Leaky gut syndrome

Various parameters are available to diagnose a leaky good syndrome. In recent years, the determination of zonulin as a sensitive and specific test procedure for the detection of damage to tight junctions has become more and more important. Zonulin is a protein that is responsible for the opening of the tight junctions in the intestinal mucosa and can therefore increase intestinal permeability. The important relationship between elevated zonulin levels and the occurrence of autoimmune diseases such as multiple sclerosis, insulin-dependent diabetes and rheumatoid arthritis is currently the subject of ongoing debate.

The increased detection of cell wall structures of Gram-negative bacteria in serum in the sense of endotoxinaemia has also proven to be a marker of impaired intestinal permeability. Endotoxins (also called lipopolysaccharides (LPS) due to their molecular structure) are heat-stable components of the outermost cell wall of Gram-negative bacteria, which are released after the death of the bacterial cell. LPS activate the cells of the innate immune system, which in turn release pro-inflammatory messenger substances and thereby cause inflammatory reactions. If the intestinal barrier is not intact, an increase in endotoxins in the blood and thus an increased availability of immunologically active LPS in the organism can occur.

Alpha-1-antitrypsin is produced as a protease inhibitor in the liver, but also to a small extent in the intestinal mucosa. Elevated levels of alpha-1-antitrypsin are found not only in enteral protein losses, but also in inflammatory bowel mucosa changes. In addition, immune reactions against food components as well as an increased incidence of mucosal toxic metabolites from the metabolism of undesirable germinal species can also result in increased permeability and thus an increase in alpha-1-antitrypsin in the stool. This condition is associated with an additionally increased risk of sensitisation to antigens from the intestinal lumen (especially food antigens).

Lactulose and mannitol are two sugars which are not metabolized in the small intestine and are therefore excreted in varying quantities with the urine. However, if the intestinal mucosa is already permeable, the absorption quantity of these two types of sugar changes. The lactulose/mannitol quotient indicates the ratio of the resorbed quantities of these two sugars. To diagnose a leaky gut syndrome, the fasting patient is given a solution of mannitol and lactulose in the morning, his urine is collected over the following five hours and examined for the resorption quantity of the two types of sugar.

As a metabolic product of pathogenic Candida fungi, D-arabinitol represents a sensitive marker for the detection of excessive intestinal yeast growth. It is produced by various Candida species (e.g. Candida albicans) during their metabolism. Since yeasts can proliferate strongly in the case of non-intact intestinal mucosa and can cause an infection, elevated values can be assumed to indicate a pronounced colonisation of the small intestine with Candida fungi and subsequently a leaky gut syndrome.

The secretory immunoglobulin A is produced in the plasma cells which are located in the region of the lamina propria mucosae of the intestinal wall. Its main tasks include the neutralisation and defence of antigens, pathogens and toxins. While lowered sIgA values are associated with insufficient stimulation of the intestinal immune system and thus with increased permeability of the intestinal mucosa, elevated sIgA values may indicate increased defence performance.

Calprotectin is a protein which neutrophil granulocytes produce in increased quantities during, among other things, inflammatory reactions. Especially in inflammatory bowel diseases such as Crohn's disease or ulcerative colitis, calprotectin levels are sometimes massively increased. The intestines of persons with an unstable micro-ecological environment contain many micro-organisms and bacteria that release toxic substances. These specific substances stimulate the granulocytes to migrate into the intestinal lumen, where antimicrobial substances such as calprotectin are released. Thus, the level of calprotectin is related to the number of granulocytes migrating into the intestinal lumen and reflects the degree of inflammatory activity.

The presence of the intestinal bacteria Akkermansia muciniphila and Faecalibacterium prausnitzii can also serve as markers of a healthy intestinal mucosa. If the germ count of the mucosaprotective flora is in the optimal range, it can be concluded that the intestinal mucosa is sufficiently or well protected by Akkermansia muciniphila and Faecalibacterium prausnitzii. On the other hand, reduced bacterial counts of both bacterial species indicate insufficient protection of the intestinal mucosa. However, in order to exclude potential inflammatory processes and increased intestinal permeability, the investigation of further parameters - such as the entire intestinal microflora, of zonulin, α1-antitrypsin, sIgA, calprotectin and possibly LPS - is recommended.

Beta-glucuronidase is an enzyme produced by germs such as Clostridium sp., Escherichia coli, Peptostreptococcus sp. and Bacteroides sp. For normal enterohepatic recirculation of endogenous compounds (vitamin D, thyroid hormones and estrogens), a certain level of beta-glucuronidase activity seems to be important. A disturbance of the intestinal flora can result in either reduced or increased production of beta-glucuronidase in the intestine. The use of broad-spectrum antibiotics leads to the suppression of the intestinal flora, the reduction of beta-glucuronidase activity and subsequently to the intestinal absorption of these compounds. In contrast, increased beta-glucuronidase activity can cause increased reabsorption and thus undesirable high blood levels of potentially harmful substances - such as drugs, toxins and steroid hormones.
 

A change in diet with temporary avoidance of foods that damage and irritate the intestinal mucosa is critical to initiate recovery from leaky gut syndrome. Foods containing compounds that promote intestinal mucosal permeability include grains (including pseudograins), dairy and products made from them, sugars, legumes, omega-6 rich processed vegetable oils and processed foods. Particularly sensitive people may additionally benefit from temporarily avoiding potenital allergens like eggs, vegetables from the nightshade family, and foods high in FODMAPs (short for fermentable oligo-, di-, and monosaccharides and polyols), if appropriate. All of this should be done under the supervision of a physician or nutritional therapist to ensure a balanced diet during this phase. It is also important to eat a balanced diet with a lot of different colored vegetables and to include foods that counteract inflammation (e.g., omega-3 fatty acids) and thus play a crucial role in helping to heal the damaged intestine. 
 

Inflammations of the intestinal mucosa result in high gastroenteric losses of electrolytes and trace elements. In addition, a suboptimal vitamin status can develop due to absorption disorders. Inflammatory processes as well as interaction with drugs, which can cause an imbalance in the nutrient balance, further increase the increased nutrient requirement. In addition to the factors mentioned above, micronutrient therapy represents an important pillar in the treatment of a leaky gut syndrome. Among the most important micronutrients with positive effects on intestinal permeability are

- Curcumin has anti-inflammatory as well as antioxidative properties and shows good results in the treatment of inflammatory diseases. The bright yellow curcumin can help to restore the epithelial structure of the intestine and reduce intestinal permeability, especially after intestinal injuries. Some studies suggest that it may counteract changes in barrier function caused by a Western style diet.

- L-glutamine plays a central role in the formation and maintenance of cell systems and is currently the best known compound for reducing intestinal permeability. The mucosa cells of the small intestine metabolise about 70% of the glutamine absorbed, making this amino acid an essential nutrient for maintaining intestinal permeability. Targeted glutamine substitution can reduce the permeability of the intestinal mucosa, contribute to maintaining the intestinal barrier and alleviate chronic inflammatory processes. In contrast, a lack of L-glutamine can lead to damage of the intestinal barrier and thus to disturbance of intestinal function. In animal experiments, the restoration of the intestinal mucosa (measured in increased intestinal mucosa weight and increased mucosal DNA) as well as the improvement in microvilli height and crypt depth have already been observed. Increased intestinal permeability and mucosal damage in the gastrointestinal tract are often associated with the regular intake of NSAIDs - such as indomethacin or diclofenac. Accompanying supplementation with L-glutamine, ideally 30 minutes before taking the drug, can improve gastrointestinal tolerance. A study from 2004 showed the protective effect of L-glutamine on the intestines of 20 patients after abdominal surgery. Ten patients received 30 glutamine per day for one week, the other ten received a placebo preparation. In the placebo group, serum glutamine levels decreased followed by a positive leaky gut test. The lactulose/mannitol ratio in the placebo group was not only much higher than in the glutamine group, the glutamine group also recovered from surgery much faster. Furthermore, the body temperature was lower in the glutamine subjects, the heart values were better and the number of leukocytes was lower. L-glutamine should not be taken continuously for more than eight weeks, followed by a break of several weeks.

- Glutathione status also plays an important role in the development of inflammatory gastrointestinal diseases. Glutathione is generally indispensable for maintaining the integrity and energy metabolism of the small intestine cells. The activity of the radicals produced during the inflammatory process perpetuates the inflammatory process, which can lead to morphological changes in the mucosa. A corresponding oral substitution of glutathione and the resulting improvement in glutathione supply can counteract these processes.

- Selected plant extracts and micronutrients are closely related to the intestinal mucosa and thus support the rehabilitation of mucosal integrity. The astringent effect of green tea extract can reduce the permeability of the intestinal mucosa for antigens and prevent the penetration of antigens and pathogenic germs. In addition, the contained epigallocatechin-3-gallate acts as a strong electron donor and acts as a powerful antioxidant in the inflammatory process.

- Acute inflammatory processes often show a high content of pro-inflammatory and immunosuppressive eicosanoids of the 2 and 4 series, which are formed from arachidonic acid. An increased supply of omega-3 fatty acids inhibits this conversion process. Increased anti-inflammatory eicosanoids are formed, which have a favourable effect on inflammatory diseases. As omega-3 fatty acids have a protective effect, it is assumed that omega-6 fatty acids increase the risk. The potential use of omega-3 fatty acids is aimed at alleviating inflammatory symptoms in the gastrointestinal tract.

- In almost all inflammatory bowel diseases, the intestinal flora is also in need of treatment. The use of a sensible combination of probiotic intestinal bacteria strains in sufficiently high concentrations shows good clinical evidence.

- As a flavonoid, quercetin causes structural changes in the tight junction complex, resulting in a more robust intestinal barrier. Indeed, research shows that quercetin can protect against known intestinal mucosal disrupting factors - such as TNF-α, indomethacin and hydrogen peroxide - possibly due to the activation of the enzyme protein kinase C-delta.

- Recent studies show that an inadequate vitamin D status not only increases mortality but is also a significant etiological factor in the pathogenesis of many diseases. According to current studies, these include inflammatory bowel diseases, autoimmune diseases, infections, and cardiovascular, oncological and neurocognitive diseases. Vitamin D unfolds its physiological effects by binding to vitamin D receptors. So far, these have been found in more than 36 cell species.

- It is now known that zinc deficiency affects the integrity of the intestinal barrier, although the mechanisms have not been clearly understood for a long time. Several studies have shown that zinc acts specifically on tight junctions and helps to regulate their permeability. In addition, zinc can compensate for the effects of substances that affect the integrity of the barrier (e.g. pro-inflammatory cytokines). In the CACO-2 cell line, zinc supplementation significantly increased transepithelial electrical resistance, i.e. barrier function improved.

In addition, magnesium, selenium, iron, B vitamins, folic acid and vitamins A, C and E contribute to the regeneration of the intestinal mucosa.