“All disease begins in the gut”; this statement is said to have been stated by the Greek doctor Hippocrates, who is sometimes named with father of modern medicine, more than 2000 years ago. Whether or not Hippocrates is the true author is debatable, yet its innate wisdom still has an impact on medical researchers and physicians nowadays.
The recognition that the brain and gut interact in continuous, bidirectional interaction dates back to Ancient Greece, when scientists such as Hippocrates, Plato, and Aristotle proposed that the brain and other parts of the body are fundamentally linked. This idea led to the realization that studying the processes of illness requires considering the full person instead of just one or two separate organ systems. Nonetheless, William Beaumont conducted experiments before the 1840s that demonstrated how emotional state impacted the pace of digestion, indicating that the brain influences the gut and that a brain-gut axis exists. Even though this notion was thereafter recognized by Darwin, Pavlov, James, Bernard, and Cannon, it took until the beginning to mid-twentieth century for the initial scientifically documented findings that associated gut physiology modifies alongside swings in emotion. However, due to primitive technologies and a scarcity of research on the reciprocal consequences of altered gut physiology on brain performance, these investigations were constrained. Recent research has supported the links between gut and brain health. Much research found a high correlation between a variety of host illnesses and alterations in the microbiome composition, or “dysbiosis”. It has been reported that any alteration in the gut microbiome may be linked to developing a variety of CNS illnesses. Furthermore, the reciprocal connections can now be seen for the first time thanks to the advancement in brain imaging, revealing that important brain areas that participate in emotion regulation may be activated by gut signals.
The human gut microbiome is a rich and diverse ecosystem made up of commensal bacteria, viruses, fungi, and archaea. This ecosystem starts to colonize the GI during in-utero life. The growth and colonization of gut microorganisms co-occur alongside brain growth during pregnancy and continue up to a few years after delivery. Throughout the initial 12 months of postnatal development, the microbiome composition differs greatly between individuals until it stabilizes and resembles an adult at around 3 years of age. This variability may affect the development of the brain and shape an individual’s immune profile. In a healthy individual, early mucosal colonization is critical for the formation and maturation of the host’s immune system. Early childhood gut dysbiosis, however, can result from exposure to conditions including maternal immune activation (MIA), improper nutrition, illness/infections, and antibiotic overuse. The disrupted gut microbiome can promote inappropriate immune function, leading to systemic inflammation and symptoms linked with neurodevelopmental psychiatric disorders (NPD). Therefore, the effectiveness of the immune system, which subsequently controls neurodevelopmental pathways, depends on the existence of a balanced microbiome.
Despite rising data, there is still a considerable gap in knowing the precise mechanisms that regulate the connection between GIT and the brain through health and illness. This review will shed a spotlight on the complex links of the microbiome-gut-brain axis and the critical roles of gut microbiome in early brain development to gain a deeper understanding of microbiome-mediated pathological conditions, noninvasive prognostic pathways, and management options utilizing microbiome-gut-brain-axis adjustments.
The gut forms a complex, bidirectional link with the CNS, known as gut-brain axis, active in both health and illness. This interaction enables gut sensory impulses, transmitted via the vagus nerve, to impact CNS activity, controlling reflexes and modulating mood. The brain then uses these signals to alter gut physiology as well as other functions. Signals are transmitted through pathways like the enteric nervous system (ENS), autonomic nervous system (ANS), hypothalamic-pituitary-adrenal (HPA) axis, sympatho-adrenal axis, and descending monoaminergic pathways, involving both afferent (signal-receiving) and efferent (signal-sending) neurons. Multiple inter-relational and neurohumoral elements regulate and closely connect to each pathway. In significant part, the innate innervation of gut functions is mediated by the intricate neuronal network known as the ENS. It is composed of the myenteric and submucosal plexuses, two ganglionated plexuses that control gut peristalsis, absorption, and secretion. In gut-brain communication, the ENS sends signals to the CNS through intestinofugal neurons that connect to the sympathetic nervous system (SNS), while sensory information travels via vagal afferent pathways.
The ANS is a network of sympathetic and parasympathetic neurons. ANS regulates respiration, heart rate, and CNS-mediated alterations in the GIT and related processes, including digestion, GI motility, and permeability, bile secretion, carbohydrate metabolism, mechanical mucosal distortion, luminal osmolality, preservation of epithelial fluid balance, mucus production, as well as mucosal immune response. The CNS sends direct signals from the ANS to the gut, affecting its physiology. The gut microbiome communicates through metabolites that are recognized by host cells, which then interact with ANS synapses in the gut. Additionally, the ANS can influence the gut epithelium, impacting immune system activation either by directly altering immune cell responses to the microbiome or by changing how the microbiome interacts with immune cells.
The signaling pathway underlying the connection between the gut-brain axis and the microbiome is very important when thinking about therapeutic approaches. The brain influences gut functions via the HPA axis and the ANS; for instance, norepinephrine (NEP) is produced by the brain under stress and has been shown to promote the proliferation of gut pathogens. On the other hand, the gut impacts CNS function through microbiome metabolites, neuroactive agents, and gut hormones that reach the brain through the vagus nerve, circulatory system, immune system, or ENS.
