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Figure 1. Mixed microbial species from human body. From A. Earl (Broad Institute/MIT, 2012).

1. Microbiome in the GI tract and the production of serotonin

GI inflammation is activated by immune cells from both the innate and adaptive immune system. In addition, inflammation is associated with alterations in the number of enterochromaffin (EC) cells that reside in the GI mucosa.   Ninety percent of the body's serotonin production comes from these EC cells in the GI tract. Serotonin is important for maintaining GI motility and restoring hemostasis after inflammation. Changes in the number of EC cells and serotonin levels are associated with a number of GI disorders, such as inflammatory bowel disease, colitis, enteric infection-induced inflammation in the gut, and inflammatory bowel syndrome.

Elaine Hsiao, PhD, from California Institute of Technology and her team demonstrated that gut microbes do regulate serotonin biosynthesis. In their study they found that when mice were germ-free, their EC cells produced 60% less serotonin than those mice with gut bacteria.   When bacteria was introduced to the germ-free mice, production was increased. Their findings suggest that EC cells depend on microbes for serotonin production. They also found that about 20 species of spore-forming bacteria were responsible for elevating serotonin levels when added to germ-free mice.

Highlights from the study by Hsaio and her team: 

• Gut microbes regulate levels of 5-HT in the colon and blood
• Spore-forming bacteria modulate metabolites that promote colon 5-HT biosynthesis
• Microbiota-dependent changes in 5-HT impact GI motility and hemostasis
• Altering the microbiota could improve 5-HT-related disease symptoms

2) Production of Serotonin and the Central Nervous System (CNS)

In the brain, serotonin acts as a neurotransmitter to relay messages from one area of the brain to the other. While the brain produces serotonin, 90% of serotonin is produced in the GI tract for gut sensory and function and the rest is circulated as peripheral serotonin to areas such as the cardiovascular and endocrine systems and muscles. Scientists believe that low serotonin levels may lead to CNS disorders such as depression, obsessive-compulsive disorder, anxiety, panic, and even excess anger resulting from either a lack of receptor sites able to receive the serotonin; inability of serotonin to reach the receptor sites; or a shortage in tryptophan to make serotonin.   It is also believed that serotonin is important for the regeneration of brain cells throughout our lifetime. One theory of the etiology of depression is the suppression of new brain cells and that stress is the most important precipitator of depression.

The term "gut-brain axis" or "second brain" was coined when the link, or communication, between the nervous systems and the digestive system was recognized. Therefore, what affects the brain, affects the gut and visa versa. Hsiao et al showed that microbes are needed for EC cells to produce normal amounts of serotonin and a number of studies have suggested that these gut microbiome can have an impact on the brain and behaviors such as anxiety and depression.   

In the experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis study, it was found that when certain bacteria in the gut are altered this can lead to proinflammatory conditions in distal effector immune sites, and may lead to autoimmunity disease, in this case multiple sclerosis (MS). Whereas certain commensal bacteria in the right balance can be protective against inflammation in the CNS. 

3) Microbiome in obesity and other metabolic diseases.

In previous studies, it's been shown that a change in diet can alter the gut microbiome. In some animal studies, it was shown that obese mice or mice fed a high-fat diet had a decrease in Bacteroidetes and increase in Firmicutes.   In a single day, a change from a low-fat to a high-fat, high-sugar diet exhibited a change in microbiome that resulted in metabolic change, and an increase in adiposity and the same trait was evident with a microbiome transplant to other mice. The microbiome controls many different facets of the host metabolism, including Tlr5 activation (e.g., through bacterial flagellin) on epithelial or myeloid cells, that ultimately regulates appetite, weight gain, and insulin sensitivity and also regulates Fiaf release from intestinal epithelial cells, which acts as an inhibitor of Lpl and thereby regulates peripheral fat storage, both of unknown mechanism.  

It is hypothesized that our microbiota also affects Ampk, a key enzyme that controls cellular energy like a fuel gauge. It signals to the liver and skeletal muscle and affects the skeletal muscle and liver fatty acid oxidation pathways. The exact mechanism is not clear. How the microbiome affects the host metabolism is very complex, as demonstrated here, but scientists are making strides in uncovering the physiology of the interactions between gut microbiome and other metabolic diseases.

4) Microbiome and its relationship to colorectal cancer

Ashlee Earl, PhD from the Broad Institute in Massachusetts and colleagues examined the role of the microbiome in patients with colorectal cancer (Figure 1). They characterized the composition of the microbiota in colorectal carcinoma using whole genome sequences from nine tumor/normal pairs.   They found four species within the Fusobacterium genus; Fusobacterium nucleatum, Fusobacterium necrophorum, Fusobacterium mortiferum, and Fusobacterium perfoetens with F. Nucleatum being the most dominant phylotype identified within cancers. The Fusobacterium species can elicit host proinflammatory response and invade epithelial cells. The absence of Bacteroidetes and Firmicutes phyla, most prominently Clostridia, in tumors was also noted. This suggested that the dominance of Fusobacterium and the dampening of Bacteroidetes and Firmicutes sets the stage for tumorgenesis by eliciting a proinflammatory response in a subset of patients and may explains why some patients get colorectal cancer and others don't. Another hypothesis is that Fusobacterium accumulates in the tumor environment, but is not involved with the development of tumors. More research is needed to confirm either hypothesis.

Others have noted that Fusobacterium species may be associated with inflammatory bowel diseases (IBD), including both ulcerative colitis and Crohn's disease and IBD is one of the three highest risk factors for developing colorectal cancer. Likewise, more research is needed to verify a causal relationship.