Has the human genome project really been completed? One could argue that in fact it will not be completed until its sequel, the Human Microbiome Project, is completed. One set of authors referred to it as “another phase of the ‘human’ genome sequencing project.”
The available evidence suggests that intestinal microbes are inherited from parent to offspring, just like the biologically heritable components (not all of which are genetic) of our Homo sapiens cells are. Just like the heritable components of our H. sapiens cells, these microbes appear to substantially contribute to our phenotype — that is, the overall end result of who we are.
What is particularly fascinating, however, is that there is evidence that variations in our metabolism that could be induced by diet or environment, such as leptin signaling, can alter the relative abundance of certain gut microbes. Thus, not only do these microbes drive our phenotype, but our phenotype drives the microbes!
This highlights a huge problem of inferring cause-and-effect relationships into inheritance patterns. While traditional “genetic” inheritance can be inferred in certain cases from solid mathematical patterns, the mere fact that a trait is heritable not only does not show that it is “genetic” but it does not even show that the inheritance is due to our H. sapiens cells, nor does it show that the trait cannot be changed by normalizing our metabolism through dietary, lifestyle, and environmental modifications.
This highlights a general principle in biology that if we have not mapped out the specific mechanistic pathway we should not make any assumptions about that pathway, or else all we are doing is confirming our own biases.
Let’s start with some information collected from Ruth E. Ley and colleagues, who wrote a 2006 review in Cell entitled “Ecological and Evolutionary Forces Shaping Microbial Diversity in the Human Intestine.”
Observational evidence in humans suggests that intestinal bacteria are directly heritable. Babies appear to acquire their first and main inoculation with gut microbes from the vagina and feces of their mother at the time of birth. Through adulthood, the microbial profiles of identical twins are more similar to each other than to the microbial profiles of the people they married, but no more similar than the microbial profiles of fraternal twins or of siblings who are not twins. These observations suggest that the initial inoculation from the mother and not the genetic makeup of the H. sapiens cells is driving the similarity.Likewise, Ley and colleagues had performed experiments with mice wherein they observed that the similarity in gut microbes among mice that were related through kinship persisted across at least two generations.
The microbial profile of unrelated mice, by contrast, differed. This difference occurred at the taxonomic level of genus and related to the specific composition of microbes. In other words, mice that were unrelated to each other had, to some extent, different genera of bacteria living in their intestines.
What was particularly remarkable, however, was that genetically defective leptin signaling caused differences at the much larger level of division (analagous to the taxonomic level of phylum when looking at animals) even among related mice. Whereas kinship was related to the specific composition of bacterial genera regardless of leptin signaling, a defect in the leptin gene was associated with a change in the relative abundance of the two main bacterial divisions regardless of kinship.
Leptin is a hormone that our adipose tissue makes, which decreases food intake and increases the metabolic rate. The defective mice had the ob/ob genotype. Ob signifies a defect in the gene that makes leptin and stands for “obese” because mice with two copies of the defective gene become obese.
While these genetically defective mice eat more and weigh more than genetically normal mice, there was one runted mouse in the study with defective leptin signaling that actually ate less and weighed less than the genetically normal mice, but it’s microbial profile was similar to the other mice with defective leptin signaling. While we would want to see a larger study to confirm this, the observation suggests that leptin-induced changes in intestinal flora are not a result of increased food intake.
Remarkably, Ley’s group later showed that if they transferred the intestinal flora from ob/ob mice to germ-free lean mice without any leptin defects, the mice gained twice as much weight and 50 percent more fat over two weeks compared to mice receiving intestinal flora from normal mice, despite no difference in food intake.
There is an abundant amount of evidence showing that leptin prevents obesity by decreasing food intake and increasing metabolism through direct effects on the central nervous system and other body systems. These results suggest, however, that leptin also prevents obesity in part by maintaining the proper balance of intestinal flora.
Genetic defects in leptin are rare in humans, but human obesity appears to be related to leptin resistance. Perhaps in humans, then, these more moderate changes in leptin signaling contribute to alterations in gut flora.
We can make a few conclusions from these studies:
- Intestinal flora clearly contribute to our phenotype. Since they are directly inherited from one generation to another, we cannot assume that any heritable characteristics of our phenotype are “genetic” or even a result of our Homo sapiens cells rather than a result of our microbial partners, without additional evidence supporting a particular mode of inheritance.
- Likewise, it makes little sense to discuss the evolution of humans over time without considering the co-evolution of our microbial partners.
- Normalizing our gut flora may be an important part of fixing our metabolic problems, but normalizing our metabolism may also be an important part of fixing our gut flora. This emphasizes the need for a multi-faceted approach to improving health.