Gut microbiota induces hepatic steatosis by modulating the T cells balance in high fructose diet mice

Abstract

Metabolic diseases are often associated with high fructose (HF) consumption. HF has also been found to alter the gut microbiota, which then favors the development of nonalcoholic fatty liver disease. However, the mechanisms underlying of the gut microbiota on this metabolic disturbance are yet to be determined. Thus, in this study, we further explored the effect the gut microbiota concerning the T cells balance in an HF diet mouse model. We fed mice 60% fructose-enriched diet for 12 weeks. At 4 weeks, HF diet did not affect the liver, but it caused injury to the intestine and adipose tissues. After 12 weeks, the lipid droplet aggregation was markedly increased in the liver of HF-fed mice. Further analysis of the gut microbial composition showed that HF decreased the Bacteroidetes/Firmicutes ratio and increased the levels of Blautia, Lachnoclostridium, and Oscillibacter. In addition, HF can increase the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in the serum. T helper type 1 cells were significantly increased, and regulatory T(Treg) cells were markedly decreased in the mesenteric lymph nodes of the HF-fed mice. Furthermore, fecal microbiota transplantation alleviates systemic metabolic disorder by maintaining liver and intestinal immune homeostasis. Overall, our data indicated that intestinal structure injury and intestinal inflammation might be early, and liver inflammation and hepatic steatosis may be a subsequent effect following HF diets. Gut microbiota disorders impairing the intestinal barrier function and triggering immune homeostasis imbalance may be an importantly responsible for long-term HF diets induced hepatic steatosis.

Wolfberry, Yam, and Chrysanthemum polysaccharides increased intestinal Akkermansia muciniphila abundance and hepatic YAP1 expression to alleviate DILI

“…ATB decreased intestinal A. muciniphila abundance in mice. Besides, ATB increased the content of IL‐6, a proinflammatory cytokine, 25 by 1.75‐fold and that of LBP, a marker of intestinal microbial leakage, 26 by 1.60‐fold, in the serum of mice. LPS, bound with LBP, is detected in the blood when the intestinal barrier is damaged 27 .…”

“…ATB decreased intestinal A. muciniphila abundance in mice. Besides, ATB increased the content of IL-6, a proinflammatory cytokine, 25 by 1.75-fold and that of LBP, a marker of intestinal microbial leakage, 26 The plating chart and counting histogram following A. muciniphila intervention in a medium containing wolfberry (L: 0.012 g/mL, M: 0.018 g/mL and H: 0.024 g/mL), yam (L: 0.03 g/mL, M: 0.045 g/mL and H: 0.06 g/ mL) or chrysanthemum (L: 0.01 g/mL, M: 0.015 g/mL, and H: 0.02 g/mL). (C) The orthogonal method was applied to explore the optimal concentration ratio of WYC to enhance A. muciniphila proliferation.…”

Mannose Supplementation Curbs Liver Steatosis and Fibrosis in Murine MASH by Inhibiting Fructose Metabolism

“…While the exact mechanisms are still being elucidated, key lipogenic regulator genes such as chREBP and SREBP1 are shown to be increased with fructose 45,46 ; future investigations into the effects of mannose on these targets and on lipidomic profiling would be of interest. Lastly, it has been shown that fructose can cause direct intestinal epithelial damage 47 and microbiome dysbiosis 48 , both of which result in gut inflammation via increased permeability, microbial/LPS translocation, and T cell modulation. These changes ultimately contribute to pathogenesis of MASLD.…”

Regulatory T cell: a double-edged sword from metabolic-dysfunction-associated steatohepatitis to hepatocellular carcinoma

“… Disease stages Role of Tregs Factors regulating Tregs Mouse/Human Treg quantity Type of Treg study Potential targets/Clinical insights Year/Ref. Cells interacting Liver Periphery Steatosis Preventing immune-mediated liver injury Anti-effector T cells – H → ↓ (Blood) In vivo – 2016 29 Hepatocytes Neutrophils γδT cells Th1 cells Th17 cells Anti-Th17 cells Ferroptosis M (SAM) ↑ ↑ In vivo Porphyromonas gingivalis 2023 46 Anti-Th1 cells Gut microbiota M (HFD) – ↓(MLN) In vivo Fecal microbiota transplantation 2023 47 Anti-effector T cells Gut microbiota M (HFD) ↓ ↓ (MLN) In vivo Administration of Lactobacillus 2019 48 Preventing inflammation Oxidative stress M (HFD) ↓ → (Spleen) In vivo & vitro Antioxidant 2007 33 Preventing insulin resistance Improving insulin tolerance Adiponectin M (HFD) – – In vivo Adiponectin-expressing Treg precursors 2021 49 Anti-insulin resistance ...…”

“…The unique visceral adipose tissue-resident Tregs are regulated by peroxisome proliferator-activated receptor (PPAR)-γ, 42 and can be upregulated by treating PPAR-γ agonist to attenuate MASLD in an HFD mouse model. 50 The suppressive function of Tregs on effector T cells plays a critical role in MASH, 47 , 48 , 52 , 54 , 55 and the equilibrium between Tregs and Th17 cells has long been regarded as an indicator to assess the degree of inflammation in the MASH liver. 46 , 53 Evidence has substantiated the role of Tregs in mitigating insulin resistance in mice and patients with MASLD, 49 , 50 , 51 , 57 thereby constraining the subsequent metabolic inflammation.…”