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2814. Khamdamov B.Z. Indicators of immunocitocine status in purulent-necrotic lesions of the lover extremities in patients with diabetes mellitus. // American Journal of Medicine and Medical Sciences, 2020. 10 (7). P. 473-478. DOI: 10.5923/j.ajmm.20201007.08.
15. Khamdamov B.Z., Nuraliev N.A. Pathogenetic approach in complex treatment of diabetic foot syndrome with critical lower limb ischemia. // American Journal of Medicine and Medical Sciences, 2020. 10 (1). 17-24 DOI: 10.5923/j.20201001.05
INFLUENCE OF INTESTINAL MICROFLORA ON THE DEVELOPMENT OF GALLSTONE DISEASE (LITERATURE REVIEW) Hikmatov J.S.1, Yo'ldoshev U.H.2
1Hikmatov Jasur Safarovich - Assistant;
Yo'ldoshev Umurzoq Holmamatovich - Assistant, DEPARTMENT OF FACULTY AND HOSPITAL SURGERY,
UROLOGY, BUKHARA STATE MEDICAL INSTITUTE, BUKHARA, REPUBLIC OF UZBEKISTAN
Abstract: gallstone disease is one of the most common diseases of the digestive system, which affects all segments of the population. Currently, gallstone disease is considered as a long, multi-stage process, in which the period of stone formation is preceded by changes in the metabolism and physicochemical properties of bile. However, among the numerous predisposing factors, insufficient attention is paid to the role of the infectious agent in the development of cholelithiasis. The analysis of the literature data showed that today there are various mechanisms for promoting enteral bacterial overgrowth in the development of cholelithiasis. First, with excessive bacterial growth, duodenobiliary reflux leads to infection of the biliary tract and the development of an inflammatory process in the gallbladder. Substances arising from the inflammatory process (proteins,
mucus, desquamated epithelium) are the matrix on which the gallstone is formed. Secondly, the essential role of dysbiosis is traced in the violation of enterohepatic circulation of bile acids. A change in the ratio of conjugated and deconjugated bile acids contributes to the formation of lithogenic bile. Keywords: gallstone disease, microflora, bacteria, intestines, endotoxinemia.
Cholelithiasis (GSD) is one of the most common diseases of the digestive system, which affects all segments of the population [1, 2]. The incidence of gallstone disease in different countries (regions of the world) is 10-15% [3]. Currently, gallstones is considered as a long, multi-stage process, in which the period of stone formation is preceded by changes in the metabolism and physicochemical properties of bile. However, among the many contributing factors, insufficient attention is paid to the role of the infectious agent in the development of cholelithiasis.
Data from studies of contamination of the biliary tract with microflora in gallstones Biliary tract infection most often occurs enterally due to insufficiency of the sphincter structures of the biliary tract, on the one hand, and bacterial overgrowth in the small intestine, on the other hand [4].
Excessive growth of opportunistic bacteria in the intestine, their dissemination in the body against the background of a decrease in barrier and other protective factors leads to the ingress of agents into the biliary tract and the development of an inflammatory process. Opportunistic enterobacteriaceae colonize the biliary tract due to translocation from the large intestine against the background of dysbiotic disorders [5]. In this case, microorganisms sensitive to bile die, and resistant ones acquire the ability to colonize the corresponding biotope with the development of an infectious and inflammatory process [6]. It was found that bile, the wall of the gallbladder and gallstones in patients with various clinical forms of cholelithiasis are infected mainly by the microflora characteristic of the intestine. Among the microorganisms isolated from the gallbladder of patients with cholecystitis and gallstone disease, opportunistic enterobacteria,
E. coli, streptococcus, staphylococcus, typhoid bacillus, protozoa (lamblia) occupy the leading place [7]. At the same time, a significant prevalence of aerobic flora over anaerobic flora is observed. The most pronounced antibacterial activity of bile and bile acids against anaerobes (bacteroids, clostridia, lactobacilli), as well as gram-positive cocci (pneumococci, staphylococci). Gram-negative microorganisms are less susceptible to their action (Salmonella, Shigella, Escherichia coli) [6].
In patients with an increased risk of stone formation in the gallbladder and with cholelithiasis, according to the results of studying short-chain fatty acids in feces, a change in the qualitative composition of microflora was revealed, expressed in an increase in the activity of those genera of microorganisms that are involved in 7-alpha-dehydroxylation of bile acids, namely, aerobic microorganisms (in particular, Escherichia coli, (and anaerobes (some strains of the genera of bacteroids, clostridia, eubacteria).
There is evidence in the literature that a similar process of bacterial translocation is possible for other intestinal microorganisms - enterobacteria (Klebsiella, serration), pseudomonads, staphylococci, enterococci, etc. [6]. The pronounced resistance to bile in E. coli strains isolated in cholecystitis is an adaptive reaction that developed as a result of prolonged contact with bile. A relatively high level of resistance was shown by E. coli copstrains obtained during intestinal dysbiosis, which is due to the functioning of the "vicious circle", when bacteria from the intestine migrate to the portal veins, enter the liver, then into the bile ducts, interact with bile and again enter the intestines [8].
The overwhelming majority of literature sources provide data that in cholecystitis, regardless of the nature of the lesion, bacteriocholia is mainly caused by enterobacteria, among which Escherichia coli accounts for 30-57%. In addition to Escherichia, biliary cultures can be represented by other representatives of the Enterobacteriaceae family: Klebsiella (1-10%), Proteus (7-8%), Enterobacter (9.2%), etc. - up to 75% in total. The share of enterococci on average accounts for 10 to 27%, staphylococci -
from 9.7 to 16.25%, streptococci - from 7.3 to 12.5%. Less common are pseudomonads, yeast-like fungi [9]. Literature data [9, 10] indicate the predominance of intestinal bacteria in bile in patients with pathology of the hepatobiliary zone, although there are other results. For example, the work of K.I. Savitskaya et al. (2003) [11], which presented data on the release of gram-positive coccal flora from the bile of patients with chronic pancreatitis in 70% of cases.
According to the results of most bacteriological analyzes of bile, carried out for gallstones, in second place after enterobacteria are microbes of the genus Enterococcus [9], which are representatives of the normal microflora of the human digestive tract.
Among the cultures of strict anaerobes obtained from bile, non-spore-forming species predominate (89%), and in 11% of cases -clostridia [6]. Among anaerobic bilicultures, representatives of the Bacteroidaceae family are more often determined, in 25% of cases Bacteroides fragilis (B. Fragilis) are represented. The proportion of anaerobic cocci (peptococci, peptostreptococci and anaerobic streptococci) can also be significant in this pathology, and is 21.4% of all anaerobic strains.
Bile can be one of the factors that regulate the microbial composition in the gallbladder, ducts, intestines, and thus form a certain microecology of the digestive tract [3]. A.V. Valyshev et al. (1996) [5] revealed the identity of pathogens isolated from feces and bile in 74% of cases, and the presence of persistence factors (antilysozyme, anti-interferon and anti-complementary signs) in isolated bacterial strains with intestinal dysbiosis and diseases of the biliary tract. This confirms the leading role of the intestinal microbiocenosis in the development of inflammatory processes in the hepatobiliary system and, as a consequence, the formation of lithogenic bile [12].
The main component of bile is primary bile acids cholic and chenodeoxycholic), which are synthesized in hepatocytes from cholesterol with the participation of the cholesterol-7a-hydroxylase enzyme. Once in the ileum, approximately 85-90% of primary gallstone with the participation of intestinal microbiota
are deconjugated, absorbed and transported through the portal vein to hepatocytes, where they are again conjugated and incorporated into bile [1, 13]. It has been established that bacteroids and lactobacilli are involved in this process [14]. Approximately 5-10% of non-absorbed primary FAs enter the large intestine, where, under the influence of bacterial 7a-dehydroxylase of gram-positive anaerobic bacteria (eubacteria and clostridia), secondary hydrophobic FAs (deoxycholic and lithocholic) are formed, which are absorbed, enter the liver and re-enter return conjugations in hepatocytes. In patients with gallstone disease, the transit time through the intestine is increased, which enhances the formation of deoxycholic acid as a result of bacterial metabolism. The increased concentration of secondary fatty acids in the gallbladder has a lithogenic effect.
Disturbance of enterohepatic circulation of bile acids is of great importance in the development of cholelithiasis [15, 16]. In patients with cholelithiasis and chronic acalculous cholecystitis, there was a violation of the enterohepatic circulation of bile acids of the fatty acid, manifested by a change in the exchange of cholic acid, cholesterol and phospholipids. This is due to an increase in the activity of anaerobic microorganisms participating in 7-alpha dehydroxylation of gallstone [17].
In patients with gallstone disease, a greater number of bacteria and 7-dehydroxylase activity are detected in intestinal aspirate from the ileum, combined with a higher pH in the colon and an increased transit time in the small and large intestine. Among the known causes of malabsorption of fatty acids, there is a prolongation of the intestinal transit period, which contributes to an increase in the time of bacterial conjugation even with a constant quantitative and qualitative composition of the microflora [18-20].
An important role in the violation of enterohepatic circulation of bile acids gallstone belongs to the acceleration of the intestinal passage time, which leads to an increase in gallstone excretion with feces and a decrease in their absorption [21]. On the other hand, there is evidence that a decrease in fatty acids decreases the antibacterial properties of bile. This promotes the activation of
opportunistic microorganisms and the development of bacterial overgrowth in the intestine. But the frequency and features of the occurrence of gallstone, as well as intestinal dysbiosis in cholelithiasis, remain insufficiently studied. To date, data have been accumulated that the intestinal microflora is capable of biotransformation of gallstone, cholesterol, and steroid hormones into various metabolites during the enterohepatic circulation of bile acids process [23].
Chronic biliary insufficiency, which leads to overgrowth of bacteria and premature deconjugation of fatty acids, which damage the mucous membrane of the small intestine and even the large intestine, has a special imprint on the course of gallstones. The inflammatory process in the mucous membrane of the small intestine leads to violations of the enterohepatic circulation of bile acids of the GI, while biliary insufficiency is aggravated. Under physiological conditions, the sterility of bile is provided by the antibacterial effect of fatty acids. In chronic biliary insufficiency, especially when combined with a reduced concentration and evacuation function of the gallbladder and dysfunction of the sphincter of Oddi, conditions are created to reduce the antibacterial properties of bile. At the stage of biliary sludge formation, biliary insufficiency is detected in 91.7% of cases (of which 54.5% are mild, and 45.5% are moderate) [18].
A decrease in the antibacterial properties of bile inevitably creates favorable conditions for the development of gallstone in the small intestine. More pronounced changes in the microflora of the small intestine occur with cholecystolithiasis. Due to a decrease in the protective function of the gallbladder, expressed in the bactericidal effect of bile, excessive bacterial growth occurs in the intestine of a patient with cholelithiasis, while the number of representatives of the obligate intestinal normal flora decreases and it is replaced by opportunistic bacteria. In biopsies of the mucous membrane of the duodenum in patients with cholelithiasis, signs of activation of opportunistic microflora with the release of up to 28 different genera of microorganisms are found. At the same time, hemolytic staphylococci (53%), bacteria of the Enterobacteriaceae family (69%), fungi of the genus
Candida (49%), bacteroids (47%) in the amount of 3.3-5.2 Ig KOE / g in combination of 2-7 cultures [19].
As shown by the studies carried out by Vakhrushev Ya.M. et al. (2017) [24], a biochemical study of bile revealed a significant decrease in the concentration of fatty acids in the gallbladder and hepatic portions of bile in patients with cholelithiasis compared with controls. Also, in patients with cholesterol, a tendency to an increase in cholesterol concentration and a significant decrease in the cholesterol coefficient in both the gallbladder and hepatic portions of bile were revealed. The study of individual gallstone fractions in patients with cholelithiasis showed a decrease in free (cholic, chenodeoxycholic, deoxycholic) and an increase in conjugated (glycocholic, glycodeoxycholic, taurocholic, taurodeoxycholic, ursodeoxycholic) gallstone in portions "B" and "C" bile in comparison with control. Disruption of the balance of free and conjugated fatty acids leads to the development of colloidal instability of bile, which is a prerequisite for the development of cholelithiasis. In a study by the same authors, the total content of fatty acids in the blood according to the results of mass spectrometry showed its decrease in patients with cholelithiasis in comparison with the control. In this case, multidirectional violations of the LC spectrum were noted. Thus, chenodeoxycholic and deoxycholic acids were reduced, while ursodeoxycholic, glycocholic, glycodeoxycholic, taurocholic and taurodeoxycholic acids were increased. The synthesis of gallstone from cholesterol occurs in the hepatocyte and includes 17 different enzymes that are located in the cytosol, endoplasmic reticulum, mitochondria, and peroxisomes [25]. It should be borne in mind that the synthesis of fatty acids is influenced not only by the state of the liver and the fatty acids themselves, which can, according to the principle of negative feedback, contribute to an increase or decrease in their content, but also cholesterol, thyroid hormones, glucocorticoids, insulin, circadian rhythms [13,25,26]. The small intestine is actively involved in maintaining gallstone homeostasis by synthesizing fibroblast growth factor-15 by enterocytes, which regulates a number of enzymes responsible for gallstone synthesis [13]. Changes in the gallstone composition
in the blood may be associated with an increase in gallstone absorption in the proximal small intestine. In patients with pre-stone stage of cholelithiasis, the development of bacterial overgrowth leads to disruption of the normal absorption of fatty acids in the distal ileum. In this case, premature deconjugation and absorption of fatty acids are characteristic [27, 28]. Against the background of the development of bacterial overgrowth, there is a decrease in free and an increase in conjugated fatty acids in bile. In addition, the development of bacterial overgrowth can serve as an initial link in the bacterial translocation mechanism [29]. There are microorganisms that are more prone to translocation due to their better ability to adhere to the intestinal epithelium (Escherichia coli, Klebsiella, enterococci). This bacterial flora is able to penetrate even through the histologically normal mucous membrane of the intestinal wall, then entering the hepatobiliary system. It can be assumed that the detected the development of bacterial overgrowth in most patients with the pre-stone stage of cholelithiasis can be a source of bacteriocholia, and bacterial colonization of the extrahepatic biliary tract contributes to gallstones [30].
Lactobacillus and bacteroid enzymes are involved in the process of gallstone deconjugation in the distal ileum and proximal colon [31]. In 100% of patients with cholelithiasis, inoculation of feces revealed intestinal dysbiosis, while in the majority of patients (91%), various variants of combined disorders of the colon microflora are noted. To a greater extent, there was a decrease in the number of lactobacilli less than 107 CFU / g in 40.9% of patients with pre-stone stage of cholelithiasis. An increase in the proportion of lactose-negative and hemolytic Escherichia coli (up to 28.6% and 18.2%, respectively) was also revealed against the background of a decrease in full-fledged Escherichia coli (in 31.8% of patients). Consequently, against the background of the development of bacterial overgrowth and colonic dysbiosis, significant changes occur in the deconjugation of gallstone, which leads to a violation of the ratio of conjugated and deconjugated gallstone in bile and blood. Violation of enterohepatic circulation of bile acids leads to
a decrease in the gallstone content in the intestine. Malabsorption syndrome develops, the composition of the intestinal microflora is disturbed, ethanol and organic acids are formed in excess, the pH of the chyme decreases and the deconjugation of fatty acids increases. The consequence is the progression of the development of bacterial overgrowth, the formation of an increased amount of endotoxins, their entry into the liver and the development of systemic inflammation [32]. That is, dysbiosis leads to a violation of the enterohepatic circulation of bile acids of the gallstone, and a decrease in the intake of gallstone in the intestine aggravates the dysbiosis.
Thus, the small intestine is an important link in the violation of the enterohepatic circulation of bile acids of the gallstone. An increase in the absorption of prematurely deconjugated fatty acids in the proximal part of the small intestine accelerates the time it takes for fatty acids to return to the liver, as a result of which their synthesis in hepatocytes and excretion into bile decreases. As a result of the development of bacterial overgrowth in the distal ileum and colonic dysbiosis, significant changes occur in the deconjugation of gallstone, which leads to a violation of the ratio of gallstone fractions in the blood and bile.
References
1. Berr F. et al. 7 alpha-dehydroxylating bacteria enhance deoxycholic acid input and cholesterol saturation of bile in patients with gallstones //Gastroenterology, 1996. ^ 111. № 6. Р. 1611-1620.
2. Bahodirovich N.B. et al. Assessment of behavior and biochemical parameters of blood in experimental animals under conditions of a technogenic rotating electric field //Science and Education Bulletin, 2020. № 23-2 (101).
3. Davlatov S.S. Application hemoperfusion as the method of homeostasis protection in multiple organ failure syndrome// Collection of scientific works of students and young scientists of the All-Russian scientific-practical conference with international participation. Yaroslavl. April 24-26, 2013. Р. 147.
4. Davlatov S.S., Kasymov Sh.Z., Kurbaniyazov Z.B., Rakhmanov K.E., Ismailov A.O. Plasmapheresis in the treatment of cholemic endotoxicosis// «Academic Journal of Western Siberia», 2013. № 1. P. 30-31.
5. Davlatov S.S., Rakhmanov K.E. Improved method of plasmopheresis in the treatment of cholemic endotoxicosis// Collection of scientific works of students and young scientists of the All-Russian scientific-practical conference with international participation. Yaroslavl. April 24-26, 2013. P. 148.
6. Davlatov S., Rakhmanov K., Qurbonov N., Vafayeva I. & Abduraxmanov D. (2020). Current State of The Problem Treatment of Mirizzi Syndrome (Literature Review) // International Journal of Pharmaceutical Research. 12, P. 19311939. DOI:https://doi.org/10.31838/ijpr/2020.SP2.340.
7. Fayziev X.B., Teshaev ShJ. Morphofunctional changes in the tissues of the spleen as a result of external factors // Problems of biology and medicine. - 2020. №4. Tom. 120. P. 241-245. DOI: http://doi.org/10.38096/2181-5674.2020A00229.
8. Fayziev Kh.B., Khuseynova G.Kh. Macroscopic topography of the spleen of white outbred rats after severe traumatic brain injury caused by road traffic accidents // Problems of Biology and Medicine, 2020. № 6. Tom 124. S. 185-188. DOI: http://doi.org/10.38096/2181-5674.2020.6.00333.
9. Kasimov Sh., Abdurakhmanov Z., Davlatov S., Aripova J. Hemosorbtion in complex management of hepatargia// Abstracts: XL ESAO Annual Congress, 11-14 September, 2013, Glasgow, Scotland. Int J Artif Organs., 2013; 36 (8).
10. Kasimov Sh.Z., Kurbaniyzov Z.B., Davlatov S.S., Saidov Sh.A. Efficacy of modified hemosorbents used for treatment of patients with multi-organ insufficiency// "The Academic Journal of Western Siberia", 2013. № 3 (46). Volume 9. P. 4446.
11. Kasymov Sh.Z., Davlatov S.S. Hemoperfusion as a method of homeostasis protection in multiple organ failure syndrome// «Academic Journal of Western Siberia», 2013. № 1. P. 31-32.
12. Khamdamov B.Z., Nuraliyev N.A. Pathogenetic approach in complex treatment of diabetic foot syndrome with critical lower limb ischemia //infection, 2020. T. 16. P. 18.
13. Khamdamov B.Z. Indicators of immunocitocine status in purulent-necrotic lesions of the lover extremities in patients with diabetes mellitus //American Journal of Medicine and Medical Sciences, 2020. T. 10. № 7. P. 473-478.
14. Kurbaniyazov Z.B., Rakhmanov K.E., Saidmuradov K.B., Davlatov S.S., RaxmatovaL.T. Surgical treatment of patients with intraoperative damages of the main cholic ducts// "Academic Journal of Western Siberia», 2013. № 1. P. 32.
15. Nabiev B.B., Khudoiberdiev D.K. Anatomy of the fetal organs of the human lymphoid system (literature review) // Achievements of Science and Education, 2020. № 16 (70). [in Russian].
16. Nazirov F.G., Kurbaniyazov Z.B., Davlatov S.S. Modified method of plasmapheresis in the treatment of patients with purulent cholangitis// European Sciences review Scientific journal, 2018. № 7-8. (July-August). P. 142-147.
17. Qurbonov N.A., Davlatov S.S., Rakhmanov K.E. & Zayniyev A.F. (2021). Current trends in the management of Mirizzi syndrome: A review of literature. Annals of the Romanian Society for Cell Biology, 25(4), 1927-1932. [Electronic Resource]. URL: www.scopus.com/ (date of access: 08.06.2021).
18. Rahmanov K., Davlatov S., Raxmatova L. Improvement of surgical treatment of intraoperative injuries of magistral bile duct // The 17th International medical congress of students and young scientists. Ternopol, April- 22-24, 2013. P. 89.
19. Rakhmanov K.E., Davlatov S.S. & Abduraxmanov D.Sh. (2021). Correction of albendazole disease after echinococcectomy of the liver. International Journal of Pharmaceutical Research, 13, 4044- 4049. doi:10.31838/ijpr/2021.13.01.596.
20. Raxmatova L.T., Rakhmanov K.E., Davlatov S.S. Improvement of surgical treatment of intraoperative injuries of magistral bile ducts// Collection of scientific works of students and young scientists of the All-Russian scientific-practical conference with international participation. Yaroslavl. April 24-26, 2013. P. 148.
21. Saydullaev Z.Y., Davlatov S.S., Murtazaev Z.I. & Rakhmanov K.E. (2021). Minimally invasive methods of treatment of patients with acute cholecystitis. Annals of the Romanian Society for Cell Biology. 25(4), 1956-1961. [Electronic Resource]. URL: www.scopus.com/ (date of access: 08.06.2021).
22. Shamsiyev A., Davlatov S. A differentiated approach to the treatment of patients with acute cholangitis// International Journal of Medical and Health Research Impact Factor: RJIF 5.54 Vol 3; Issue 11; November, 2017. P. 80-83.
23. Wang Y. et al. Role of the biliary microbiome in gallstone disease //Expert review of gastroenterology & hepatology, 2018. T. 12. № 12. P. 1193-1205.
