The Other Genome

With the advent of molecular biology and such techniques as RNA gene sequencing, quantitative polymerase chain reaction, metagenomic analysis of the infant gut microbiome, and short-chain fatty acid (SCFA) analysis have provided an “ecological perspective” in a new frontier of human biology. This frontier is the human gut microbiome. We are now in a position to explore how changes in its composition may result in, or predict disease.

The distal gastrointestinal tract has recently been recognized as an ecosystem in which the genome of trillions of microbes collectively known as the microbiome reside. An ensemble of interactions between the host and these microbial inhabitants is occurring and exerting a significant multidimensional impact on the interacting partners. Metabolic reconstructions of a “core” microbiome reveal activity for several functional categories, including those involved in transcription and translation. Sequences from 18 representative fecal microbiomes also demonstrated activity in amino acid metabolism, carbohydrate and lipid metabolism, metabolism of cofactors and vitamins, energy metabolism, membrane transport, and cellular processes and signaling protein families.

The expression “microbiome” is said to have been originated by Joshua Lederberg in whose estimation the gut microbes ought to be included in the concept of the human genome as a function of their profound influence on human physiology. A core microbiome contains genes important for life. Massive microbial gene sequences related to carbohydrate and amino acid metabolism revealed strains of Bacteroides and Firmicutes that regulate secretion systems and membrane transport.

The uptake and fermentation of otherwise indigestible carbohydrates into SCFAs is seen as a contribution to the obese phenotype in both mice and humans. SCFAs also act as ligands for G-protein coupled receptors that ultimately mediate expression of peptide YY (known to inhibit food intake and gut motility). A variety of other metabolic intermediates suggest a role of SCFAs in the pathogenesis of obesity, and additional microbiome factors regulate fatty acid uptake and its oxidation. Moreover, the Bacteroides to Firmicutes ratio appears to reflect vulnerability of the host to obesity.

It is tempting to speculate that gut microbiome factors may explain such clinical conundrums as the lifelong battle with obesity in patients who restrict caloric intake and exercise regularly. And consider the spectrum of sometimes crippling symptoms in those with Irritable Bowel Disease who receive little or no relief despite our armamentarium of antibiotics, anti-dysmotility agents, and probiotics.

The empiric relationship between gut bacteria (their metabolites, their interaction with peptide hormones produced in the bowel) and with neurochemistry/ neurotransmitter systems is a reality, albeit terribly complex. Nonetheless, the indicative applications of the wide-ranging clinical importance of the microbiome remain unexplored.

Work in the last decade suggests that gut microbiota can contribute to excess host adiposity. Conversely, this microbiota may protect against the development of type I diabetes, lower the threshold for inflammatory bowel disease, and reduce the risk of metabolic syndrome.

A recent longitudinal study of infants assessed serial fecal specimens along with a diary of health status and diet. Analysis of more than 300,000 16S rRNA genes revealed the diversity of the microbiome over time. It appears that shifts in the microbiome once thought to be chaotic are in fact closely associated with life events. These shifts in microbial metabolite pools co-varied with shifts in the relative abundances of taxonomic groups. Thus, it is no surprise that the microbiota is increasingly suggested as a target for therapeutic intervention for several chronic diseases. Imagine the identification of particular dietary constituents that may serve to sustain health-promoting microbiota, stable and resilient to disturbance in the face of particular vulnerabilities or life stressors.

Changes in the gut microbiome induced by antibiotics, dietary change, nutritional supplements, and illness may prove to be important observations, paving the way for the medical nutrition interventions noted above. More importantly, future medical nutrition research and food product development will reflect the exquisite sensitivity of the distal gut and its microbiome in delineating and explaining syndromes and constellations of symptoms that have thus far been termed idiopathic or “functional” in nature. Microbial profiling may further provide insights into specific disease vulnerabilities and help us target dietary and medical interventions. Finally, based upon our experience in developing countries, including war-torn regions where malnutrition and diarrheal illness are rampant killers, it may be critical for us to consider the value of profiling modal microbiota toward the provision of interventions that may help us to promote stability and a chance at life. 

Peter Pressman, M.D.,
Contributing Editor
CDR, Medical Corps, U.S. Navy, Director Expeditionary Medicine, Task Force for Business & Stability Operations 
[email protected]

Roger Clemens, Dr.P.H.,
Contributing Editor
Chief Scientific Officer, ETHorn, La Mirada, Calif.
[email protected]