Äîñë³äæåííÿ ì³êðîá³îìó êèøê³âíèêà (ÌÊ), à òàêîæ ïîãëèáëåííÿ óÿâëåíü ïðî ïàòîãåíåç òà ìîæëèâîñò³ êîðåêö³¿ íåàëêîãîëüíî¿ æèðîâî¿ õâîðîáè ïå÷³íêè º ïðîâ³äíèìè íàïðÿìêàìè ñâ³òîâî¿ ãàñòðîåíòåðîëî㳿 îñòàíí³õ 3-5 ðîê³â. Çíà÷åííÿ ÌÊ ó ïàòîãåíåç³ ïîçàêèøêîâèõ çàõâîðþâàòü ïîãëèáëþºòüñÿ øâèäêèìè òåìïàìè. Çâè÷àéíî, òåîðåòè÷í³ çíàõ³äêè çàâæäè ñëóãóþòü ï³ä´ðóíòÿì äëÿ íàñòóïíèõ òåðàïåâòè÷íèõ ³íòåðâåíö³é.
Òîìó ìåòîþ íàøî¿ ðîáîòè áóâ ì³í³-îãëÿä ë³òåðàòóðè, ïðèñâÿ÷åíèé çì³íàì ó ÌÊ ïðè àóòî³ìóííèõ õîëåñòàòè÷íèõ çàõâîðþâàííÿõ ïå÷³íêè, ìîæëèâèì ïåðñïåêòèâàì êë³í³÷íîãî âïëèâó íà ÌÊ ç ìåòîþ îïòèì³çàö³¿ ÿê êèøêîâîãî òðàâëåííÿ, òàê ³ ìîæëèâèõ ïîçèòèâíèõ çì³í â ïåðåá³ç³ õðîí³÷íèõ çàõâîðþâàíü ïå÷³íêè. Ó ÿêîñò³ ³ëþñòðàö³¿ áóäå íàâåäåíî ïðèêëàä ç âëàñíî¿ êë³í³÷íî¿ ïðàêòèêè.
Çì³íè ÌÊ ó ïàö³ºíò³â ç çàõâîðþâàííÿìè ïå÷³íêè ìàþòü áàãàòîêîìïîíåíòíèé ð³çíîñïðÿìîâàíî-ïîâ'ÿçàíèé õàðàêòåð, àëå, ó ñïðîùåíîìó âèãëÿä³, ¿õ ìîæíà ðîçãëÿäàòè íàñòóïíèì ÷èíîì: 1) äèñá³îç êèøê³âíèêà ñïðèÿº ïðîäóêö³¿ ë³ïîïîë³ñàõàðèä³â òà ïðîçàïàëüíèõ öèòîê³í³â ³ õåìîê³í³â, ÿê³, âñìîêòóþ÷èñü ñëèçîâîþ îáîëîíêîþ êèøê³âíèêà, ë³ìôîâåíîçíèì øëÿõîì äîñÿãàþòü ïå÷³íêè é ³íäóêóþòü/ï³äòðèìóþòü çàïàëåííÿ ÿê ïàðåíõ³ìè, òàê ³ æîâ÷íîâèâ³äíèõ øëÿõ³â [1-5], 2) çì³íà ÿê³ñíîãî ³ ê³ëüê³ñíîãî ñêëàäó æîâ÷³ ïðè ð³çíèõ õðîí³÷íèõ çàõâîðþâàííÿõ ïå÷³íêè íåãàòèâíî âïëèâຠíà òðàâëåííÿ òà ôóíêö³îíàëüíèé/ ÿê³ñíèé ñêëàä ÌÊ. Îñòàííº âàæêî äîâåñòè ÿê ³çîëüîâàíó ã³ïîòåçó, òîìó ùî õàð÷îâî-òîêñè÷í³ àáî ìåäèêàìåíòîçí³ âïëèâè íà ñêëàä æîâ÷³ îäíî÷àñíî áåçïîñåðåäíüî âïëèâàþòü íà ñòàí ÌÊ, íàïðèêëàä, êîëè ÌÊ çì³íþºòüñÿ ï³ñëÿ êóðñîâîãî ïðèçíà÷åííÿ óðñîäåçîêñèõîëåâî¿ êèñëîòè (ÓÄÕÊ) [6] ÷è õîëåñòèðàì³íó [7].
Ïåðåõîäÿ÷è äî õðîí³÷íèõ àóòî³ìóííèõ õîëåñòàòè÷íèõ çàõâîðþâàíü, à ñàìå, ïåðâèííîãî ñêëåðîçóþ÷îãî õîëàíã³òó (ÏÑÕ) òà ïåðâèííîãî á³ë³àðíîãî õîëàíã³òó (ÏÁÕ, ðàí³øå âèêîðèñòîâóâàâñÿ òåðì³í ïåðâèííèé á³ë³àðíèé öèðîç), âàðòî çàçíà÷èòè, ùî âñ³ àâòîðè àêöåíòóþòü óâàãó íà çìåíøåííÿ àëüôà- ð³çíîìàí³òòÿ ó ïàö³ºíò³â ç ÏÁÕ ç³ çá³ëüøåííÿì ðîä³â Weisella [8] ÷è Veillonella, Haemophilus, Streptococcus [9]. Ó ïàö³ºíò³â ç ÏÑÕ ñèòóàö³ÿ àíàëîã³÷íà – çìåíøåííÿ àëüôà-ð³çíîìàí³òòÿ ç³ çá³ëüøåííÿì àáî ñàïðîô³òíèõ, àáî óìîâíî-ïàòîãåííèõ ðîä³â, â çàëåæíîñò³ â³ä ãåîãðàô³¿ ïîïóëÿö³¿, ÿêà äîñë³äæóâàëàñü [10-12]. Êð³ì òîãî, äàâíî â³äîì³ àñîö³àö³¿ ÏÑÕ/ÏÂÕ ç çàïàëüíèì çàõâîðþâàííÿì êèøê³âíèêà ó êîíêðåòíîãî ïàö³ºíòà çíàõîäÿòü ï³äòâåðäæåííÿ íà ð³âí³ çì³íåíèõ ðåàêö³é ÌÊ íà ð³çí³ åíäî- òà åêçîãåíí³ ÷èííèêè [13].
Ïîçèòèâíèé âïëèâ ÓÄÕÊ íà ïåðåá³ã ÏÑÕ – çîëîòèé ñòàíäàðò. ßêùî ðîçãëÿíóòè ö³ ñàíîãåíí³ çì³íè ÓÄÕÊ ç áîêó ÌÊ, òî âèÿâëÿºòüñÿ, ùî çàô³êñîâàíà ÷àñòêîâà êîðåêö³ÿ ïàòîãåííîãî ÌÊ ó öèõ ïàö³ºíò³â [6,14]. Ùîäî àíòèá³îòèê³â: êèøêîâî-íåðîç÷èííèé ðèôàêñèì³í [15], íà â³äì³íí³ñòü â³ä ì³íîöèêë³íó [16], íå ïðîäåìîíñòðóâàâ ïîçèòèâíîãî âïëèâó íà á³îõ³ì³÷í³ ïîêàçíèêè ïîçèòèâ³çàö³¿ ïåðåá³ãó ÏÑÕ.
Êë³í³÷í³ äîñë³äæåííÿ, âèêîíàí³ á³ëüøå 10 ðîê³â òîìó, ç âèêîðèñòàííÿì âàíêîì³öèíó ó ïîºäíàíí³ ç ìåòðîí³äàçîëîì [17] ÷è ìåòðîí³äàçîëó ç ÓÄÕÊ [18] ó ïàö³ºíò³â íà ÏÁÕ ïðîäåìîíñòðóâàëè ïîçèòèâíó ëàáîðàòîðíó äèíàì³êó õîëåñòàçó, ùî, íåïðÿìî, ìîæå ñâ³ä÷èòè ïðî ïîçèòèâíèé âïëèâ ìîäèô³êàö³¿ ÌÊ íà ïåðåá³ã ÏÁÕ. Àíàëîã³÷í³ ïîçèòèâí³ çì³íè ó ö³º¿ æ êàòåãî𳿠ïàö³ºíò³â ïðîäåìîíñòðîâàí³ ï³ñëÿ òðàíñïëàíòàö³¿ ôåêàëüíî¿ ì³êðîá³îòè [19].
Ó ñòàòò³ áóäü-ÿêîãî îáñÿãó íåìîæëèâî ïðîàíàë³çóâàòè íàâ³òü 1% äàíèõ ùîäî îñîáëèâîñòåé ÌÊ ó ð³çíèõ ïîïóëÿö³ÿõ, ó ïàö³ºíò³â ç ð³çíîþ êèøêîâîþ òà ïîçàêèøêîâîþ ïàòîëî㳺þ. Ìîæó ñòâåðäæóâàòè, ùî ³ íà ñüîãîäí³øí³é äåíü ïðîäîâæóºòüñÿ ïåðâèííå íàêîïè÷åííÿ äàíèõ áåç äîâåäåíèõ çàãàëüíîâèçíàíèõ ìåõàí³çì³â âçàºìî䳿 ÌÊ ç ëþäèíîþ-ãîñïîäàðåì, ó òîìó ÷èñë³ ³ ïðè ÏÑÕ/ÏÁÕ. Äëÿ êë³í³öèñò³â º ãàðíà çâ³ñòêà – ê³ëüê³ñòü îáíàä³éëèâèõ ñïðîá êîðåêö³¿ ÌÊ ç ïðèö³ëîì íà ïîêðàùåííÿ ïåðåá³ãó ÏÑÕ/ÏÁÕ çðîñòຠ³, ìîæëèâî, â íàéáëèæ÷îìó ìàéáóòíüîìó ïðîòîêîëè áåí³ô³êàö³¿ ÌÊ áóäóòü ñêëàäîâîþ íàñòàíîâ ç êóðàö³¿ ïàö³ºíò³â ç àóòî³ìóííèìè õîëåñòàòè÷íèìè çàõâîðþâàííÿìè ïå÷³íêè.
Êë³í³÷íèé ïðèêëàä
Ïàö³ºíò Í.Ð.²., 1972 ð.í., çíàõîäèòüñÿ ï³ä ìî¿ì ë³êàðñüêèì íàãëÿäîì íà ïîñò³éíîìó àìáóëàòîðíîìó ë³êóâàíí³ ç ïðèâîäó: ÏÁÕ, ìåäèêàìåíòîçíî-êîìïåíñîâàíèé, ó ïîºäíàíí³ ç õâîðîáîþ Êðîíà ç ì³í³ìàëüíîþ àêòèâí³ñòþ.
Ïî÷àòîê õâîðîáè – ó 2017 ð., âåðèô³êàö³ÿ – ä³àãíîñòè÷íèé òèòð ÀÌÀ. Òîä³ æ ïî÷àòà òåðàï³ÿ ìåòèëïðåäí³çîëîíîì (ìåäðîë), ä³àïàçîí äîç - 6-12 ìã/äîáà, â çàëåæíîñò³ â³ä êë³í³÷íî¿ êàðòèíè, ð³âíÿ òðàíñàì³íàç, ãàììà-ãëóòàì³ëòðàíñôåðàçè òà ëóæíî¿ ôîñôàòàçè) + ÓÄÕÊ, ä³àïàçîí äîç – 500-1000 ìã/äîáà.
Ïåð³îäè÷íî, çà ïîêàçàìè ç áîêó ñóïóòí³õ çàõâîðþâàíü ÷è ñòàí³â (äèñê³íåç³ÿ æîâ÷íî-âèâ³äíèõ øëÿõ³â, ìàëüä³ãåñò³ÿ, ïðîô³ëàêòèêà ñòåðî¿ä-³íäóêîâàíî¿ ãàñòðîïàò³¿) ïàö³ºíò îòðèìóâàâ ïàíòîïðàçîë, êðåîí, ì³íåðàëüíó âîäó «Ïîëÿíà Êâàñîâà».
Ó ãðóäí³ 2020 ðîêó, ó çâ'ÿçêó ç ïîÿâîþ ïðîíîñ³â, âèêîíàíå äîñë³äæåííÿ ÌÊ ç íàñòóïíîþ êîðåêö³ºþ (ëåâîôëîêñàöèí 0,5 ïî 1 òàá â îá³ä, 10 äí³â + ìåòðîí³äàçîë 0,5 ïî 1 òàá 3 ðàçè íà äîáó, 10 äí³â).
Ó âåðåñí³ 2021 ðîêó, âèõîäÿ÷è ç òîãî, ùî ñõèëüí³ñòü äî ïðîíîñ³â çáåð³ãàëàñü, íå äèâëÿ÷èñü íà çàñòîñóâàííÿ ôåðìåíò³â (êðåîí) òà ïðîá³îòèê³â, çàï³äîçðåíà íàÿâí³ñòü ñóïóòíüî¿ õâîðîáè Êðîíà, ÿêà ï³äòâåðäæåíà âèñîêèì ð³âíåì êàëüïðîòåêòèíà â êàë³. ³ä ô³áðîêîëîíîñêîﳿ ïàö³ºíò â³äìîâèâñÿ, âðàõîâóþ÷è íà â³äñóòí³ñòü êðîâ³ â êàë³ – ÿ ³ íå íàïîëÿãàâ. Ïðèçíà÷åíèé ìåñàëàç³í (ïåíòàñà), äîáîâà äîçà ÿêîãî ïîñòóïîâî äîâåäåíà äî 3000 ìã/äîáà.
Ïðèçíà÷åííÿ ïåíòàñè íå äîçâîëèëî äîñÿãòè êîíòðîëþ çà ïðîíîñàìè (ïðîíîñè áóëè ïðèñóòí³ ùîäíÿ, 2-3 ðàçè íà äîáó), õî÷à ð³âåíü êàëüïðîòåêòèíó çìåíøèâñÿ äî âåðõíüî¿ ìåæ³ ðåôåðåíòíîãî çíà÷åííÿ.
Áåç ïîâòîðíîãî òèïóâàííÿ ì³êðîá³îìó êèøê³âíèêà áóâ ïðèçíà÷åíèé êóðñ ðèôàêñèì³íó (àëüôà-íîðì³êñ) ó äîç³ 0,8 ã/äîáà íà ïðîòÿç³ 12 ä³á ç íàñòóïíèì ïðîëîíãîâàíèì çàñòîñóâàííÿì ïðîá³îòèê³â ç ñàõàðîì³öåòàìè (ñïî÷àòêó îïåôåðà, à ïîò³ì ìåãàëàêò; ñóìàðíî - 3 ì³ñÿö³). Öå äîçâîëèëî äîñÿãòè êîíòðîëþ çà ïîºäíàíèì çàõâîðþâàííÿì ÏÁÕ + õâîðîáà Êðîíà ³, íàâ³òü, ïîâí³ñòþ â³äìîâèòèñü â³ä ìåäðîëó. Ïðè öüîìó, ð³âåíü òðàíñàì³íàç êðîâ³ òà êàëüïðîòåêòèíó â êàë³ íå âèõîäèâ çà ìåæ³ ðåôåðåíòíèõ çíà÷åíü íà ïðîòÿç³ òðüîõ ì³ñÿö³â ï³ñëÿ â³äì³íè ìåäðîëó. Íà ñüîãîäí³øí³é äåíü ó ïàö³ºíòà êîíòðîëüîâàíèé ïåðåá³ã ÏÁÕ ó ïîºäíàíí³ ç õâîðîáîþ Êðîíà äîñÿãàºòüñÿ ïðèéîìîì ÓÄÕÊ 500 ìã óâå÷åð³ òà ìåñàëàç³íó 1000 ìã 3 ðàçè íà äîáó, ùîäíÿ.
Ñïèñîê ë³òåðàòóðè
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2. Mafra D, Julie CL, Barros AF, et al. Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. Future Microbiol. 2014. Vol. 9. Issue 3. P. 399–410.
3. Schwenger KJP, Clermont-Dejean N., Allard JP. The role of the gut microbiome in chronic liver disease: the clinical evidence revised. JHEP Rep. 2019 Sep; 1(3): 214–226.
4. Macpherson AJ, Heikenwalder M, Ganal-Vonarburg SC. The Liver at the Nexus of Host-Microbial Interactions. Cell Host Microbe. 2016 Nov 9; 20(5): 561-571
5. Milosevic I, Vujovic A, Barac A, Djelic M, Korac M, Radovanovic SA, et al. Gut-Liver Axis, Gut Microbiota, and Its Modulation in the Management of Liver Diseases: A Review of the Literature. Int J Mol Sci. 2019 Jan 17; 20(2): 395.
6. Tang R, Wei Y, Li Y, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut; 2018; 67: 534-541.
7. Li B, Zhang J, Chen Y, Wang Q, Yan L, Wang R, et al. Alterations in Microbiota and Their Metabolites are Associated With Beneficial Effects of Bile Acid Sequestrant on Icteric Primary Biliary Cholangitis. Gut Microbes. 2021; 13:1946366.
8. Lammert C, Shin A, Xu H, Hemmerich C, O'Connell TM, Chalasani N. Short-Chain Fatty Acid and Fecal Microbiota Profiles are Linked to Fibrosis in Primary Biliary Cholangitis. FEMS Microbiol Lett (2021) 368(6): fnab038.
9. Liwinski T, Casar C, Ruehlemann MC, Bang C, Sebode M, Hohenester S, et al. A Disease-Specific Decline of the Relative Abundance of Bifidobacterium in Patients With Autoimmune Hepatitis. Aliment Pharmacol Ther. 2020, 51:1417–28.
10. Nakamoto N, Sasaki N, Aoki R, Miyamoto K, Suda W, Teratani T, et al. Gut Pathobionts Underlie Intestinal Barrier Dysfunction and Liver T Helper 17 Cell Immune Response in Primary Sclerosing Cholangitis. Nat Microbiol. 2019, 4:492–503.
11. Fukui H. Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far? Diseases. 2019, 7(4): 58.
12. Özdirik Burcin, Tobias Müller, Alexander Wree, Frank Tacke, and Michael Sigal. The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies. Int. J. Mol. Sci. 2021, 22(13), 6975.
13. Little R, Wine E, Kamath BM, Griffiths AM, Ricciuto A. Gut Microbiome in Primary Sclerosing Cholangitis: A Review. World J Gastroenterol. 2020, 26(21): 2768–80.
14. Han W, Huang C, Zhang Q, Tao S, Hu X, Xu J, et al. Alterations in Gut Microbiota and Elevated Serum Bilirubin in Primary Biliary Cholangitis Patients Treated With Ursodeoxycholic Acid. Eur J Clin Invest. 2022, 52: e13714.
15. Tabibian JH, Gossard A, El-Youssef M, Eaton JE, et al. Prospective Clinical Trial of Rifaximin Therapy for Patients with Primary Sclerosing Cholangitis. Am. J. Ther. 2017, 24, 56–63.
16. Silveira MG, Torok NJ, Gossard AA, Keach JC, et al. Minocycline in the treatment of patients with primary sclerosing cholangitis: Results of a pilot study. Am. J. Gastroenterol. 2009, 104, 83–88.
17. Tabibian JH, Weeding E, Jorgensen RA, Petz JL, Keach JC, Talwalkar JA, et al. Randomised Clinical Trial: Vancomycin or Metronidazole in Patients With Primary Sclerosing Cholangitis - A Pilot Study. Aliment Pharmacol Ther. 2013, 37(6):604–12.
18. Färkkilä M, Karvonen AL, Nurmi H, Nuutinen H, Taavitsainen M, et al. Metronidazole and Ursodeoxycholic Acid for Primary Sclerosing Cholangitis: A Randomized Placebo-Controlled Trial. Hepatology. 2004, 40(6):1379–86.
19. Allegretti JR, Kassam Z, Carrellas M, Mullish BH, Marchesi JR, Pechlivanis A, et al. Fecal Microbiota Transplantation in Patients With Primary Sclerosing Cholangitis: A Pilot Clinical Trial. Am J Gastroenterol. 2019, 114 (7): 1071–9.
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