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Review
. 2024 Mar 26;25(7):3694.
doi: 10.3390/ijms25073694.

Underlying Mechanisms behind the Brain-Gut-Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

Júlia Pauli De Cól  1 , Enzo Pereira de Lima  1 , Fernanda Moris Pompeu  1 , Adriano Cressoni Araújo  1   2 , Ricardo de Alvares Goulart  2 , Marcelo Dib Bechara  1   2 , Lucas Fornari Laurindo  3 , Nahum Méndez-Sánchez  4   5 , Sandra Maria Barbalho  1   2   6
Affiliations
Review

Underlying Mechanisms behind the Brain-Gut-Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

Júlia Pauli De Cól et al. Int J Mol Sci. .

Abstract

Metabolic-associated fatty liver disease (MAFLD) includes several metabolic dysfunctions caused by dysregulation in the brain-gut-liver axis and, consequently, increases cardiovascular risks and fatty liver dysfunction. In MAFLD, type 2 diabetes mellitus, obesity, and metabolic syndrome are frequently present; these conditions are related to liver lipogenesis and systemic inflammation. This study aimed to review the connection between the brain-gut-liver axis and MAFLD. The inflammatory process, cellular alterations in hepatocytes and stellate cells, hypercaloric diet, and sedentarism aggravate the prognosis of patients with MAFLD. Thus, to understand the modulation of the physiopathology of MAFLD, it is necessary to include the organokines involved in this process (adipokines, myokines, osteokines, and hepatokines) and their clinical relevance to project future perspectives of this condition and bring to light new possibilities in therapeutic approaches. Adipokines are responsible for the activation of distinct cellular signaling in different tissues, such as insulin and pro-inflammatory cytokines, which is important for balancing substances to avoid MAFLD and its progression. Myokines improve the quantity and quality of adipose tissues, contributing to avoiding the development of MAFLD. Finally, hepatokines are decisive in improving or not improving the progression of this disease through the regulation of pro-inflammatory and anti-inflammatory organokines.

Keywords: MAFLD; brain–gut–liver axis; diabetes; dyslipidemia; insulin resistance; metabolic-associated fatty liver disease; obesity; organokines.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Differences between the diagnosis and definition of nonalcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) stem from environmental factors and genetics, which contribute to increased lipid deposition in liver tissue, leading to inflammation and oxidative stress. In NAFLD, the presence of steatosis is primarily related to genetics but not to other causes beyond insulin resistance. DM2: type 2 diabetes mellitus; ER: endoplasmic reticulum; FFAs: free fatty acids; HCC: hepatocellular carcinoma; MetS: metabolic syndrome; ROS: reactive oxygen species; TAG: triglycerides.
Figure 2
Figure 2
The complex interaction of the brain–gut–liver axis. In the figure, bidirectional communication pathways occur among the brain, gut, and liver. These pathways include endocrine, immune, and neurological connections. Microbiota can release tryptophan (Trp)/5-hydroxytryptamine, short-chain fatty acids (SCFAs), Noradrenalin (NA), and Gamma-aminobutyric acid (GABA), which have systemic actions. The hypothalamic–pituitary–adrenal (HPA) axis in the endocrine pathways can respond to the environment or endogenous stress, producing corticotropin-releasing hormone (CRH) and resulting in the release of cortisol. This stressor substance interferes with microbiome, neuronal, and physiological processes. In the immune pathways, the gut can interact with the brain through signaling biomarkers such as pro-cytokines, influencing neuroimmune responses. Microbiota products can modulate immune cells and regulate inflammation both locally and systemically. The liver is connected to the enteric system thanks to the portal vein and can liberate hepatokines, which also have systemic actions. The colored arrows only indicate the interrelationships between one organ/system and another.
Figure 3
Figure 3
The relationships of metabolic-associated fatty liver disease (MAFLD). Increased gut permeability triggers immune system activation and the release of pro-inflammatory cytokines that contribute to brain inflammation and the production of stressors, which is related to increased inflammation and oxidative stress in the liver. The products of the low-grade inflammation of adipose tissue aggravate this pro-inflammatory scenario, which contributes to systemic inflammation, leading to cognitive impairment. IL-6: Interleukin-6; ROS: reactive oxygen species; TNF-α: Tumor Necrosis Factor-α. The colored arrows only indicate the interrelationships between one organ/system and another.
Figure 4
Figure 4
Risk factors and the possibilities for treatment. Lifestyle modification (a change from a Western diet to healthier foods, the practice of physical exercise, and a reduction in body weight and waist circumference) associated with medicines such as Glucagon-like peptide-1 receptor agonists (GLP-1), sodium–glucose cotransporter-2 (SGLT2), pioglitazone, Sirtuins (SIRTs), and antioxidants such as vitamin E can reducerisk factors and can reduce inflammation, oxidative stress, lipid accumulation, steatosis, and cirrhosis.
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