| Risk Factor |
Pathogenesis |
Current Evidence |
Core Tip |
| Obesity |
Increased Firmicutes/Decreased Bacteroidetes in comparison to lean counterparts
Suppression of Fiafleads to increased lipoprotein lipase (LPL), thereby increasing cellular uptake of fatty acids and adipocyte triglyceride accumulation
Increased SCFAs induce the release of peptide YY (PYY)
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Germ-free mice fed a high-fat, high-sugar diet were resistant to development of obesity; introduction of gut flora led to increased body weight, body fat, increased hepatic lipogenesis, and fat deposition [11,16,17]
Colonization of gut with Bacteroidetesthetaiotaomicron and Methanobrevibactersmithii leads to increased suppression of Fiaf and subsequent obesity [26]
Excess Firmicutes can result in increased SCFA production and increased calorie absorption via PYY, ultimately leading to obesity; further, excess SCFAs can be converted into triglycerides within the liver increasing hepatic steatosis [11,19,20] |
Obesity is clearly a strong risk factor in the pathogenesis of NAFLD with a prevalence twice that of lean comparators.
Obese patients may have a characteristic increased Firmicutes/decreased Bacteroidetes within their gut microbiota.
Further investigation into the regulation of gut hormones and the regulatory factors for lipolysis and lipogenesis will help expand our understanding of the relationship between the gut microbiota and obesity in NAFLD. |
| Insulin Resistance |
Primarily driven by inflammatory mediators and immune responses
Link between insulin resistance and liver inflammation through these inflammatory pathways
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Gut microbiota can suppress the expression of AMP kinase and thereby predispose the host to insulin resistance [26]
Lipopolysaccharide (LPS) from gram negative bacteria can lead to decreased activation of insulin receptor substrate 1 (IRS-1) leading to insulin resistance in muscle and adipose tissue [34,35]
LPS can also hamper the activity of LPL, worsening insulin resistance by increasinglevels of circulating fatty acids [34,37] |
Insulin resistance affects a wide variety of biochemical pathways involved in the pathogenesis of NAFLD. In particular, it appears to incorporate both the immune responses and inflammatory changes that occur in NAFLD.
Currently, specific alterations in the gut microbiota relating to insulin resistance have not been found in NAFLD due to the vast role of insulin signaling in metabolism; however, continued investigation may prove to isolate more specific gut alterations related to insulin resistance. |
| Immune Responses |
TLR4 is activated by LPS from gram negative bacteria and leads to inflammatory responses
TLR9 can lead to activation of IL-1β and a subsequent increase in liver steatosis, inflammation, and fibrosis
TLR2 and TLR5 may play protective roles
NLRP6 inflammasome may be protective in the maintenance of intestinal homeostasis by clearing enteric pathogens and dampening bacterial dissemination
TNF-α and IL-1β are the major proinflammatory cytokines driving liver injury and progression of NAFLD à NASH |
Rodents on a high-fat diet (HFD) have increased inflammation through induction of TLR4, resulting in increased intestinal permeability and endotoxin levels; these changes are not reproducible in TLR deficient mice. Additionally, TLR4 deficient mice are resistant to NAFLD[46,49]
TLR9 deficient mice have decreased steatosis, inflammation, fibrosis, insulin resistance and weight gain in comparison to controls.[55]
TLR2 deficient mice on a HFD have disrupted tight junctions that was preserved in wild type mice given a TLR2 agonist.[47,60] TLR5 deficient mice showed obesity and steatohepatitis that was exacerbated by a HFD. [61]
NLRP6 deficiency has been associated with decreased IL-8, increased Bacteroidetes, defective autophagy of goblet cells, impaired mucin secretin into gut lumen, and enhanced activation of MAP kinase and NF-Kβ upon TLR binding [62-66].
TNF-α can increase insulin resistance by altering insulin receptor function; additionally, it can increase cholesterol accumulation in hepatocytes through inhibition of LDL receptors and efflux transporters. [12]
IL-1β suppresses PPARα causing accumulation of triglycerides within hepatocytes and increasing expression of pro-apoptotic pathways. [12] |
Disruption of the normal gut microbiota can result in altered immune system activation. These immune responses affect a number of pathways related to the risk factors for NAFLD. Additionally, they can promote the progression of NAFLD to NASH through increased inflammation.
Particularly important to the maintenance of gut homeostasis are the control of intestinal permeability and the levels of bacterial products, which can activate TLRs, triggering additional immune responses. |
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