Fig.2 A schematic outline of gut-liver/brain interactions, focusing on pathways and representative metabolites. Abbreviations: LPS, lipopolysaccharide; NAFLD, non-alcohol fatty liver disease; SCFAs, short-chain fatty acids.
2.2 Gut-brain axis
Compared to the gut-liver axis, the gut-brain axis is a rather new concept that was initiated from a series of behavioral observations in germ-free and specific bacteria and antibiotics treated animals. It allows bidirectional communication between gut and brain, integrating nervous, endocrine, and immunological systems with gut and microbiota within (Fig.1). On the one hand, alterations in nervous, endocrine and immunological systems impact gut microbial composition and function, such as Helicobacter pylori infection (Budzyński and Kłopocka, 2014); on the other hand, modification of gut microbiota promotes or hampers mental health and cognitive function and has been presented as an attractive target for treating mental disorders such as Parkinson’s disease (PD) (Fang, 2019), Alzheimer’s disease (Khan et al., 2020), schizophrenia (Klein-Petersen et al., 2019), and autism (Aabed et al., 2019). Moreover, gut microbiota is involved in circadian rhythms of a wide spectrum of diseases including metabolic diseases, psychiatric disorders, and neurodegenerative diseases, along the gut-brain axis (Teichman et al., 2020). Pathways for reciprocal communication between gut microbiota and brain are situated in the gut lumen, gut epithelium, periphery, and brain (Fig.2), including hepatic and gallbladder metabolism, immune-modulatory responses, neuronal innervation, enteroendocrine, and microbial metabolite signaling (Cryan et al., 2019). Of note, hepatic and gallbladder metabolism is involved in the gut-brain axis with bile acids found to influence brain function directly (Liu et al., 2018), indicating an intimate relationship between liver and brain. Besides, gut-derived neurotransmitters such as γ-amino butyric acid (GABA), noradrenaline, and dopamine are especially significant gut microbial metabolites in bidirectional communication between the gut and brain. An intriguing fact is that both microbiota and brain development undergoes sensitive periods (early life, adolescence, and aging) during lifespan which may be implicitly intertwined since it is evidenced that antibiotic usage during perinatal stage may induce severe brain damage to the newborn and the aged are vulnerable to mental disorders with gut microbiota implicated. However, despite these flourishing discoveries of the gut-brain axis, many of the theories remain to be hypotheses, and much endeavor is needed to inject into fully elucidating mechanisms of how gut microbiota and brain communicate.