The brain and gut can be connected through a variety of pathways, including the enteric nervous system (ENS), vagus nerve, the immune system, or the metabolic processes of gut microorganisms.

The gastrointestinal tract is an organ that is co-dominated by the CNS, the autonomic nervous system, and the ENS. Regulation of enteric nerves consists of four levels of nervous regulation []. The first level is the local regulation by the ENS. The ENS consists of two nerve plexuses, the myenteric and submucosal plexuses, and the motor neurons and the sensory neurons of the ENS connect to each other to perform an independent information integration and processing function, which is similar to the situation for the brain and the spinal cord. The second level is located at the prevertebral ganglia, which receives information transmitted from both ENS and CNS nerves. The third level is the CNS. After integrating various pieces of information from various centers of the brain and spinal cord when they receive signals regarding internal or external environmental changes, the CNS transmits its regulatory information to the ENS or directly acts on gastrointestinal effector cells through the autonomic nervous system and the neuroendocrine system to regulate the smooth muscle, glands and blood vessels. The fourth level consists of advanced brain centers; information from the cortex and the subcortical region converges downward to specific brain stem nuclei from the basal ganglia. This type of neuroendocrine network, which connects the gastrointestinal tract with the CNS at different levels, is the structural basis for the function of the microbiota gut-brain axis. Disorders of neurological control at any level will affect the function of the gut and brain. The gut has a direct neural connection with the brain through the vagus nerve, and bacteria can stimulate the afferent neurons of the ENS []. Disorders of the microbiota gut-brain axis are associated with depression, anxiety, irritable bowel syndrome, inflammatory bowel disease, CNS diseases and other diseases.

The vagus nerve of the body can control the function of multiple organs, such as heart rate and gut motility; the vagus nerve can also transmit peripheral immune signals to the CNS. The vagus signal from the gut can trigger an anti-inflammatory response against the sepsis induced by microorganisms. Gut microorganisms can affect brain functions through the vagus nerve; after a vagotomy, the microorganisms will not be able to regulate behaviors []. After vagotomy in mice, no behavioral change was found even for mice that were treated with probiotics. Similarly, the bifidobacteria treatment, which had been previously reported to be effective, did not improve the behavior of vagotomized mice [].

Because gut microorganisms can directly affect the immune system, immune activation may be the pathway for transmitting microbial actions to the CNS []. Microorganisms can also enhance the anti-tumor immune effect of drugs by promoting T cell accumulation and transformation [], and microorganisms are very important for the immune function of organisms. The immune system plays an important role in maintaining health by maintaining gut homeostasis. The elderly have a decreased immune function, resulting in a change in the microorganism-brain connection and subsequent behavioral change. Microglia are immune cells in the CNS, and studies have found that the metabolism of gut microorganisms can regulate the maturation and function of microglia, thereby affecting CNS function [].

Microorganisms can also cause neurophysiological changes in the host by producing chemical substances that bind to the receptors inside and outside of the gut. Bravo et al. found that mice fed L. rhamnosus (JB-1) probiotics exhibited fewer anxiety-like and depressive behaviors and a change in the GABA Aα2 mRNA content in the brain area that controls specific behaviors []. Short-chain fatty acids (SCFAs) are produced from the dietary fibers fermented by gut microorganisms in the large intestine. In animal models, SCFAs can improve the neurodevelopment and cognitive function of animals with neurodegenerative disorders []. However, Macfabe injected a specific type of SCFA, i.e., propionic acid (PPA), into rats, which then exhibited autism-related characteristics and neurochemical changes []. These neurochemical changes included neuroinflammation, increased oxidative stress, and depletion of antioxidants, thereby leading to mitochondrial dysfunction. Other microorganism-derived molecules, such as the neural activation molecules serotonin, melatonin, histamine, and acetylcholine also have a role in the microbiota gut-brain axis [].

In addition, studies have shown that the microbiota may affect the CNS by altering adult hippocampal neurogenesis (AHN). The adult hippocampus and lateral ventricle have the function of generating new neurons. AHN has a role in learning and memory and can have affect on the pathogenesis of many neurological disorder-related diseases and symptoms, such as epilepsy, depression, Alzheimer’s disease (AD), and Parkinson’s disease (PD) []. In a recent study, Ogbonnaya et al. found a difference between the hippocampal neurons of sterile mice and those of normal mice and that microbiota colonization after weaning did not alter the amount of AHN, suggesting that early in life, microorganisms play an important role in AHN [].