Table I.
Summary of studies on the underlying mechanisms of gut microbiota dysbiosis in NAFLD/NASH.
| Mechanism/first author (year) | Notable results | (Refs.) |
|---|---|---|
| Gut-liver axis | ||
| Zorn (2009) | The anatomical and biological functions of the intestine and liver are closely associated | (48) |
| Compare (2012) | The majority of blood supply to the liver is derived from the intestinal tract through the portal vein, and the transcription of various pro-inflammatory genes and cytokines in the liver is induced by the toxic substances entering the liver | (51) |
| Clemente (2016) | Change of gut microbes increases the exposure of the liver to pathogen-associated molecular patterns and activates the molecular mechanisms of the innate immune response, therefore contributing to the development of NAFLD | (50) |
| Poeta (2017) | Common origin of the gastrointestinal tract and liver from the ventral foregut endoderm, contributing to the definition of the gut-liver axis | (47) |
| Baffy (2018) | Gut microbiota dysbiosis increases the gut-derived bacterial products entering the liver and induces the proinflammatory response in the liver | (49) |
| SIBO | ||
| Rafiei (2018) | Bloating, dyspepsia, watery diarrhea and hepatic steatosis may all be | (52–54) |
| Sabate (2008) | symptoms of SIBO, which promotes NAFLD progression by increasing | |
| King (2004) | intestinal permeability and endotoxin absorption | |
| Wigg (2001) | SIBO increased endotoxin absorption, leading to the progression of NAFLD by | (55,57) |
| Boulange (2016) | raising TNF-α levels | |
| Ghoshal (2017) | Low-grade SIBO observed in NASH patients with the currently recognized gold standard method | (56) |
| Shanab (2011) | SIBO may have an important role in NASH by interacting with TLR-4 and inducing the expression of proinflammatory cytokine IL-8 | (58) |
| Fukunishi (2014) | SIBO is associated with endogenous ethanol production, which may impair | (59,60) |
| Ferolla (2014) | intestinal function and morphology, thereby leading to systemic inflammation and insulin resistance | |
| Microbial metabolites | ||
| D'Mello (2015) | The metabolites of the gut microbiota, including endotoxins, activate the | (61,62) |
| Mutlu (2009) | inflammatory response in the liver when they cannot be cleared by kuppfer cells | |
| Vrieze (2012) | Gut bacterial-derived endotoxins may interact with pattern recognition receptors, | (46,63) |
| Li (2016) | including TLRs, which are expressed in various cells in the liver, including macrophages and kuppfer cells | |
| Leavy (2015) | The complex formed by LPS and LBP binds with CD14 to activate the innate immune recognition system | (64) |
| Ruiz (2007) | Elevated serum LBP levels and TNF-α overexpression were observed in NAFLD and NASH patients, and the serum LBP levels and TNF-α expression were higher in NASH patients than in NAFLD patients | (65) |
| Liu (2014) | Activation of the TLR4 signaling pathway significantly increases the release of a series of inflammatory cytokines, including TNF-α, IL-1β, IL-6 and IL-12, and participates in multiple steps of the development and progression of NAFLD | (66) |
| Leoni (2018) | Dysregulation of proinflammatory cytokines and adipokines is almost universally | (67–70) |
| Nobili (2012) | present in NAFLD patients, which directly or indirectly (mainly through the | |
| Yoon (2014) | TLR4 signaling pathway) lead to hepatocyte injury. In addition, oxidative stress | |
| Temple (2016) | and hepa tocyte apoptosis are associated with the progression of NASH | |
| Berardis (2014) | TLR antagonists possess the effect of inhibiting the activation of inflammation, and may therefore be regarded as effective therapeutic agents for the treatment of NASH Effects of BA | (71) |
| Yu (2018) | A variety of transporters participate in the circulation of BAs between liver and | (72,73) |
| Chow (2017) | intestine; BAs promote the absorption of fat-soluble vitamins, and regulate lipids and glucose homeostasis | |
| Chavez-Talavera (2017) | BAs regulate the metabolism and inflammation through FXR and Takeda G-protein | (74,75) |
| Park (2016) | receptor 5, which possess the function of controlling the metabolism of BAs, lipids and carbohydrates, and regulating the expression of inflammatory genes | |
| Janssen (2017) | FXR is able to activate small heterodimer partner to reduce the expression of | (76,77) |
| Puri (2017) | sterol regulatory element-binding protein 1, which is a major regulator in new fat formation; inhibition of FXR leads to the abnormal lipid metabolism and development of NAFLD | |
| Zhang (2016) | Hereditary obesity, insulin resistance and NAFLD may be prevented or reversed by glycine-β-muricholic acid, an intestinal FXR antagonist, which possesses the ability to change the intestinal bacterial composition. | (78) |
| Sepe (2018) | FXR has been identified as a promising pharmacological target for NAFLD | (79,80) |
| Cruz-Ramón (2017) | considering its significant role in homeostasis of BAs, glucose and lipids |
NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; TGF, transforming growth factor; TNF, tumor necrosis factor; SIBO, small intestinal bacterial overgrowth; FXR, farnesoid X receptor; TLR, Toll-like receptor; IL, interleukin; LPS, lipopolysaccharides; LBP, LPS binding protein; BA, bile acids.