Gut-Liver Axis in Liver Disease

유수종 ( Su Jong Yu ) 대한간학회 2021 간학회 싱글토픽 심포지움 Vol.2021 No.1

The gut-liver axis denotes the reciprocal interaction between the gut and gut microbiota, and the liver, resulting from the incorporation of signals generated by dietary, genetic and environmental factors. This bidirectional relationship is established by the portal vein which allows transport of gut-derived products directly to the liver, and the hepatic feedback route of bile and antibody secretion to the gut. The intestinal mucosal and vascular barrier is the anatomical and functional structure that serves as a field for the interactions between the gut and the liver, limiting the systemic dissemination of gut microbiota and toxins while permitting nutrients to access the circulation and to reach the liver. The control of commensal communities is crucial to maintaining homeostasis of the gut-liver axis, and as part of this reciprocal communication the liver shapes gut commensal communities. The gut-liver axis is widely participated in the pathogenesis of liver diseases, where it is increasingly the attention of clinical research. Alcohol disturbs the gut-liver axis at multiple interrelated levels, including the gut micro-biota, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the hepatic proinflammatory environment. Growing evidence shows the pathogenetic role of microbe-derived metabolites, such as secondary bile acids (BAs), trimethylamine, ethanol, and short-chain fatty acids, in the pathogenesis of non-alcoholic fatty liver disease. Liver cirrhosis by itself is linked with profound alterations in gut microbiota and damage at the different levels of defense of the intestinal barrier, including the epithelial, immune, and vascular barriers. The relevance of the severe disturbance of the intestinal barrier in liver cirrhosis has been linked to live bacterial translocation, bacterial infections and disease progression. Recent research has revealed the carcinogenic effects of small molecules including lipopolysaccharide (LPS), BAs, and lipoteichoic acid (LTA) produced by the gut microbiome that downregulate the immune system in the liver. LPS can activate Toll-like receptor (TLR) 4 to contribute to the pathogenesis of liver cancer. Secondary BAs regulate liver cancer via natural killer T (NKT) cells. A study by Ma et al. showed that gut microbiome composition in mice closely associates with liver cancer by influencing the immune system. This group provided evidence showing that changing commensal gut bacteria in mice affected the accumulation of hepatic C-X-C chemokine receptor type 6 (CXCR6)⁺ NKT cells through mediation of chemokine (C-X-C motif) ligand 16 (CXCL16) expression in liver sinusoidal endothelial cells. CXCL16 is the only ligand for the chemokine receptor CXCR6, which mediates NKT cell survival and accumulation in the liver. The accumulation of CXCR6 in hepatic NKT cells enhances the production of interferon-,upon antigen stimulation, which contributes to the inhibition of tumor growth. The accumulation of NKT cells is known to be mainly regulated by a type of Clostridium species that metabolizes primary BAs to secondary BAs because depletion of Clostridium by vancomycin increases hepatic NKT cells and colonization of C. scindens induces a rapid decrease in liver NKT cells. This evidence highlighted the significant contribution of the gut microbiome to regulating anti-tumor immunity in liver and hepatic cancers. LTA, a major constituent of the cell wall of gram-positive bacteria, has also been shown to accumulate in the livers of high-fat diet (HFD)-fed mice in the presence of DMBA (7,12- dimethylbenz(a)anthracene, a chemical carcinogen) that can give rise to HCC. Both deoxycholic acid and LTA cooperatively induce the senescence-associated secretory phenotype (SASP) of hepatic stellate cells to produce various inflammatory and pro-tumorigenic factors, including interleukin-6, growth-regulated oncogene-alpha, CXCL9, and prostaglandin E2 (PGE2), leading to a tumorigenic microenvironment that promotes liver cancer development in mice. The identification of the factors of the gut-liver axis primarily injured in each chronic liver disease provides possibilities for intervention. Beyond antibiotics, upcoming therapies centered on the gut include new generations of probiotics, postbiotics (bacterial metabo-lites), fecal microbial transplantation, and carbon nanoparticles. Farnesoid X receptor-agonists target both the gut and the liver and are presently being tested in various liver diseases. Finally, phages, synthetic biotic medicines that target specific bacteria or treatments that create physical barriers between the gut and the liver offer new therapeutic strategies. Considering these approaches, the armamentarium for targeting the gut-liver axis will keep expanding. Further clinical trials, translated from our up-to-date knowledge of the gut-liver axis, promise a thrilling future in the treatment of liver diseases.

한국인 비알코올성 지방간 질환 환자에서 P2/MS 및 기타 비침습적 섬유화 지표의 유효성

유수종 ( Su Jong Yu ),김동희 ( Dong Hee Kim ),이정훈 ( Jeong Hoon Lee ),정고은 ( Goh Eun Chung ),임정윤 ( Jeong Yoon Yim ),박민정 ( Min Jung Park ),김윤준 ( Yoon Jun Kim ),윤정환 ( Jung Hwan Yoon ),장자준 ( Ja June Jang ),이효석 ( 대한소화기학회 2011 대한소화기학회지 Vol.57 No.1

Background/Aims: P2/MS is a noninvasive marker for detecting hepatic fibrosis in patients with viral hepatitis. However, the applicability of P2/MS in patients with nonalcoholic fatty liver disease (NAFLD) has not yet been validated. This study aimed to validate P2/MS and compare it to other noninvasive fibrosis scoring systems in Korean patients with NAFLD. Methods: Consecutive patients who underwent liver biopsy between January 2002 and December 2009 at Seoul National University Hospital, Seoul, Korea were enrolled in this study. Fibrosis stage was determined using the METAVIR scoring system. Results: A total of 235 patients were included in the study: advanced fibrosis (METAVIR F3-F4) was present in 7 patients. No patient was over-staged among 162 patients with a P2/MS score above the high cut-off (95), resulting in a high negative predictive value (NPV) of 100% (95% confidence interval, 97.1-100). There was no significant difference between the area under the receiver-operating characteristic curve (AUROC) of the FIB-4 (0.964) and the AUROC of the NAFLD fibrosis score (0.964) or P2/MS (0.940) for detecting advanced fibrosis. If P2/MS was implemented in the Korean patients with NAFLD, 68.9% of liver biopsies might be avoided. Conclusions: P2/MS has a high NPV for excluding advanced fibrosis in Korean patients with NAFLD, and can reduce the burden of liver biopsy in the majority of cases. Since there were few patients with advanced fibrosis, further studies are warranted in a cohort including more patients with advanced fibrosis to validate the low cut-off value. (Korean J Gastroenterol 2011;57:19-27)

복부 방선균증이 동반된 크론병 1예

유수종 ( Su Jong Yu ),안동원 ( Dong Won Ahn ),송호준 ( Ho June Song ),김상균 ( Sang Gyun Kim ),김주성 ( Joo Sung Kim ),정현채 ( Hyun Chae Jung ),송인성 ( In Sung Song ) 대한내과학회 2006 대한내과학회지 Vol.70 No.6

The clinical features of abdominal actinomycosis are nonspecific and commonly confused with a neoplasm. Although any condition that allows the agents of actinomycosis to breach the gastrointestinal mucosa has the potential to be complicated by this infecti 복통, 종괴, 누공 및 공동과 같은 복부 방선균증의 임상 양상은 위장관을 침범한 경우 비특이적이며, 크론병과 같은 염증성 장질환과 유사한 경과를 밟아 감별 진단에 어려움을 겪을 수 있다. 복부 방선균증은 주로 복부수술이나 외상과 관련하여 발생하며 거대세포바이러스에 의한 궤양 점막 병변 등이 선행질환이 될 수 있으나, 크론병에 합병된 복부 방선균증은 매우 드문 것으로 알려져 있다. 본 증례는 크론병에 동반된 복부 방선균증의 사례로서 복부 방선균증과 크론병을

만성 B형 간염의 자연 경과 중 연령에 따른 e항원의 혈청 음전율의 비교

최문선 ( Mun Sun Choi ),이정훈 ( Jeong-hoon Lee ),박진명 ( Jin Myung Park ),유수종 ( Su Jong Yu ),김윤준 ( Yoon Jun Kim ),윤정환 ( Jung-hwan Yoon ),김정룡 ( Chung Yong Kim ),이효석 ( Hyo-suk Lee ) 국군의무사령부 2013 대한군진의학학술지 Vol.44 No.1

Objectives: Persistence of hepatitis B virus (HBV) e antigen (HBeAg) in chronic hepatitis B (CHB) is known to be associated with increased risk for cirrhosis and hepaticelluar carcinoma. In this study we aimed to evaluate HBeAgseroconversion rate in recent years according to age groups. Methods: This study included CHB patients who visited or admitted at Armed Force Capital Hospital (Sungnam, Korea) from July 2007 to June 2010. Patients who underwent antiviral therapy were excluded. Results: Of total 853 patients, 716 patients who met inclusion criteria were analyzed. The mean age was 27.0 years (range, 1871) and 708 patients (98.9%) were male. 548 patients (76.5%) were under 30 years of age. HBeAgseroconversion rate was 39.5% (81 of 205) in teenagers, 40.6% (142 of 350) in twenties, 65.7% (23 of 35) in thirties, 75.7% (56 of 74) in forties, and 75.0% (39 of 52) in over fifties. Among 135 HBeAg-negative CHB patients whose HBV DNA level data were available and age were < 40, 102 patients (75.6%) were in inactive carrier phase (HBV DNA<2,000 IU/mL). Ultrasonography showed that one patient (0.7 %) in inactive carrier phase developed liver cirrhosis. Conclusion: This study indicates that median age of HBeAgseroconversion is younger in recent years as compared to the past. Thus, further studies regarding the cause of earlier HBeAgseroconversion and the effect of earlier seroconversion on long-term prognosis of CHB patients might be warranted.

증례 : 소화기 ; 오른쪽 첫 번째 중족골로 전이된 간세포암 1예

진은효 ( Eun Hyo Jin ),이명진 ( Myung Jin Lee ),정광현 ( Kwang Hyun Chung ),조유리 ( Yu Ri Cho ),유수종 ( Su Jong Yu ),문경철 ( Kyung Chul Moon ),이효석 ( Hyo Suk Lee ) 대한내과학회 2013 대한내과학회지 Vol.84 No.1

간세포암이 사지 말단으로 전이되는 경우는 매우 드물며, 병변이 양성 종양이나 감염증과 비슷한 양상으로 오진되기도 한다. 일반적으로 악성 종양이 손, 발과 같은 말단 부위로 전이되는 경우는 드물며, 더욱이 간세포암이 발의 말단으로 전이된 증례는 보고된 바 없다. 본 연구자 등은 간세포암이 첫 번째 중족골에 국한된 종괴의 형태로 발견되어 수술 및 조직검사를 통해 간세포암의 뼈전이로 확진된 매우 드문 증례를 경험하였기에 보고하는 바이다. Metastases from hepatocellular carcinoma to the bones of the hands or feet are rare. They are usually a late manifestation of a disseminated tumor but may also be the primary manifestation of an occult cancer. Clinically, the metastasis may mimic benign tumors or non-neoplastic osteoarthritic conditions; thus, resulting in misdiagnosis and improper treatment. We report a case of acrometastasis to the right first metatarsal bone in a 70-year-old man with hepatocellular carcinoma. (Korean J Med 2013;84:81-84)

간 절제술 후 반복적인 복막 재발을 보인 간세포암종 환자에서 수술 절제로 완치된 1예

이효영 ( Hyo Young Lee ),이정훈 ( Jeong-hoon Lee ),남준열 ( Joon Yeul Nam ),장영 ( Young Chang ),조혜기 ( Hyeki Cho ),조영윤 ( Young Youn Cho ),조은주 ( Eun Ju Cho ),유수종 ( Su Jong Yu ),김윤준 ( Yoon Jun Kim ),윤정환 ( Jung-hwa 대한간암학회 2017 대한간암학회지 Vol.17 No.2

Recurrence of hepatocellular carcinoma (HCC) after hepatic resection is quite common. Peritoneal recurrence has been considered incurable status and related to poor prognosis. Although peritoneal metastasectomy is a therapeutic option for some selected patients with a few peritoneal metastasis, the indication and therapeutic effect has not been clear. We report a case of a 61-year-old man achieving complete remission of recurrent peritoneal metastasis after repeated surgical resection by a multidisciplinary approach. Peritoneal metastasectomy might be a therapeutic option for selected patients with localized oligonodular peritoneal metastasis. (J Liver Cancer 2017;17:153-157)

복부 방선균증의 임상 양상 및 치료에 대한 반응

김지원 ( Ji Won Kim ),정지봉 ( Ji Bong Jeong ),정용진 ( Yong Jin Jung ),김병관 ( Byung Kwan Kim ),이국래 ( Kook Lae Lee ),유수종 ( Su Jong Yu ),김미나 ( Mi Na Kim ),김주성 ( Joo Sung Kim ),정현채 ( Hyun Chae Jung ),송인성 ( In Sun 대한장연구학회 2007 Intestinal Research Vol.5 No.2

Background/Aims: Abdominal actinomycosis is a rare entity and difficult to differentiate from a malignant neoplasm. A study of clinical features and therapeutic responses will contribute to the understanding of this disease. Methods: We analyzed the clinical features and therapeutic responses of 12 cases of abdominal actinomycosis from 1989 to 2007. Results: The male to female ratio of patients was 1:1, and the patients had a median age of 50 years (range 38-60 years). Abdominal pain was the most common symptom, and seven of twelve patients had a history of abdominal surgery, trauma, DM or IUD (intrauterine device) use. An abdominal CT examination revealed infiltrative lesions with disruption of the tissue plane in eight cases, and colonoscopic findings showed luminal stenosis, nodular lesions and ulceration in four cases. Surgical resection was performed in eleven cases with a right hemicolectomy with or without a salpingo-ooporectomy, a left hemicolectomy or mass excision. Of the eleven patients who underwent surgical resection, seven patients received intravenous penicillin G (10-15×106 U) followed by administration of oral antibiotics for a median 8 months (range 4-12 months) according to the presence of symptoms and signs. Conclusions: With combined adequate surgical resection and high-dose antibiotic therapy, the therapeutic responses are favorable in most of the abdominal actinomycosis patients. (Intest Res 2007;5:177-183)