Our study suggested that combinatorial application with natural resources and beneficial gut microbes might favorable pharmacological efficacy on NAFLD. We employed the systemic analysis by integrating key components to be identified by data mining and found that luteolin (referred to as postbiotics or metabolites), myricetin (referred to as postbiotics or metabolites), AKT1 (target), CFTR (target), PIK3R1 (target), Enterococcus sp. 45 (probiotics), Escherichia sp.12 (probiotics), Escherichia sp.33 (probiotics), and Bacterium MRG-PMF-1 (probiotics) on
cAMP signaling pathway. In parallel, we surveyed luteolin-rich and myricetin-rich natural food resources. As a result, the pepper, carrot, broccoli, celery, cabbage, and parsley are luteolin-rich natural resources, which are related deeply to AKT1 and CFTR. Likewise, Enterococcus sp. 45 (probiotics) can convert orientin (prebiotics) (flavone species), and cymaroside (prebiotics) (flavone species) into luteolin (postbiotics) [41, 42].
In addition, the spinach, pea, turnip, carrot, cauliflower, and cranberry are significant suppliers of myricetin, which are associated closely with PIK3R1. Similarly, Escherichia sp.12 (probiotics), Escherichia sp.33 (probiotics), and Bacterium MRG-PMF-1 (probiotics) can convert myricitrin (prebiotics) into myricetin (postbiotics) [43].
An animal test demonstrated that cAMP level of NAFLD rats was elevated to as fivefold as control groups, conversely, the cAMP level had negative correlation with high density lipoprotein (HDL) cholesterol [44]. Furthermore, cAMP triggers gluconeogenesis in NAFLD as well as causes insulin resistance [45–47]. It has been suggested that inhibitors of cAMP signaling pathway might be of significance therapeutic agents in the treatment of NAFLD.
Both luteolin and myricetin are secondary metabolites in natural resources or postbiotics in specific gut microbes. The luteolin improves sensitivity level of insulin as an antidiabetic agent, including antioxidant and anti-inflammatory properties [48]. Likewise, myricetin has not only potent stimulatory effect of insulin, but accelerates lipogenesis in rat adipocytes [49]. The MK-2206 reached at clinical trial phase II as an AKT inhibitor suppressed the progression of NAFLD [50]. Uncommonly, there was no relationship between CFTR and hepatic steatosis in the development of NAFLD [51]. Wortmannin as PIK3R1 (PI3K) inhibitor reduced interleukin 1β (IL-1β) and interleukin 18 (IL-18), which leads to protecting mice from NAFLD [52]. The results suggested that effectors (AKT1, PIK3R1) and agents (luteolin, myricetin) might be critical elements to alleviate NAFLD, on a pharmacological viewpoint.
The relevance of the top 10 signaling pathways with NAFLD were shortly discussed as follows, the criteria of which is based on false discovery rate (FDR < 0.05). cAMP signaling pathway: Metformin with AMPK-dependent mechanisms dampens mitochondrial respiratory system, activating AMPK, and lowering cAMP, and thereby enhancing of liver enzymes and fat content in NAFLD [53]. Interestingly, an animal test demonstrated that metformin as cAMP suppressor is associated with changes of intestinal microbes diversity and even reduced the production of bacterial endotoxin on the outset of NAFLD [54]. It elicits that cAMP blocker might have synergistic effects: positive pharmacological mechanism, and favorable intestinal microbiota composition on NAFLD.
Cyclic Guanosine MonoPhosphate Protein Kinase G (cGMP-PKG) signaling pathway: The Gene Expression Omnibus (GEO) database analysis shows that cGMP-PKG signaling pathway is related deeply to insulin resistance and occurrence of steatosis by aggravating cytotoxic cascades of NAFLD [55]. JAnus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway: The mice experiment reported that the deletion of JAK2 induces fatty liver, thereby elevating liver triglyceride as twenty times as normal group [56]. Neurotrophin signaling pathway: A logistic regression study demonstrated that brain-derived neurotrophic factor (BDNF) has a negative independent factor with 0.041 (Odds ratio) in NAFLD patients, by comparison with control groups [57]. T cell receptor signaling pathway: The recognition of antigen on T cell is an initial step to maintain the homeostasis of the gut microbes, affecting liver immune system in gut-liver axis [58]. NF-kappa B signaling pathway: O. indicum seed extract (OISE) with anti-inflammatory effects inhibit the activity of NF-kappa B which leads to the development nonalcoholic steatohepatitis (NASH) [59]. Chemokine signaling pathway: The concentrations of the C-C Motif Chemokine Ligand 2 (CCL2) and CXC Motif Ligand 9 (CXCL8) in NAFLD group were significantly greater than the control group [60]. Oxytocin signaling pathway: Oxytocin is an accelerator to promote liver rejuvenation via autophagy, maintaining liver metabolic homeostasis [61, 62]. Insulin signaling pathway: Insulin resistance a key risk factor to aggravate NAFLD, insulin sensitizers (thiazolidinediones) taken to ameliorate NAFLD might be of significance therapeutic agents [63, 64]. Thyroid hormone signaling pathway: The reduction in thyroid hormone can elevate the concentration of blood lipid and stimulate the progression of NAFLD [65]. It implies that thyroid hormone can alleviate the hyperlipidemia related to occurrence of NAFLD.
To sum up, we believe that the correlative analysis of prebiotics, probiotics, postbiotics, and targets would be helpful to understand the complex microbiome system. Furthermore, dietary plant- derived natural resources play important role to incorporate with gut microbiota against NAFLD. Collectively, we indicate relationship of the key microbiota or dietary plant-derived natural resources, metabolites, targets, and a key signaling pathway for the treatment of NAFLD. From a holistic perspective, we suggest the endogenous (gut microbiota) or exogenous (dietary plant-derived natural resources) elements might be exerted the combinatorial effects on NAFLD.