Gut microbiome can produce neurotransmitters and communicate with the central nervous system (CNS). They regulate many neurotransmitters in the CNS and the expression levels of their receptors. This may lead to a positive or negative outcome owing to the cross-talk pathways. For example, they maintain the level of serotonin in the CNS and prevent obesity but can reduce the expression of 5HT1A mRNA and promote obesity. They can alleviate depression by increasing central norepinephrine and serotonin levels but may trigger rest tremor in Parkinson’s disease (PD). They can increase gamma-aminobutyric acid (GABA) level and may prevent/reduce epilepsy, epilepsy-induced PD, and respiratory depression, but GABA itself may induce respiratory depression through GABAA and GABAB receptors. Similarly, they are involved in improving cognitive function but may trigger neurodegeneration. They can secrete acetylcholine and delay the progression of Alzheimer’s disease (AD) and dementia. Conversely, acetylcholine induces JAK-2. JAK-2 negatively regulates GSK-3β/Fyn/CDK5 and suppresses neuronal differentiation, leading to AD and dementia. JAK-2 activates STAT3. This, along with PI3K/AKT/mTOR, will affect memory and learning, leading to AD and dementia. They produce methane. Methane suppresses the JAK1/STAT1/NF-κB-p65 pathway, thereby improving cognitive function. These findings represent microbiome-mediated neurotransmitter regulation as a double-edged sword.