Introduction

Biliary adverse events manifest in approximately 25% of liver transplant recipients. Among these, anastomotic biliary strictures (ABS) are the most prevalent, occurring in approximately 6%‐12% of cases and can be successfully managed endoscopically.

Aims & Methods

Our study aims to present the evolution of method and long-term results of placing multiple plastic stents to treat ABS after orthotopic liver transplantation (OLT). All consecutive patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) for liver transplantation-related biliary complications at our Endoscopy Unit between July 1994 and September 2022 were retrospectively identified. The analysis focused only on the patients diagnosed with ABS undergoing dilatation by a progressively increasing number of plastic stents. Follow-up after stent removal was obtained by office visit, telephone contact with the patient or referring physician and extended to this year or until patient succumbed.

Results

Two hundred and ninety-five patients referred by 4 Liver Transplant Units underwent ERCP in need of endoscopic treatment for biliary complications after liver transplantation. However only 151 represented our intention-to-treat group with ABS. Out of these, 21 patients were excluded because of split liver transplantation, the use of metallic stents or incomplete endoscopic treatment. The mean age of the remaining 130 patients was 56 ± 9 years old and included 107 males and 23 females. We divided these patients in 2 groups according to similar timeframes, 28 ABS patients being treated before 2008 and 102 patients after 2008. In the first group the median number of stents was 4 (range 2-7), with a median of 3 ERCPs (range 2-5) per patient. Patients treated after 2008 received a median number of 6 stents (range 3-9) (p = .000, Mann-Whitney U), with a median of 4 ERCPs (range 3-7) (p = .002, Mann-Whitney U). The mean treatment duration was 15.3 ± 16.7 months in the first group and 14 ± 10 months in the second. Stricture recurrence was noted in 14.2% of patients treated before 2008 versus 4.9% after 2008. Nevertheless, the follow-up period was 10.6 ± 7.5 years for the first group and 4.7 ± 4 years in the second group.

Conclusion

The endoscopic treatment with multiple plastic stents proved to be effective for the majority of patients with ABS after OLT. In the last decade, the endoscopists shifted towards a more aggressive treatment strategy, with an increased number of stents and a reduced period between stent replacement procedures. This intensive approach seems also to underline a lower stricture recurrence rate however a longer follow-up period needs to be considered for the patients treated after 2008.

Introduction

Previous research indicate the contact system (CAS) is associated with ulcerative colitis (UC). The activation of coagulation factor XII leads to the activation of plasma kallikrein. Plasma kallikrein generates bradykinin and cleaved H-kininogen (cHK) by cleaving H-kininogen. Bradykinin induces inflammation. C1 inhibitor (C1-INH) is the most important regulator of CAS, while activated factor XII and plasma kallikrein are the accelerators. Interestingly, experimental colitis can be induced and alleviated in UC animal models by respectively activating and inhibiting CAS^1-3. Increased activity of CAS in plasma and colonic tissue was detected in patients with active disease^{4, 5}. Human studies are still limited. We, therefore, aimed to characterise CAS in patients with active UC by employing our unique panel of CAS assays.

Aims & Methods

We included adults with active UC at the Section of Gastroenterology, Esbjerg and Grindsted Hospital, Denmark from May 2021 to June 2023. Inclusion criteria were: Patient reported outcome 2 (PRO2) score ≥1, Mayo endoscopic subscore (MES) ≥1 and negative stool culture. The PRO2 considers stool frequency and passage of blood. Pregnancy and conditions influencing CAS or inflammation was prohibited. Patient were not allowed to use oral contraceptives, non-steroid anti-inflammatory drugs, systemic corticosteroids or anticoagulants. Controls were gender-matched blood donors recruited at the Unit for Thrombosis Research, Esbjerg and Grindsted Hospital, Denmark from 2019 to 2021. In- and exclusion criteria were the Danish blood donation criteria. We used the Montreal classification, MES, Nancy histological index, PRO2, CRP, and fecal calprotectin to describe the UC activity. Biochemical assays determined the kallikrein generation and plasma concentrations of coagulation factor XII, prekallikrein, H-kininogen, C1-INH and cHK (a surrogate marker of bradykinin generated by plasma kallikrein).

Results

We included 94 patients and 100 controls. Patients were primarily female (n=53) non-smokers (n=91) with a median age of 43 years and limited comorbidity (n=26). Half of the patients had proctitis. Patients displayed mild to moderate disease with medians: MES 2, Nancy histologic index 2, PRO2 4, CRP 2.5 mg/L and fecal calprotectin 515 mg/kg. Although, patients and controls generated similar amounts of plasma kallikrein, patients still had higher cHK levels in plasma than controls (1.38 [0.21-3.98] µg/mL vs 0.83 [0.02-2.88] µg/mL, p <0.0001). The same applied for C1-INH levels (0.22 [0.14-0.33] g/L vs 0.21 [0.16-0.29] g/L, p =0.0340). The remaining CAS components were similar in patients and controls. Nor, did CAS correlate to UC extension or severity. Interestingly, cHK remained higher even in patients displaying mild disease (see Table 1).

Conclusion

This is currently the largest study to profile CAS in patients with UC. By employing unique and novel assays, we can conclude that CAS contributes to active UC as verified by increased plasma levels of cHK and C1-INH in patients. Further, cHK might be useful as a serological marker for distinguishing patients with UC from healthy subjects.

References

1. Wang B, Yang A, Zhao Z, et al. The Plasma Kallikrein-Kininogen Pathway Is Critical in the Pathogenesis of Colitis in Mice. Front Immunol 2018;9:21.
2. Arai Y, Takanashi H, Kitagawa H, et al. Effect of icatibant, a bradykinin B2 receptor antagonist, on the development of experimental ulcerative colitis in mice. Dig Dis Sci 1999;44:845-51.
3. Lu F, Fernandes SM, Davis AE, 3rd. The role of the complement and contact systems in the dextran sulfate sodium-induced colitis model: the effect of C1 inhibitor in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2010;298:G878-83.
4. Stadnicki A, Gonciarz M, Niewiarowski TJ, et al. Activation of plasma contact and coagulation systems and neutrophils in the active phase of ulcerative colitis. Dig Dis Sci 1997;42:2356-66.
5. Stadnicki A, Pastucha E, Nowaczyk G, et al. Immunolocalization and expression of kinin B1R and B2R receptors in human inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2005;289:G361-6.

Disclosure

The authors have nothing to declare

Introduction

Liver cirrhosis (LC) is the end stage of liver fibrosis that leads to various critical conditions, including hepatic encephalopathy (HE). Although recent evidence indicates that liver fibrosis is reversible, there is no intervention to promote this recovery process to date. The gut microbiota is thought to be involved in the pathogenesis of LC and HE. Rifaximin (RFX), a nonabsorbable broad-spectrum antibiotic, is widely used for HE treatment. Although the efficacy of RFX for HE has been established, the underlying mechanism of the efficacy of RFX remains unclear, while this antibiotic is considered to affect the gut microbiome. Since the microbial compositions are different between anatomical sites in the gastrointestinal (GI) tract, we hypothesized that the effects of RFX on the gut microbiome can vary among GI sites. Hence, we conceived the present study investigating the impacts of RFX on the gut microbiome along the GI tract to clarify the mechanism of RFX as well as to explore the role of the gut microbiota in the pathophysiology of LC and HE.

Aims & Methods

To investigate the impact of RFX on the gut microbiota and clinical manifestations of LC, RFX was orally administered to a carbon tetrachloride (CCl₄)-induced LC murine model. Blood ammonia (NH₃) concentration, liver pathological findings, and endotoxin concentration in the portal vein were examined. In each GI site, bacterial loads using qPCR of the Tuf gene and the bacterial compositions with 16S rRNA gene amplicon sequencing were assessed. Shotgun metagenomic sequencing was performed for jejunal and ileal contents to analyze the functional pathways in the small intestinal microbiota. On the host side, the gene expressions of the intestinal mucosa were examined using qPCR. To explore the clinical efficacy of A. muciniphila as a microbial intervention, we orally administered A. muciniphila ATCC BAA-835 (AKK) to the CCl₄-induced LC murine model. The analyses described above for investigating the impacts of RFX were also performed for animals.

Results

RFX administration improved blood NH₃ concentration, liver fibrosis, and endotoxin concentration in the portal vein. The 16S rRNA gene amplicon sequencing analyses showed that the changes in the bacterial compositions were larger in the small intestine (jejunum and ileum) compared to the cecum, colon, and stool. The genus-level analysis of the small intestinal microbiota demonstrated that increases in Faecalibaculum, Akkermansia, and Muribaculaceae were associated with the improvement of liver fibrosis. Shotgun metagenomic sequencing showed that RFX administration altered the metabolic functions of the small intestinal microbiota. On the host side, the mRNA expression levels of tight junction proteins, antimicrobial peptides, and toll-like receptors in the small intestinal mucosa were altered by RFX administration. In the analyses of a microbial intervention, AKK administration improved liver fibrosis and blood NH₃ concentration. In addition, AKK administration significantly changed the small intestinal bacterial compositions in the murine LC model. The mRNA expression levels of tight junction proteins, antimicrobial peptides, and toll-like receptors in the small intestinal mucosa were altered by AKK administration.

Conclusion

This study demonstrated that the small intestinal microbiota was involved in the pathophysiology of LC and HE and proposed a new concept of “small intestine-liver axis” in LC and HE. The present study also suggests that oral administration of A. muciniphila is promising as a microbial intervention for these pathological conditions.

Disclosure

Mitsubishi Tanabe Pharma Corp., Takeda Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., AbbVie GK, EA Pharma Co., Ltd., Pfizer Japan Inc., Alfresa Pharma Corp., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Daiichi Sankyo CO., Ltd., JIMRO Co., Ltd.

Introduction

Dietary animal protein effect on gastric cancer (GC) taking Helicobacter pylori status into account has rarely been reported and has therefore been investigated in this study.

Aims & Methods

GC patients and healthy subjects were prospectively registered by 6 hospitals from October 2016 to December 2018. Multivariate analysis adjusted for many epidemiological factors (Model I) and additionally H. pylori (Model II) was conducted to investigate dietary protein effect on GC. Dietary animal protein groups included red meat, processed meat, white meat, eggs, and fishes.

Results

A total of 5,535 subjects (1,629 GCs) were enrolled. In Model I, red meat, fish, and eggs showed non-linear associations. Two serving/week for red meat, 1 serving/week for fish, 2-3 serving /week for egg was associated with the lowest risk of GC. Both low (aOR, 1.33) and high intake (aOR, 1.49) of red meat were associated with increased risk of GC. Both low (aOR, 1.76) and high intake (aOR, 1.74) of fish were associated with increased risk of GC. Both low (aOR, 3.07) and high intake (aOR, 1.33) of egg were associated with increased risk of GC. High intake of processed meat was associated with GC (adjusted odd ratio [aOR], 1.78; 95% CI, 1.27-2.49). Frequent intake of white meat was associated with GC risk (aOR, 1.67 for 1 serving/week, 2.15 for 2 servings/week, and 4.16 for ≥3 servings/week). In model II, these non-linear or positive association were sustained. Sub-analysis by sex showed similar association in both men and women.

Conclusion

Dietary animal proteins had non-linear or positive association with GC after adjusted for H. pylori. Nonlinear relationships of some food groups with GC suggests modest intake of such foods may reduce GC risk.

Disclosure

No COI