shown to be associated with clinical improvement in ulcerative colitis and has a strong impact on the metabolic activity of sulfur-reducing bacteria in inflammation of the colonic mucosa (10).
A high protein diet also increases the production of potentially harmful bacterial metabolites. In a typical western diet that contains about 100 grams of protein per day, about 12 grams of protein can escape digestion in the small intestine and reach the large intestine. Endogenous proteins (e.g. mucus, digestive enzymes, and dead epithelial cells), together with indigestible dietary proteins make the total amount of proteins that reach the large intestine exceed the metabolic capacity of the permanent microflora. This results in the decomposition processes and the production of toxic compounds, i.e. ammonia, amines, phenols, indoles, and sulfides. Ammonia can alter the morphology and metabolic activity of colon cells, shorten their lifespan, and may affect the growth of tumors. Ammonia accumulation is also involved in the pathogenesis of encephalopathy. Indoles, phenols, and amines have been implicated in the pathophysiology of schizophrenia and migraine, and are considered co-carcinogens, playing a role in the etiology of bladder and bowel cancer. Another group of carcinogens released during the cooking of meat products are the heterocyclic aromatic amines that cause damage to the DNA of epithelial cells. This action may be enhanced by enzymes of certain bacteria species, e.g. Bacteroides and Clostridium, or moderated by other species, e.g. Lactobacillus and Bifidobacterium (10, 22). A diet rich in unprocessed carbohydrates lowers intestinal pH, facilitates the digestion of proteins, reduces the amounts of toxic metabolites, and reduces their effects on the intestinal epithelium (10). A diet high in animal protein has specific effects on the intestinal microflora. Although the diet does not significantly alter the composition of the microflora, it increases the activity of certain bacterial enzymes, such as beta-glucuronidase, azoreductase, and nitroreductase. Increased activity of these enzymes results in the production of potentially toxic metabolites. For example, bacterial azoreductase can reduce the azo-bond found in many food dyes, releasing potent carcinogens, namely, phenyl- and naphthylamines. Many carcinogens released during metabolic processes in the human body are neutralized in the liver by conjugation with glucuronic acid. Glucuronides then pass through the biliary system into the intestine to be excreted in the faeces. However, the enzyme beta-glucuronidase, produced by certain species of intestinal bacteria, hydrolyzes these glucuronides to the original toxic metabolites and is eventually absorbed back into the enterohepatic circulation. In this way, toxic metabolites can recirculate in the human body for a long time before their elimination (4, 10, 22).
Diet rich in processed sugars
A diet rich in simple processed sugars reduces the transit time of the intestine and increases the activity of the intestinal microflora, as well as the concentration of secondary bile acids in the feces. Shorter bowel transit time may cause prolonged exposure of the colon epithelium to potentially toxic products. Unlike the unprocessed carbohydrates in the vegetarian diet, which are metabolized slowly with the gradual release of SCFAs, the processed sugars are rapidly metabolized to toxic end products, such as acetic acid and alcohol. In addition, processed sugars, by increasing bile production, indirectly mediate an excessive increase in the opportunistic bacterial species that use bile acids in their metabolism (10). However, insufficient carbohydrate intake can cause increased use and a decline of the protective layer of mucus that covers the intestinal epithelium. This in turn can lead to increased adhesion of intestinal bacteria, the development of chronic inflammation, and epithelial damage (10).
The impact of psychological stress on the intestinal microflora
Stress first of all can change the composition of the intestinal microflora, reducing the number of beneficial probiotic bacteria, e.g., Lactobacillus and Bifidobacterium, and promoting the growth of potentially harmful species. Changes in the physiology of the gastrointestinal tract associated with stress e.g. inhibition of gastric acid release, changes in motility, increased production of bicarbonate by the duodenum, create an unfavorable environment for the proliferation and attachment of Lactobacillus, resulting in increased elimination of these bacilli. Interestingly, the effect of the increased expulsion of Lactobacillus lasts for up to 6 days after a short period of emotional stress. Reducing the number of Lactobacilli increases the possibility of colonization of the intestine by exogenous microorganisms. In addition, stress may be responsible for the reduced production of mucus, which is important for preventing the attachment of pathogenic bacteria. In addition, stress results in decreased sIgA levels in both the intestinal mucosa and saliva (10, 24).
Salivary sIgA concentration has been shown to be inversely proportional to norepinephrine levels, indicating that activation of the sympathetic nervous system may suppress sIgA production. In addition, catecholamines appear to act as inducers of bacterial growth and stimulate the overgrowth of intestinal microflora, as well as the expression of their infectious agents, such as certain adhesion molecules and toxins. Even normal concentrations of catecholamines significantly stimulate the growth of bacteria in the gut and may be associated with their displacement into the bloodstream, as demonstrated in experimental animals and in vitro experiments. These studies are of great importance for the pathophysiology of sepsis after surgery. Damage to noradrenergic neurons during surgery leads to the release of catecholamines in the circulation. This, in turn, stimulates the overgrowth of bacteria in the intestinal tract, their movement in the blood, and sepsis. In recent years, some catecholamine inhibitors have been considered to prevent sepsis through bacterial movement during surgery.
By taking care of the intestinal microflora we can increase our immunity and prevent the development of many diseases of modern civilization such as obesity, allergies, cardiovascular diseases, or irritable bowel syndrome which in some countries have reached epidemic ratios. However, there is still hope that the continuously increasing number of data on the beneficial effects of probiotic bacteria on human health will draw our attention to what we choose to eat and that proper nutrition will have the same importance as medicine in the prevention and treatment of diseases.
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Author: Beata Magdalena Sobieszczańska, Department of Microbiology, Wroclaw Medical University, Poland, Gastroenterologia Polska 2008, 15(5), 287-290
Editorial Article
Translation - Editing: Vasilis Sideris
