A New Metabolic Organ: “Intestinal Microbiota” – 23.01.2019

Since the moment which we have born there are many microorganisms accompanying us in our body. The human body contains a microbial population, mostly bacteria, including fungi, viruses and protozoa. Bacteria are generally known as disease-causing pathogens. However, humans live in a symbiotic balance with bacteria. It should not be forgotten that we need bacteria and their beneficial effects to stay healthy.

 

Many different microbial populations reside in the human body, mostly bacteria, including fungi, viruses, and protozoa. This population contains 10 times more microbial cells than human cells and 150 times more genes than the human genome. This ecological community formed by commensal, symbiotic and pathogenic microorganisms that share our body is called “microbiota”. “Microbiome” is defined as the total genome of microorganisms living in this environment. (1)

The human microbiota has been colonized in the skin, genitourinary system, respiratory system, and most often in the gastrointestinal tract. The gastrointestinal tract contains the richest microorganism community in our body, due to its surface area of approximately 200m² and rich nutrients for microorganisms. In healthy individuals, the microbiota includes a large number and variety of microorganisms. It begins to form immediately after birth. It varies according to nutrition, genetics, age and geographic region. Bacteria count is 10⁹ ml/saliva in the mouth, 102-4 g/material in the stomach, 10¹¹ g/material in the colon and 10¹² g/material in the stool. The mode of birth, diet, and genetic factors affect the microbiota in infants. Intestinal microbiota may change after treatment applications such as infections and antibiotic use (2)

Dietary content plays an important role in the change of intestinal flora. A diet rich in fiber foods facilitates the proliferation of Firmicutes bacteria such as Eubacterium rectale, Eubacterium halli, Rumicoccus bromii (Picture 1).

 

 

Picture 1: Effect of nutrition on intestinal microbiota (Flint et al.) WK: Wheat-containing food BS: Fiber-containing food EW: Protein-containing food

Intestinal microbiota; It plays a very complex and active role on the physiological, metabolic and immune system in our body. Intestinal bacteria control the necessary metabolic processes by acting as energy carriers or releasing immune-modulating substances. For this reason, the intestinal microbiota is now defined as a new “metabolic organ” (3).

Commensal intestinal bacteria;

  • It breaks down indigestible foods and makes them useful for the body.
  • Supports the digestion of complex carbohydrates and fibers.
  • It prevents the reproduction of pathogenic bacteria.
  • Contributes to the production of vitamins B1, B2, B6, B12 and K.
  • Contributes to the detoxification of toxins and wastes.
  • They ferment carbohydrates and proteins taken with food and turn them into short-chain fatty acids such as lactic acid, butyric acid, acetic acid, and gases such as hydrogen and carbon dioxide.
  • Short-chain fatty acids are an energy source for intestinal mucosal cells.
  • Short-chain fatty acids contribute to proper intestinal peristalsis.
  • Butyrate provides a strong anti-inflammatory activity by inactivating Nuclear Factor Kappa (Factor NF-kB) transcription and IL-8 production. It is accepted that Firmicutes bacteria, especially Faecalibacterium prausnitzii, play the most active role in butyrate production. These bacteria make up 5-15% of the intestinal flora. Acute phase reactant proteins such as alpha 1 antitrypsin and calprotectin are responsible for inflammatory irritation in the intestinal mucosa.

A decrease in F. prausnitzii correlates with an increase in the degree of inflammation.

  • Colon epithelial cells in healthy individuals are covered with a protective mucous layer. Bacteria of the genus Verrucomicrobia contribute to immune modulation by promoting mucosal production, especially from Akkermansia muciniphila goblet cells. When the mucosal layer is damaged or mucin production is insufficient, pathogens, pollutants and allergens come into direct contact with the mucosal cells and cause inflammation. (4,5)

DYSBIOSIS

Intestinal microbiota may change due to chronic gastrointestinal diseases as antibiotic use. Disturbance in the intestinal microbiota balance is defined as “dysbiosis”. It has been shown that there is an increase in intestinal permeability, a change in the production of short-chain fatty acids, and a decrease in colonic resistance when the microbiota balance is disturbed. A decrease in Firmicutes strains and an increase in Proteobacteria species such as Salmonella, Shigella, Klebsiella, Proteus, Escherichia coli are associated with various diseases.

Sulfate-consuming bacteria lead to the production of hydrogen sulfide (H2S), paving the way for the development of intestinal diseases. H2S is a toxic metabolic product that damages the intestinal epithelium, resulting in cellular atypia. Bilophilia wadworthii, Desulfomonas pigra and Desulfovibrio piger species are bacteria that play an important role in H2S production. Clostridium species, which are obligate anaerobes, are pathogenic bacteria due to their immune modulatory effects and increasing IL-10 production. Toxin-producing origins of bacteria of the genus Clostridium, in particular, are detected in patients with autistic spectrum, often causing intestinal and extra-intestinal autistic complaints.

Haemophilus and Fusobacteria species, which are known as vepathogens in the respiratory tract mucosa, can also be detected in the intestines. Studies show that these pathogenic strains are associated with chronic inflammatory bowel diseases, colorectal carcinomas and appendicitis. As molecular-genetic studies in stool increase, this relationship will be better defined (6,7).

RELATIONSHIP OF DYSBIOSIS AND CLINICAL SYMPTOMS

Pretty valuable results have been obtained with detailed analyzes of the intestinal microbiota. The ideal organization of the intestinal flora population is one of the main elements of a healthy physiological life. When the intestinal microbiota is defined personally, solutions such as diet regulation according to the presence of increased or decreased origins and the use of appropriate prebiotic probiotics can be applied.

 

1. Obesity and Metabolic Syndrome

In healthy individuals, the Firmicutes/Bacteroidetes ratio usually ranges from 1:1 to 1:3. In overweight people, this ratio varies from 3:1 to 25:1. It has been shown to reach a ratio of 200:1 in some overweight individuals (8 ,9).

Another consequence of obesity is a significant decrease in the amount of Faecalibacterium prausnitzii belonging to the firmicute genus. F.prausnitzii is one of the 3 most common bacteria in the intestinal flora. It produces butyrate. Butyrate supports the development of the intestinal mucosa. Butyric acid salts inhibit the transcription of Factor NF-kB and inhibit the release of additional chemokines and interleukin 8. In obese, hsCRP and interleukin 6 levels are significantly increased, at the same time the amount of F.prausnitzii is decreased. In these patients, when the amount of F.prausnitzii is increased, the mucosa can be protected and inflammatory reactions can be reduced (4).

A. muciniphila species that contribute to the production of mucus produced from goblet cells are also frequently reduced in overweight individuals. Mucus covers the intestinal epithelial cells and forms a barrier that protects them from chemical and mechanical effects. It has been shown that the amount of Akkermansia muciniphila is significantly reduced in people who are fed a high-fat diet. The number of bacteria can be partially increased by adding prebiotics containing oligosaccharides to the diet of these people. In animal experiments, the positive effects of A. muchiniphila supplementation on weight loss, development of mucosal layer and reduction of fasting blood glucose and insulin resistance have been shown. It has been reported that similar results have been obtained in humans (10).

2. Intestinal Inflammation

Irritable bowel syndrome is a common, long-lasting clinical picture that is seen in many people and manifests itself with attacks. Recent studies have shown that the amount of F. prausnitzii is reduced by approximately 30% in people with irritable colon complaints and Crohn’s disease. Considering that F. prausnitzii species play the most important role in the production of butyrate, which has an anti-inflammatory effect, and the inhibitory effect of butyrate on Factor NF-kB and IL-8, this decrease negatively affects the anti-inflammatory effect on the mucosa (4,6)

Campylobacter species are isolated in approximately 70% of children newly diagnosed with Crohn’s disease. For this reason, when Campylobacter species are isolated in the stool, there is a growing debate that administration of probiotics will reduce pathogenic bacteria (11).

Leaky gut syndrome is a clinical pattern suggested to be closely related to the intestinal microbiota. The amounts of A. muchinophilia and F. prausnitzii were decreased in these individuals. Intestinal cells are like bricks lined up next to each other. There are “tight connections” between them, which we can call cement between bricks. Thus, undesirable substances cannot pass out of the intestine (ie inside the body) from here, they remain in the intestine and are excreted from the large intestine. In order for the shape of the intestinal cells and the connection between the cells to be healthy, the cells must be taut, which is when the intestines have enough energy to stay taut. F. prausnitzii species use dietary polysaccharides to form short-chain fatty acids. Energy is also produced from short-chain fatty acids. Just on the outer surface of the intestine, there are immune system cells that examine the substances passing through the intestine. When there is an excessive passage through the gut, these immune system cells become active and initiate a reaction, but this reaction is too small to cause disease.

This is called low-level inflammation. Low-level inflammation does not end as long as intestinal permeability continues, which causes all the body’s energy to be used by immune system cells in a long time. Therefore, sufficient energy cannot go to other organs in need, and some problems begin to occur in these organs. Another bad side of hyperpermeable bowel syndrome is that unwanted substances that enter the body go to the weak tissues of the body and accumulate there, and in the long term, the immune system attacks these tissues, causing autoimmune diseases (12,13).

3. Intestinal Tumors and Intestinal Cancers

In addition to other known carcinogenic effects that acids, especially hydrogen sulphate, increase atypical cell growth, cause mucosal irritation and predispose to colorectal cancer. Sulfate producing bacteria are Desulfomonas piger, Desulfovibrio piger and H2S producing Clostridium species. Pro-prebiotic therapies can be applied when an increase in the number of sulfate-producing bacteria is seen in the stool microbiome analysis.

It has also been shown that intestinal microbiota changes in intestinal tumors. In these individuals, the amount of F. prausnitzii is frequently reduced to an undetectable (13).

4. Arthritis

Bacterial imbalances are detected in the intestinal microbiome of patients with rheumatoid arthritis, paralleling the development and progression of the disease. For example, Prevotella copri is beneficial for the immune and digestive system when it is within physiological limits in the intestinal microflora. However, it has been reported that the amount of Prevotella copri and other prevotella species is significantly increased in patients with rheumatoid arthritis. It is suggested that this situation prevents other beneficial bacteria from reproducing and performing their functions (14).

5. Autism

Genetic factors play a big role in autism. However, many other factors can also cause the development of the disease. Many intestinal diseases accompany clinical complaints including the autistic spectrum. Studies show that the use of antibiotics not only eases intestinal complaints, but also increases other symptoms of autism. It is suggested that intestinal microflora also contributes to brain development through the brain-gut axis. It has been reported that the deterioration of gut biodiversity not only leads to the development of autism, but also increases the severity of symptoms. Toxin-producing Clostridium species are found to be increased in children with autism. More Clostridium species are isolated in children with autism than in the control group with normal neurological development. However, it is not yet fully understood how the excess of Clostridium species plays a role in the onset and development of autism. When toxin-producing strains of Clostridium species are detected in the stools of children with autism, appropriate probiotic use is recommended (7,15).

6. Alzheimer Disease

In a recent study, it was shown that the amount of F. prausnitzii decreased by 100% in the intestinal microflora of Alzheimer’s patients (n=52). In addition, inflammation indicators such as calprotectin and antitrypsin were found to be increased in 87.5% of the stools of these patients. hsCRP values are high in 91% of these patients. These data indicate the presence of a systemic inflammation in the body, and it is suggested that a decrease in the amount of F. prausnitzii may be the cause of this inflammation (16). As a result, with personalized advice and personalized treatment approaches are possible by determining the personal gut microbiota.

References & Sources

  1. Turnbaugh, P.J.; Ley, R.E.; Hamady, M.;Fraser-Liggett,C.M.; Knight, R.; Gordon,J.I. (2007). “The Human Microbiome Project”. Nature 449: 804-81O.
  2. Bull M.J., Plummer N.T.. Part 1: The Human Gut Microbiome in Health and Disease. in: lntegrative Medicine: A Clinician’s Journal 13(6), S. 17-22, 2014
  3. Jandhyala, S. M. et al: Role of the normal gut microbiota. in: World J Gastroenterol 21(29), S.8787-8803,2015
  4. Miquel, S. et al.: Faecalibacterium prausnitzii and human intestinal health. in: Curr Opin Microbiol. 16(3), S. 255-261, 2013
  5. Everard A., et al.: Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. in: PNAS 110(22), S. 9066-9071, 2013
  6. Ramezani, A. et al.: The Gut Microbiome, Kidney Disease, and Targeted lnterventions. in: JASN 25(4), S. 657-670, 2014
  7. Song, Y. et al.: Real-Time PCR Quantitation of Clostridia in Feces of Autistic Children . in: AEM 70, S.6459-6465,2004
  8. The NIH HMP Working Group et al.: The NIH Human Microbiome Project. in: Genome Res. 19, S. 2317-2323, 2009.
  9. Kasai et al. Comparison ofthe gut microbiota composition between obese and non-obese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and next-generation sequencing BMC Gastroenterology (2015) 15:100 DOI10.1186/sl 2876-015-0330-2
  10. Everard, A. et al.: Cross-Talk between Akkermansia muciniphila and lntestinal Epithelium Controls Diet-lnduced Obesity. in: PNAS 110(22), S. 9066-9071, 2013
  11. Deshpande, N. P. et al.: Comparative genomics of Campylobacter concisus isolates reveals genetic diversity and provides insights into disease association. in: BMC Genomics 14, 585, 2013
  12. Michielan, A. et al.: lntestinal Permeability in lnflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut. in: Mediators of lnflammation, 2015, 628157
  13. Nava G.M. et al.: Abundance and diversity of mucosa-associated hydrogenotrophic microbes in the healthy human colon. in: The iSME Journal 6(1), S. 57-70, 2012
  14. Seher, J. U. et al.: Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. in: elife, 2, e0l 202, 2013
  15. Smith, P.A.: Brain, meet gut. in: Nature 526, S. 312-314, 2015
  16. Leblhuber, F. et al.: Elevated fecal calprotectin in patients with Alzheimer’s dementia indicates leaky gut. J Neural Transm (Vienna) 122(9) S. 1319-1322, 2015
  17. Mandal, S. et al.: Analysis of composition of microbiomes: a novel method for studying microbial composition. in: MEHD 26, S. 27663-27670, 2015