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.