The microbiome — a major determinant of health?

There is a lot of excitement about the microbiome (1), the name given to the collection of genes within a microbial community such as in the oral cavity, skin, tonsils, intestine, and genital tract. The excitement stems from increasing recognition of the critical role played by the microbiome in health and disease. Bear in mind that the microbiome contains about 150 times as many genes as the genes in the human genome. Early studies of microflora depended on culturing the bacteria but only a small percentage of bacteria are culturable. Researchers have circumvented this limitation by identifying the full complement of microbial genes in specific areas of the body. They do this by extracting then sequencing the DNA to detect marker genes for each microbe that is present. Data on relative abundance of the various organisms and on function of the genes are also being compiled. Developments in high-speed, low-cost DNA sequencing have allowed this field to advance rapidly and the dream is that we will understand how to maintain and restore health-promoting microbiomes.

The “good bacteria” produce vitamins, energy sources, and metabolites that include anti-inflammatory and antioxidant properties, and that regulate the barrier function of the intestine (2). Bacterial metabolites act not only in the intestine but also in tissues all over the body, following absorption into the circulation. Probiotics represent one attempt to make use of the desirable properties of the good bacteria.

It has long been known that the gut protects against pathogenic bacteria through its physical barrier and its immune function. However, the role of the gut microbiome extends far beyond these, and the rich diversity of the 500 to 1000 species in the human intestine is critical to maintaining health. When that diversity is compromised, as occurs following exposure to antibiotics, the effect of stress, or aging, diseases such as Clostridium difficile colitis can develop. Clostridium difficile is present in the normal intestinal flora but can cause devastating disease when the protective effect of the normal flora is removed, often by antibiotics. The most effective treatment for recurrent C. difficile infection appears to be replacement of the missing microbial protectors by a fecal transplant, but a complex mixture of about 30 microorganisms cultivated in the laboratory may be as effective as the fecal transplant (3). Other enteric diseases caused by the gut microflora include ulcers and cancer caused by Helicobacter pylori, and inflammatory bowel disease. Also, bacteria in the colon are reported to be important in carcinogenesis of the colon through their ability to trigger macrophages to produce chromosome-breaking factors.

The gut microbiome is also important in educating the immune system to learn to differentiate between harmful and commensal microbes. It is therefore not surprising that the microbiome appears to play a role in immune-mediated diseases such as multiple sclerosis and asthma.

The gut-brain axis links the central and enteric nervous systems, providing a connection between what goes on in the intestine and emotional and cognitive centers in the brain. This involves signaling through neural, humoral, endocrine and immune pathways and is bidirectional, with messages going from brain to gut and gut to brain. The gut-brain axis appears to be involved in certain neurological diseases including some cases of autism (4). One clue was that gastrointestinal disorders are common in patients with autism and that the severity of gastrointestinal disease correlates with severity of autism. Furthermore, prospective studies in mice and rats clearly show that the gut flora can affect levels of neurohormones in the brain and can cause behavioral changes, and that metabolites of gut bacteria can cause architectural changes and inflammation in the brain of rats. Also, studies in humans have associated alterations in gut microflora with autism and preliminary studies have reported improvements in autistic children following manipulation of the gut flora with antimicrobials and probiotics (4).

Several other conditions appear to have a connection with the gut microbiome. These include Parkinson’s disease, obesity, and diabetes.

Investigation of microbiomes and their roles in health and disease is challenging because of the complexity of interactions among microflora components and of interactions with the host, variation from one person to another, and the fact that the microbiome is affected by factors such as diet, sanitation, vaccination, and antimicrobials (1,2). A consistent theme that has emerged is that loss of diversity of the microbiome leads to a wide range of untoward effects, possibly including impairment in brain maturation.

Follow the microbiome story. It is likely to lead to new understanding of how the body works and to new approaches to therapy in animals and humans.