Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.

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Immunological mechanisms and therapeutic targets of fatty liver diseases

Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance

https://link.springer.com/content/pdf/10.1007/s11605-021-05188-7.pdf

The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases.

Background Intestinal dysbiosis has been shown to be associated with the pathogenesis of alcoholic liver disease (ALD), which includes changes in the microbiota composition and bacterial overgrowth, but an effective microbe-based therapy is lacking. Pediococcus pentosaceus (P. pentosaceus) CGMCC 7049 is a newly isolated strain of probiotic that has been shown to be resistant to ethanol and bile salts. However, further studies are needed to determine whether P. pentosaceus exerts a protective effect on ALD and to elucidate the potential mechanism. Aim To evaluate the protective effect of the probiotic P. pentosaceus on ethanol-induced liver injury in mice. Methods A new ethanol-resistant strain of P. pentosaceus CGMCC 7049 was isolated from healthy adults in our laboratory. The chronic plus binge model of experimental ALD was established to evaluate the protective effects. Twenty-eight C57BL/6 mice were randomly divided into three groups: The control group received a pair-fed control diet and oral gavage with sterile phosphate buffered saline, the EtOH group received a ten-day Lieber-DeCarli diet containing 5% ethanol and oral gavage with phosphate buffered saline, and the P. pentosaceus group received a 5% ethanol Lieber-DeCarli diet but was treated with P. pentosaceus. One dose of isocaloric maltose dextrin or ethanol was administered by oral gavage on day 11, and the mice were sacrificed nine hours later. Blood and tissue samples (liver and gut) were harvested to evaluate gut barrier function and liver injury-related parameters. Fresh cecal contents were collected, gas chromatography-mass spectrometry was used to measure short-chain fatty acid (SCFA) concentrations, and the microbiota composition was analyzed using 16S rRNA gene sequencing. Results The P. pentosaceus treatment improved ethanol-induced liver injury, with lower alanine aminotransferase, aspartate transaminase and triglyceride levels and decreased neutrophil infiltration. These changes were accompanied by decreased levels of endotoxin and inflammatory cytokines, including interleukin-5, tumor necrosis factor-α, granulocyte colony-stimulating factor, keratinocyte-derived protein chemokine, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. Ethanol feeding resulted in intestinal dysbiosis and gut barrier disruption, increased relative abundance of potentially pathogenic Escherichia and Staphylococcus, and the depletion of SCFA-producing bacteria, such as Prevotella, Faecalibacterium, and Clostridium. In contrast, P. pentosaceus administration increased the microbial diversity, restored the relative abundance of Lactobacillus, Pediococcus, Prevotella, Clostridium and Akkermansia and increased propionic acid and butyric acid production by modifying SCFA-producing bacteria. Furthermore, the levels of the tight junction protein ZO-1, mucin proteins (mucin [MUC]-1, MUC-2 and MUC-4) and the antimicrobial peptide Reg3β were increased after probiotic supplementation. Conclusion Based on these results, the new strain of P. pentosaceus alleviated ethanol-induced liver injury by reversing gut microbiota dysbiosis, regulating intestinal SCFA metabolism, improving intestinal barrier function, and reducing circulating levels of endotoxin and proinflammatory cytokines and chemokines. Thus, this strain is a potential probiotic treatment for ALD.

New strain of Pediococcus pentosaceus alleviates ethanol-induced liver injury by modulating the gut microbiota and short-chain fatty acid metabolism.

Over 650 million adults are obese (body mass index ≥ 30 kg/m2) worldwide. Obesity is commonly associated with several comorbidities, including cardiovascular disease and type II diabetes. However, compiled estimates suggest that from 5 to 40% of obese individuals do not experience metabolic or cardiovascular complications. The existence of the metabolically unhealthy obese (MUO) and the metabolically healthy obese (MHO) phenotypes suggests that underlying differences exist in both tissues and overall systemic function. Macrophage accumulation in white adipose tissue (AT) in obesity is typically associated with insulin resistance. However, as plastic cells, macrophages respond to stimuli in their microenvironments, altering their polarization between pro- and anti-inflammatory phenotypes, depending on the state of their surroundings. The dichotomous nature of MHO and MUO clinical phenotypes suggests that differences in white AT function dictate local inflammatory responses by driving changes in macrophage subtypes. As obesity requires extensive AT expansion, we posit that remodeling capacity with adipose expansion potentiates favorable macrophage profiles in MHO as compared with MUO individuals. In this review, we discuss how differences in adipogenesis, AT extracellular matrix deposition and breakdown, and AT angiogenesis perpetuate altered AT macrophage profiles in MUO compared with MHO. We discuss how non-autonomous effects of remote organ systems, including the liver, gastrointestinal tract, and cardiovascular system, interact with white adipose favorably in MHO. Preferential AT macrophage profiles in MHO stem from sustained AT function and improved overall fitness and systemic health.

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Adipose Tissue Macrophage Polarization in Healthy and Unhealthy Obesity

Fat and sweeteners contribute to obesity. However, it is unknown whether specific bacteria are selectively modified by different caloric and noncaloric sweeteners with or without a high-fat diet (HFD). Here, we combined extensive host phenotyping and shotgun metagenomics of the gut microbiota to investigate this question. We found that the type of sweetener and its combination with an HFD selectively modified the gut microbiota. Sucralose and steviol glycosides led to the lowest α-diversity of the gut microbiota. Sucralose increased the abundance of B. fragilis in particular, resulting in a decrease in the abundance of occludin and an increase in proinflammatory cytokines, glucose intolerance, fatty acid oxidation and ketone bodies. Sucrose+HFD showed the highest metabolic endotoxemia, weight gain, body fat, total short chain fatty acids (SCFAs), serum TNFα concentration and glucose intolerance. Consumption of sucralose or sucrose resulted in enrichment of the bacterial genes involved in the synthesis of LPS and SCFAs. Notably, brown sugar and honey were associated with the absence of metabolic endotoxemia, increases in bacterial gene diversity and anti-inflammatory markers such as IL-10 and sIgA, the maintenance of glucose tolerance and energy expenditure, similar to the control group, despite the consumption of an HFD. These findings indicate that the type of sweetener and an HFD selectively modify the gut microbiota, bacterial gene enrichment of metabolic pathways involved in LPS and SCFA synthesis, and metabolic endotoxemia associated with different metabolic profiles.

https://www.tandfonline.com/doi/pdf/10.1080/19490976.2020.1801301

The development of metabolic endotoxemia is dependent on the type of sweetener and the presence of saturated fat in the diet.

Alcohol overconsumption disrupts the gut microbiota and intestinal barrier, which decreases the production of beneficial microbial metabolic byproducts and allows for translocation of pathogenic bacterial-derived byproducts into the portal-hepatic circulation. As ethanol is known to damage liver sinusoidal endothelial cells (LSEC), here we evaluated dietary supplementation with a previously studied synbiotic on gut microbial composition, and hepatocyte and LSEC integrity in mice exposed to ethanol. We tested a chronic-binge ethanol feeding mouse model in which C57BL/6 female mice were fed ethanol (5% vol/vol) for 10 days and provided a single ethanol gavage (5 g/kg body weight) on day 11, 6 h before euthanasia. An ethanol-treatment group also received oral supplementation daily with a synbiotic; and an ethanol-control group received saline. Control mice were pair-fed and isocalorically substituted maltose dextran for ethanol over the entire exposure period; they received a saline gavage daily. Ethanol exposure decreased gut microbial abundance and diversity. This was linked with diminished expression of adherens junction proteins in hepatocytes and dysregulated expression of receptors for advanced glycation end-products; and this coincided with reduced expression of endothelial barrier proteins. Synbiotic supplementation mitigated these effects. These results demonstrate synbiotic supplementation, as a means to modulate ethanol-induced gut dysbiosis, is effective in attenuating injury to hepatocyte and liver endothelial barrier integrity, highlighting a link between the gut microbiome and early stages of acute liver injury in ethanol-exposed mice.

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Dietary Synbiotic Supplementation Protects Barrier Integrity of Hepatocytes and Liver Sinusoidal Endothelium in a Mouse Model of Chronic-Binge Ethanol Exposure.

Over the last 40 years, there has been a doubling in the prevalence of urinary stone disease (USD), representing a broad shift in public health. Nearly 80% of uroliths are comprised primarily of calcium oxalate. Oxalate, an organic acid commonly found in plant-based foods and produced endogenously as a terminal metabolite in the liver, is in part metabolized by bacteria in the gut. Remaining oxalate can be excreted as waste through the gastrointestinal or urinary tracts. In the urinary tract, oxalate can bind to calcium and aggregate into stones. Thus, to effectively prevent recurrent episodes of calcium oxalate stone formation, it is vital to understand how the intestinal microbiome maintains oxalate homeostasis and low levels of oxalate excretion. While much of the work has focused on the role of the intestinal bacterium, Oxalobacter formigenes, an oxalate-degrading specialist, recent metagenomic studies show that oxalate homeostasis is maintained more by a symbiotic community of bacteria rather than isolated species. Here we provide an overview of oxalate homeostasis by the intestinal microbiome, how this function can be disrupted, and its relevance for USD.

Aaron W. Miller

Papers

The development of metabolic endotoxemia is dependent on the type of sweetener and the presence of saturated fat in the diet.

Dietary Synbiotic Supplementation Protects Barrier Integrity of Hepatocytes and Liver Sinusoidal Endothelium in a Mouse Model of Chronic-Binge Ethanol Exposure.

The Role of the Intestinal Microbiome in Oxalate Homeostasis