Faecal cytokine profiling as a marker of intestinal inflammation in acutely decompensated cirrhosis

Abstract

Background & Aims: Gut dysbiosis and inflammation perpetuate loss of gut barrier integrity (GBI) and pathological bacterial translocation (BT) in cirrhosis, contributing to infection risk. Little is known about gut inflammation in cirrhosis and how this differs in acute decompensation (AD). We developed a novel approach to characterise intestinal immunopathology by quantifying faecal cytokines (FCs) and GBI markers. Methods: Faeces and plasma were obtained from patients with stable cirrhosis (SC; n = 16), AD (n = 47), and healthy controls (HCs; n = 31). A panel of 15 cytokines and GBI markers, including intestinal fatty-acid-binding protein-2 (FABP2), D-lactate, and faecal calprotectin (FCAL), were quantified by electrochemiluminescence/ELISA. Correlations between analytes and clinical metadata with univariate and multivariate analyses were performed. Results: Faecal (F) IL-1b, interferon gamma, tumour necrosis factor alpha, IL-21, IL-17A/F, and IL-22 were significantly elevated in AD vs. SC (q <0.01). F-IL-23 was significantly elevated in AD vs. HC (p = 0.0007). FABP2/D-lactate were significantly increased in faeces in AD vs. SC and AD vs. HC (p <0.0001) and in plasma (p = 0.0004; p = 0.011). F-FABP2 correlated most strongly with disease severity (Spearman's rho: Child-Pugh 0.466; p <0.0001; model for end-stage liver disease 0.488; p <0.0001). FCAL correlated with plasma IL-21, IL-1b, and IL-17F only and none of the faecal analytes. F-cytokines and F-GBI markers were more accurate than plasma in discriminating AD from SC. Conclusions: FC profiling represents an innovative approach to investigating the localised intestinal cytokine microenvironment in cirrhosis. These data reveal that AD is associated with a highly inflamed and permeable gut barrier. FC profiles are very different from the classical innate-like features of systemic inflammation. There is non-specific upregulation of T H 1/T H 17 effector cytokines and those known to mediate intestinal barrier damage. This prevents mucosal healing in AD and further propagates BT and systemic inflammation.

Soluble TIM3 and Its Ligands Galectin-9 and CEACAM1 Are in Disequilibrium During Alcohol-Related Liver Disease and Promote Impairment of Anti-bacterial Immunity

“…As expected, plasma concentrations of both D -lactate and soluble-CD163, two surrogate markers of gut permeability and bacterial translocation, (i) were significantly higher in ALD patients (SAH > ARC) compared to HC ( Figure 3B ) reconfirming our previous findings ( Markwick et al, 2015 ; Riva et al, 2018 , 2020 ), and (ii) were strongly correlated with clinical indices of disease severity (Child-Pugh score, MELD score, bilirubin) ( Figure 3C and Supplementary Table 6 ). D -lactate was also positively correlated with total leukocyte, neutrophil and monocyte counts, and with all the cytokine measurements ( Figure 3C and Supplementary Table 6 ).…”

SARS-CoV-2-specific IgA and limited inflammatory cytokines are present in the stool of select patients with acute COVID-19

“…The detection of SARS-CoV-2 genome in the stool of multiple donors and the inverse association with fecal consistency led us to investigate if viral infection was causing intestinal inflammation associated with diarrhea among this cohort. Cytokines can be measured in fecal samples, and this method has been used as a sensitive and non-invasive way to monitor intestinal immune responses in inflammatory disease and during enteric infection [25-31]. In particular, fecal levels of IL-6, IL-8 and IL-1β are elevated in the context of acute bacterial or viral gastroenteritis and ulcerative colitis [28, 29].…”

Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations

“…In cirrhosis, SBP is a major precipitating factor initiates gut-liver axis dysfunction. It is mainly due to the fact that intestinal microbiota dysbiosis, bacterial overgrowth and bacterial translocation [4], which originates intestinal mucosal dysfunction and damage at the systemic immune cell functions [50]. Moreover, inflammation and oxidative stress are other contributing factors that can influence the barrier function of both the small and the large intestine and probably result in the occurrence of SBP in cirrhosis.…”

“…The intestinal barrier consists of several layers, including mucus layer, intestinal epithelial cells, lamina propria and Peyer's patches. They determine the extent to which gut microbes and their products (endotoxin) can access the host vasculature [4].…”