The gut-liver axis in liver disease: Pathophysiological basis for therapy.

Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease. Emerging evidence indicates that these disorders are characterized by alterations in the intestinal microbiota composition and its metabolites, which translocate from the gut across a disrupted intestinal barrier to affect various metabolic organs, such as the liver and adipose tissue, thereby contributing to metabolic inflammation. Here, we discuss some of the recently identified mechanisms that showcase the role of the intestinal microbiota and barrier dysfunction in metabolic inflammation. We propose a concept by which the gut microbiota fuels metabolic inflammation and dysregulation. Here, the authors describe how metabolic disorders, such as type 2 diabetes and nonalcoholic fatty liver disease, are driven by alterations in the composition of the intestinal microbiota and its metabolites, which translocate from the gut across a disrupted intestinal barrier and contribute to metabolic inflammation.

The intestinal microbiota fuelling metabolic inflammation

EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update

The blood that flows perpetually through our veins and arteries performs numerous functions essential to our survival. Besides distributing oxygen, this vast circulatory system facilitates nutrient transport, deters infection and dispenses heat throughout our bodies. Since human blood has traditionally been considered to be an entirely sterile environment, comprising only blood-cells, platelets and plasma, the detection of microbes in blood was consistently interpreted as an indication of infection. However, although a contentious concept, evidence for the existence of a healthy human blood-microbiome is steadily accumulating. While the origins, identities and functions of these unanticipated micro-organisms remain to be elucidated, information on blood-borne microbial phylogeny is gradually increasing. Given recent advances in microbial-hematology, we review current literature concerning the composition and origin of the human blood-microbiome, focusing on bacteria and their role in the configuration of both the diseased and healthy human blood-microbiomes. Specifically, we explore the ways in which dysbiosis in the supposedly innocuous blood-borne bacterial microbiome may stimulate pathogenesis. In addition to exploring the relationship between blood-borne bacteria and the development of complex disorders, we also address the matter of contamination, citing the influence of contaminants on the interpretation of blood-derived microbial datasets and urging the routine analysis of laboratory controls to ascertain the taxonomic and metabolic characteristics of environmentally-derived contaminant-taxa.

/pdf/the-healthy-human-blood-microbiome-fact-or-fiction-3net53hep0.pdf

The Healthy Human Blood Microbiome: Fact or Fiction?

The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.

https://gut.bmj.com/content/gutjnl/69/6/1127.full.pdf

Albumin in decompensated cirrhosis: new concepts and perspectives

We read with interest the recent review by Tilg et al ,1 which summarised the role of microbiota in liver diseases and pointed out that a causal link with systemic inflammation has still not been established. This letter fills in this gap and provides an analysis of the circulating microbiota in portal vein as the link between gut and liver. The access to portal circulation is possible during the implantation of a transjugular intrahepatic portosystemic shunt (TIPS). Therefore, we characterised the circulating microbiome in portal vein (first venous outflow in gut–liver axis), liver outflow, central venous blood and peripheral venous blood from seven patients with decompensated liver cirrhosis receiving TIPS for either variceal bleeding (n=3) or refractory ascites (n=4) (mean Model for End-stage Liver Disease (MELD) 8.4 (range 6–13), Child-Pugh-Score (CHILD) A: n=4, CHILD B: n=3) (figure 1A). We performed 16S ribosomal RNA (rRNA) gene sequencing of buffy coat samples and identified 65 genera belonging to four phyla (predominantly Proteobacteria) in this cohort (online supplementary figure 1 and figure 1B). Blood microbiome phylum compositions identified in our …

/pdf/circulating-microbiome-in-blood-of-different-circulatory-awj33nxkm7.pdf

Circulating microbiome in blood of different circulatory compartments.

Increase in liver stiffness after transjugular intrahepatic portosystemic shunt is associated with inflammation and predicts mortality

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic β-cell destruction and hyperglycemia. While monocytes and NOD-like receptor family-pyrin domain containing 3 (NLRP3) are associated with T1D onset and development, the specific receptors and factors involved in NLRP3 inflammasome activation remain unknown. Herein, we evaluated the inflammatory state of resident peritoneal macrophages (PMs) from genetically modified non-obese diabetic (NOD), NLRP3-KO, wild-type (WT) mice and in peripheral blood mononuclear cells (PBMCs) from human T1D patients. We also assessed the effect of docosahexaenoic acid (DHA) on the inflammatory status. Macrophages from STZ-induced T1D mice exhibited increased inflammatory cytokine/chemokine levels, nitric oxide (NO) secretion, NLRP3 and iNOS protein levels, and augmented glycolytic activity compared to control animals. In PMs from NOD and STZ-induced T1D mice, DHA reduced NO production and attenuated the inflammatory state. Furthermore, iNOS and IL-1β protein expression levels and NO production were lower in the PMs from diabetic NLRP3-KO mice than from WT mice. We also observed increased IL-1β secretion in PBMCs from T1D patients and immortalized murine macrophages treated with advanced glycation end products and palmitic acid. The present study demonstrated that the resident PMs are in a proinflammatory state characterized by increased NLRP3/iNOS pathway-mediated NO production, up-regulated proinflammatory cytokine/chemokine receptor expression and altered glycolytic activity. Notably, ex vivo treatment with DHA reverted the diabetes-induced changes and attenuated the macrophage inflammatory state. It is plausible that DHA supplementation could be employed as adjuvant therapy for treating individuals with T1D.

Carl Christian Kolbe

Papers

Circulating microbiome in blood of different circulatory compartments.

Increase in liver stiffness after transjugular intrahepatic portosystemic shunt is associated with inflammation and predicts mortality

Macrophage inflammatory state in Type 1 diabetes: triggered by NLRP3/iNOS pathway and attenuated by docosahexaenoic acid.