Impact of Gut Recolonization on Liver Regeneration: Hepatic Matrisome Gene Expression after Partial Hepatectomy in Mice.

The hepatic matrisome is involved in the remodeling phase of liver regeneration. As the gut microbiota has been implicated in liver regeneration, we investigated its role in liver regeneration focusing on gene expression of the hepatic matrisome after partial hepatectomy (PHx) in germ-free (GF) mice, and in GF mice reconstituted with normal gut microbiota (XGF). Liver mass restoration, hepatocyte proliferation, and immune response were assessed following 70% PHx. Hepatic matrisome and collagen gene expression were also analyzed. Reduced liver weight/body weight ratio, mitotic count, and hepatocyte proliferative index at 72 h post PHx in GF mice were preceded by reduced expression of cytokine receptor genes Tnfrsf1a and Il6ra, and Hgf gene at 3 h post PHx. In XGF mice, these indices were significantly higher than in GF mice, and similar to that of control mice, indicating normal liver regeneration. Differentially expressed genes (DEGs) of the matrisome were lower in GF compared to XGF mice at both 3 h and 72 h post PHx. GF mice also demonstrated lower collagen expression, with significantly lower expression of Col1a1, Col1a2, Col5a1, and Col6a2 compared to WT mice at 72 h post PHx. In conclusion, enhanced liver regeneration and matrisome expression in XGF mice suggests that interaction of the gut microbiota and matrisome may play a significant role in the regulation of hepatic remodeling during the regenerative process.

Gut Microbiota Composition in Prediabetes and Newly Diagnosed Type 2 Diabetes: A Systematic Review of Observational Studies.

Evidence of gut microbiota involvement in regulating glucose metabolism and type 2 diabetes mellitus (T2DM) progression is accumulating. The understanding of microbial dysbiosis and specific alterations of gut microbiota composition that occur during the early stages of glucose intolerance, unperturbed by anti-diabetic medications, is especially essential. Hence, this systematic review was conducted to summarise the existing evidence related to microbiota composition and diversity in individuals with prediabetes (preDM) and individuals newly diagnosed with T2DM (newDM) in comparison to individuals with normal glucose tolerance (nonDM). A systematic search of the PubMed, MEDLINE and CINAHL databases were conducted from inception to February 2021 supplemented with manual searches of the list of references. The primary keywords of "type 2 diabetes", "prediabetes", "newly-diagnosed" and "gut microbiota" were used. Observational studies that conducted analysis of the gut microbiota of respondents with preDM and newDM were included. The quality of the studies was assessed using the modified Newcastle-Ottawa scale by independent reviewers. A total of 18 studies (5,489 participants) were included. Low gut microbial diversity was generally observed in preDM and newDM when compared to nonDM. Differences in gut microbiota composition between the disease groups and nonDM were inconsistent across the included studies. Four out of the 18 studies found increased abundance of phylum Firmicutes along with decreased abundance of Bacteroidetes in newDM. At the genus/species levels, decreased abundance of Faecalibacterium prausnitzii, Roseburia, Dialister, Flavonifractor, Alistipes, Haemophilus and Akkermansia muciniphila and increased abundance of Lactobacillus, Streptococcus, Escherichia, Veillonella and Collinsella were observed in the disease groups in at least two studies. Lactobacillus was also found to positively correlate with fasting plasma glucose (FPG), HbA1c and/or homeostatic assessment of insulin resistance (HOMA-IR) in four studies. This renders a need for further investigations on the species/strain-specific role of endogenously present Lactobacillus in glucose regulation mechanism and T2DM disease progression. Differences in dietary intake caused significant variation in specific bacterial abundances. More studies are needed to establish more consistent associations, between clinical biomarkers or dietary intake and specific gut bacterial composition in prediabetes and early T2DM.

Delayed liver regeneration in C3H/HeJ mice: possible involvement of haemodynamic and structural changes in the hepatic microcirculation.

NEW FINDINGS: What is the central question of this study? The liver regenerative process is complex and involves a sequence of signalling events, but the possible involvement of structural and haemodynamic changes in vivo during this process has never been explored. What is the main finding and its importance? Normal sinusoidal blood flow and velocity are crucial for a normal regenerative response, and delays in these haemodynamic events resulted in impaired liver regeneration in lipopolysaccharide-insensitive, C3H/HeJ mice. Toll-like receptor 4 signalling is required for restoration of normal liver architecture during the liver regenerative process. Liver regeneration is delayed in mice with a defective Toll-like receptor 4 (TLR4; C3H/HeJ mice) but is normal in TLR4 knockouts (TLR4-/- ). Here, we investigated the possible involvement of structural and haemodynamic changes in vivo in the underlying mechanism. In lipopolysaccharide-sensitive (C3H/HeN and C57BL/6) and lipopolysaccharide-insensitive (C3H/HeJ and TLR4-/- ) mice, a 70% partial hepatectomy (PH) was performed under inhalational anaesthesia. At days 3 and 7 after PH, the hepatic microcirculation was interrogated using intravital microscopy. Delayed liver regeneration was confirmed in C3H/HeJ, but not in C3H/HeN, C57BL/6 (WT) or TLR4-/- mice by liver weight-to-body-weight ratio, the percentage of proliferating cell nuclear antigen (PCNA)-positive cells and mitotic index data. At day 3 after PH, sinusoidal red blood cell velocity increased by 100% in C3H/HeN mice, but by only 40% in C3H/HeJ mice. Estimated sinusoidal blood flow was significantly higher at day 7 after PH in C3H/HeN than in C3H/HeJ mice. The hepatic cord width was significantly larger in C3H/HeN than in C3H/HeJ mice at day 3 and it was significantly larger in TLR4-/- than in C57BL/6 WT mice at day 7 after PH. Hepatocyte nucleus density and functional sinusoidal density was significantly reduced at days 3 and 7 after PH in all mouse strains compared with their zero-time controls. Functional sinusoidal density was significantly lower in C3H/HeJ compared with C3H/HeN mice at day 7 after PH. The present study indicates that altered sinusoidal blood flow and velocity in C3H/HeJ mice may contribute to the observed delay in the regenerative response in these mice. In addition, restoration of normal liver architecture may be delayed in TLR4-/- mice.

Protection by glycyrrhizin against warm ischemia-reperfusion-induced cellular injury and derangement of the microcirculatory blood flow in the rat liver.

BACKGROUND/AIM: The mechanism by which ischemia-reperfusion (I/R)-induced derangement of the hepatic microcirculation leads to tissue injury is not fully understood. We postulated that alterations to the hepatic microcirculation, including hemodynamic derangement and increased leukocyte-endothelium interaction, play a role, and that glycyrrhizin exerts its hepatoprotective effects, in part, by reducing these microcirculatory changes. MATERIALS AND METHODS: Wistar rats were subjected to 30-60 minutes segmental hepatic ischemia, followed by 120 minutes of reperfusion. Glycyrrhizin was administered prior to ischemia. Using intravital fluorescence microscopy, the administration of fluorescein isothiocyanate-conjugated erythrocytes allowed the measurement of erythrocyte-velocity (RBC(vel)), lobular, and sinusoidal perfusion. Bleb formation was observed by electron microscopy. Blood and tissue were taken for the assessment of liver injury. RESULTS: Glycyrrhizin reduced I/R-induced liver injury (histology, liver enzymes) and reduced hepatocyte apoptosis (TUNEL, caspase-3 activity). Glycyrrhizin inhibited hepatocyte bleb formation and reversed the I/R-induced reductions in lobular perfusion and RBC(vel). Leukocyte rolling and adherence in postsinusoidal venules and neutrophil infiltration were reduced by glycyrrhizin. I/R-induced elevation in HMGB1 was prevented by glycyrrhizin. CONCLUSIONS: Early bleb formation with deranged microcirculatory flow and leukocyte-endothelium interaction would appear to contribute to I/R-induced hepatocellular injury. Glycyrrhizin exerts its hepatoprotective effect by preventing these changes, in addition to a direct cellular effect.