Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury

Abstract

Proton pump inhibitor or long-term antibiotics intake, which have been linked to intestinal dysbiosis, are associated with increased risk of acute liver failure in the 500,000 participants of the UK BioBank population-based cohort. In mice, APAP intoxication prompts intestinal dysbiosis, barrier impairment, and bacterial translocation. Dysbiotic microbiota of Nlrp6-/mice induces a Ly6C hi phenotype of hepatic monocyte-derived macrophages and amplifies acute liver injury, a phenotype that is transferable to WT mice by fecal microbiota transfer. BACKGROUND & AIMS: Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF. METHODS: To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK Bio-Bank population-based cohort. For functional studies, male Nlrp6-/mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF. RESULTS: Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3-3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6-/mice displayed exacerbated APAP-and LPS

Gut Microbiota and Chemical-Induced Acute Liver Injury

“…Similarly, compared with wild-type mice, Nlrp6 − /− mice (an intestinal dysbiosis model) also showed that microbial dysbiosis could aggravate APAP-induced liver injury. This phenotype was reproduced after fecal bacteria transplantation (Elinav et al, 2018 ; Schneider et al, 2020 ).…”

“…Schneider KM et al analyzed a cohort of 500,000 participants in the British Biobank and found that proton pump inhibitors (PPI) or long-term antibiotics (ABX) can cause intestinal microbial dysbiosis. The risk of ALF induced by APAP was significantly increased in participants with intestinal microbial dysbiosis (Schneider et al, 2020 ). Similarly, compared with wild-type mice, Nlrp6 − /− mice (an intestinal dysbiosis model) also showed that microbial dysbiosis could aggravate APAP-induced liver injury.…”

“…The oral gavage of APAP weakens the intestinal mucosal barrier function during intestinal absorption and allows plasma albumin to seep into the intestinal cavity. Similarly, a higher intestinal permeability can also allow abundant harmful substances to enter the liver, which aggravates the inflammatory reaction and the hepatotoxicity of APAP (Schneider et al, 2020 ). Niu et al confirmed that the disruption of the intestinal barrier integrity, which may be mediated by intestinal immune microenvironments, can aggravate APAP-induced hepatotoxicity (Niu et al, 2020 ).…”

The aryl hydrocarbon receptor in liver inflammation

“…In patients, alcoholic liver disease was associated with low levels of intestinal microbiota-derived tryptophan metabolites, underscoring the clinical impact of the AHR pathway in alcoholic liver disease [49]. Interestingly, the alteration in gut microbiota composition has also been implicated as a risk factor for exacerbated acetaminophen-induced acute liver injury [51]. Although here, the underlying molecular mechanisms were not focus of the study, it is likely that dysbiosis was accompanied with changes in gut bacteria-derived metabolites, including AHR ligands.…”

Subcellular spatio-temporal intravital kinetics of aflatoxin B1 and ochratoxin A in liver and kidney

“…However, even relatively advanced PBPK models consider individual organs as single compartments (Thiel et al 2015 ) or at most differentiate a limited number of compartments within one organ (Bartl et al 2015 ; Ghallab et al 2016 ; Schliess et al 2014 ). Relatively little is known about local concentrations in sub-compartments of tissues (Reif et al 2017 ; Schneider et al 2021 ; Schuran et al 2021 ). Experimentally, local distributions of test compounds in tissues can be analyzed by autoradiography (Groothuis et al 1982 ).…”