Recent evidences have linked indole-3-acetic acid (IAA), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However, data supporting IAA-mediated protection against nonalcoholic fatty liver disease (NAFLD) from an in vivo study is lacking. In this study, we assessed the role of IAA in attenuating high-fat diet (HFD)-induced NAFLD in male C57BL/6 mice. Administration of IAA (50 mg/kg body weight) by intraperitoneal injection was found to alleviate HFD-induced elevation in fasting blood glucose and homeostasis model assessment of insulin resistance (HOMA-IR) index as well as plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), and glutamic-pyruvic transaminase (GPT) activity. Histological examination further presented the protective effect of IAA on liver damage induced by HFD feeding. HFD-induced an increase in liver total triglycerides and cholesterol, together with the upregulation of genes related to lipogenesis including sterol regulatory element binding-protein 1 (Srebf1), steraroyl coenzyme decarboxylase 1 (Scd1), peroxisome proliferator-activated receptor gamma (PPARγ), acetyl-CoA carboxylase 1 (Acaca), and glycerol-3-phosphate acyltransferase, mitochondrial (Gpam), which were mitigated by IAA treatment. The results of reactive oxygen species (ROS) and malonaldehyde (MDA) level along with superoxide dismutase (SOD) activity and glutathione (GSH) content in liver tissue evidenced the protection of IAA against HFD-induced oxidative stress. Additionally, IAA attenuated the inflammatory response of liver in mice exposed to HFD as shown by the reduction in the F4/80-positive macrophage infiltration and the expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α). In conclusion, our findings uncover that IAA alleviates HFD-induced hepatotoxicity in mice, which proves to be associated with the amelioration in insulin resistance, lipid metabolism, and oxidative and inflammatory stress.

Human gut microbiota has been increasingly recognized as a pivotal determinant of non-alcoholic fatty liver disease (NAFLD). Apart from the changes in the composition of gut microbiota, the components and metabolites derived from intestinal microbiota have emerged as key factors in modulating the pathological process of NAFLD. Compelling evidences have revealed that gut microbiota generates a variety of bioactive substances that interact with the host liver cells through the portal vein. These substances include the components derived from bacteria such as lipopolysaccharides, peptidoglycan, DNA, and extracellular vesicles, as well as the metabolites ranging from short-chain fatty acids, indole and its derivatives, trimethylamine, secondary bile acids, to carotenoids and phenolic compounds. The mechanisms underlying the hepatic responses to the bioactive substances from gut bacteria have been associated with the regulation of glycolipid metabolism, immune signaling response, and redox homeostasis. Illuminating the interplay between the unique factors produced from gut microbiome and the liver will provide a novel therapeutical target for NAFLD. The current review highlights the recent advances on the mechanisms by which the key ingredients and metabolites from gut microbiota modulate the development and progression of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is recognized as the most frequent classification of liver disease around the globe. Along with the sequencing technologies, gut microbiota has been regarded as a vital factor for the maintenance of human and animal health and the mediation of multiple diseases. The modulation of gut microbiota as a mechanism affecting the pathogenesis of NAFLD is becoming a growing area of concern. Recent advances in the communication between gut and hepatic tissue pave novel ways to better explain the molecular mechanisms regarding the pathological physiology of NAFLD. In this review, we recapitulate the current knowledge of the mechanisms correlated with the development and progression of NAFLD regulated by the gut microbiome and gut–liver axis, which may provide crucial therapeutic strategies for NAFLD. These mechanisms predominantly involve: (1) the alteration in gut microbiome profile; (2) the effects of components and metabolites from gut bacteria (e.g., lipopolysaccharides (LPS), trimethylamine-N-oxide (TMAO), and N,N,N-trimethyl-5-aminovaleric acid (TMAVA)); and (3) the impairment of intestinal barrier function and bile acid homeostasis. In particular, the prevention and therapy of NAFLD assisted by nutritional strategies are highlighted, including probiotics, functional oligosaccharides, dietary fibers, ω-3 polyunsaturated fatty acids, functional amino acids (L-tryptophan and L-glutamine), carotenoids, and polyphenols, based on the targets excavated from the gut–liver axis.

The cellular and molecular mechanisms by which indole-3-acetic acid (IAA), a tryptophan-derived metabolite from gut microbiota, attenuates inflammation and oxidative stress has not been fully elucidated. The present study was to unearth the protective effect and underlying mechanism of IAA against lipopolysaccharide (LPS)-induced inflammatory response and free radical generation in RAW264.7 macrophages. IAA significantly ameliorated LPS-induced expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) as well as generation of reactive oxidative species (ROS) and nitric oxide (NO). LPS-triggered nuclear translocation of nuclear factor kappa B (NF-κB) p65 was mitigated by IAA treatment. Further, an up-regulation of heme oxygenase-1 (HO-1) was observed in IAA-treated cells in dose-dependent manner under both normal and LPS-stimulated condition. Interference of HO-1 activity by tin protoporphyrin IX (SnPP) impeded the alleviative effects of IAA on expression of IL-1β and IL-6 induced by LPS, whereas demonstrated no effect on its suppression of ROS and NO production. This result suggests a HO-1-dependent anti-inflammatory effect of IAA and its direct scavenging action on free radicals. Treatment with CH-223191, a specific antagonist of aryl hydrocarbon receptor (AhR), showed no significant effects on the beneficial role of IAA against inflammation and free radical generation. In summary, our findings indicate that IAA alleviates LPS-elicited inflammatory response and free radical generation in RAW264.7 macrophages by induction of HO-1 and direct neutralization of free radicals, a mechanism independent of AhR.

Maternal undernutrition or overnutrition during pregnancy alters organ structure, impairs prenatal and neonatal growth and development, and reduces feed efficiency for lean tissue gains in pigs. These adverse effects may be carried over to the next generation or beyond. This phenomenon of the transgenerational impacts is known as fetal programming, which is mediated by stable and heritable alterations of gene expression through covalent modifications of DNA and histones without changes in DNA sequences (namely, epigenetics). The mechanisms responsible for the epigenetic regulation of protein expression and functions include chromatin remodeling; DNA methylation (occurring at the 5´-position of cytosine residues within CpG dinucleotides); and histone modifications (acetylation, methylation, phosphorylation, and ubiquitination). Like maternal malnutrition, undernutrition during the neonatal period also reduces growth performance and feed efficiency (weight gain:feed intake; also known as weight-gain efficiency) in postweaning pigs by 5–10%, thereby increasing the days necessary to reach the market body-weight. Supplementing functional amino acids (e.g., arginine and glutamine) and vitamins (e.g., folate) play a key role in activating the mammalian target of rapamycin signaling and regulating the provision of methyl donors for DNA and protein methylation. Therefore, these nutrients are beneficial for the dietary treatment of metabolic disorders in offspring with intrauterine growth restriction or neonatal malnutrition. The mechanism-based strategies hold great promise for the improvement of the efficiency of pork production and the sustainability of the global swine industry.