Wednesday, March 17, 2010

Perception and sense and nutrient partitioning.

In a fairly recent study on mice of the C57BL/6J strain, a very curious thing happened. Restricting mice to ninety-five percent of the calorie intake of control mice, the result was that the restricted mice became much fatter, with less lean mass than the control mice.

The authors of the study put it this way;

Mild CR altered body composition, energy expenditure, and meal patterns in female C57BL/6J mice. The increase in fat and decrease in lean mass may be a stress response to uncertain food availability.

A stress response to uncertain food availability. The control mice were given unlimited access to food. An all-you-can-eat buffet. The calorie-restricted mice only ate slightly less food than the control mice, but the control mice were given the opportunity to eat way more food. The mouse's body somehow reacted to the perception that food was limited by a shift in body mass away from lean tissue and protein storage and towards the storage of fat in adipose. This is a sensible adaptation if winter or a dry season, anything that would cause a prolonged food-shortage, is coming. And it illustrates a point; how the animal perceives the food is an important determinant of the fate of that food in the body. You might argue that these are special, genetically inbred mice; this doesn't matter to human obesity. But when we look at the extremes, certain things become obvious. That is the real value of studies in genetically-modified mice.

The mice saw, and smelled and ate less food. But these are not the only ways that animals metabolisms sense food. In the stomach and digestive track, there are numerous receptors, some of them similar to the taste receptors on the tongue. So even after an animal has eaten, signals are being sent, the nutrients being digested are "perceived" by the metabolism. That isn't all that's being perceived; the gut is full of bacteria, these bacteria put out various products that interface with various gut receptors.

Germ free mice fed a diet that causes mice with a normal gut bacteria culture to grow fat, fail to become obese.

The trillions of microbes that colonize our adult intestines function collectively as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. Given the worldwide epidemic in obesity, there is interest in how interactions between human and microbial metabolomes may affect our energy balance. Here we report that, in contrast to mice with a gut microbiota, germ-free (GF) animals are protected against the obesity that develops after consuming a Western-style, high-fat, sugar-rich diet.

Metabolome refers to the complete set of small-molecule metabolites (such as metabolic intermediates, hormones and other signalling molecules, and secondary metabolites) to be found within a biological sample, such as a single organism.

That's from wikipedia. So the study authors are writing about the interplay of various hormones and molecules. This is certainly going on. I think just as important to a discussion of what goes on in germ-free mice is the effect of bacteria on the metabolism's sense of the nutritional environment. Do you have a bad cold? Tongue all covered with microbial-rich white stuff? How does this affect your taste of smell? I think that it's reasonable to at least conjecture, from the information presented so far, that something akin to this may be taking place in the gut; as a clean tongue without visible buildup gives a clearer sense of taste, a clean gut should improve the body's ability to sense the nutrients present in the gut. This should make the dance between nutrition and metabolism go that much smoother.

It is tempting to think that the interplay between our native metabolism and our gut bacteria is one way-- bad gut bacteria are to blame for our obesity. But it doesn't necessarily work that way. The following is from an article in DOC (diabetes, obesity and cardiovascular disease) news.

Gordon's team initially identified a link between gut microbiota and the amount of energy mice harvested and stored from food. The team observed that conventionally raised mice—those harboring microbiota since birth—had 42% more total body fat than comparable mice raised in the absence of microorganisms. This held although the conventional mice consumed about 29% less chow than the germ-free mice. When the researchers colonized distal intestine microbiota from the conventional mice to the germ-free mice, the previously lean germ-free mice increased body fat by roughly 60% in just 14 days.

See? Those darn bacteria made those poor rodents fat, even though they ate less, not more, food than the germ-free mice. A fecal transplant from control to germ-free mice corrected for this patent inequity.

But wait. Further on in the same article;

During their analysis of the gut microbial community structure of two mice sets from a common mother, researchers led by microbial ecologist Ruth Ley found differing proportions of two principal groups of gut bacteria most commonly associated with mammals, including humans, in the obese and lean mice. One set was genetically obese because of a leptin gene mutation, while the other was lean, carrying either a single copy or no copy of this mutation. Despite having the same diet, obese mice had a 50% higher representation of the gut bacterium Fermicutes and a proportionally lesser representation of the bacterium Bacteroidetes than the lean mice.

Notice that these are genetically obese mice, suffering from the consequences of a leptin gene mutation. We are not helpless against our bacteria; I find it hard to look at the above paragraph without seeing a certain amount of regulation of the gut bacteria population by the hormone leptin. The firmicute bacteria that are more common in obesity may worsen obesity; but many of them may only be present because of an hormonal imbalance. The effect of leptin will be modulated by all the other hormones, as well. So, once again by looking at an extreme, we have learned a basic principle; gut bacteria population is strongly influenced by the host. How does leptin regulate gut bacteria? One likely mechanism would be by affecting nutrient availability; individual species of microbes tend to lean very heavily on particular nutrients, some prefer glucose, some certain proteins, glutamate for instance, etc. Glutamate may be pivotal in all of this, or at least one of several key pivots, which I'll go into later.

Gut bacteria ferment carbohydrates and proteins, and various fibers; this alters availability of nutrients to the host. So by interacting with the gut bacteria by hormonally altering their nutrient availability, the host in effect alters the nutrients which will be absorbable by the host itself. The host is not totally defenseless against the environment, and that includes the interior environment. There are certainly environments to which the host is incapable of adequate adjustment, outside of the host's homeostatic range of metabolic adaptation. But it does what it can. Implanting gut bacteria from obese mice to germ free mice makes the mice obese, bacteria from lean mice keeps them lean. Perhaps the bacteria from the obese mice simply present the previously germ-free mice with an internal environment which is outside of their proper homeostatic range; perhaps some nutrient is provided to the host in greater or lesser supply, or perhaps the nutrient sensing by taste receptors in the gut is altered.

Let's look at another interaction between animal and environment, the effect of calorie-restriction. Calorie restriction is well known to increase lifespan across a wide range of animals, from mouse to monkeys. There are caveats; death rates early in life often increase. But the animals who survive this early danger tend to live much longer than controls. I see this as another artifact of the interface between environment including food, and metabolism.

From Science Daily, april 20, 2007;

Changes caused to bugs in the gut by restricting calorie intake may partly explain why dietary restriction can extend lifespan, according to new analysis from a life-long project looking at the effects of dietary restriction on Labrador Retriever dogs.

Them crazy gut bacteria at work again.


The scientists believe that differences in the makeup of gut microbes between the two sets of dogs could partly explain their metabolic differences. The dogs that were not on a restricted diet had increased levels of potentially unhealthy aliphatic amines in their urine. These reflect reduced levels of a nutrient that is essential for metabolising fat, known as choline, indicating the presence of a certain makeup of gut microbe in the dogs. This makeup of gut microbes has been associated in recent studies with the development of insulin resistance and obesity.

So again, we have gut microbe environment affecting whole-body homeostasis. That leptin would only have some sort of interplay with gut bacteria in mice, and that leptin is the only hormone that does so, seems unlikely. Life is largely based on repeating themes, a simple strategy that is once successful will tend to reoccur again and again. This is of great help when trying to understand this sort of study.

We see choline-wastage in this study. And the dogs get fat. Choline is useful to metabolize fat. Might the dogs have a limited ability to "steer" the gut bacteria away from the type of bacteria that destroy the much-needed choline? The calorie-restricted dogs may have merely been within the limits of their proper metabolic range, compared to the ad-lib fed dogs. Alternately, the dog's limit for choline uptake may simply have become saturated.

One thing about this study, it's not just about calorie restriction it's also about food selection; without a control dog population that self-selects its own nutrients (which can be frightening in a lab), we can't know how much the results are an artifact of a difference in calories, and how much is caused by effectively tieing one arm of the dog's metabolism behind it's back, so to speak. Perhaps a non-calorie restricted dog would simply eat more choline, or more or less of some other element of the diet and thus avoid ill-health.

A key principle of calorie-restriction theory is "hormesis," which refers to an adaptation in an animal's gene expression, in reaction to some stress which is put on the organism. Calorie restricted animals are generally leaner, have longer maximum lifespans, prolonged breeding capability, and less cancer. But stress is just one of many inputs; again we return to taste, smell, sight, perception of food availability (although this counts as stress), the effect on gut bacteria population and the range of the animal's metabolism's ability to adjust to and to adjust its environment that includes those gut bacteria and the their effect on the general environment of the gut through the fermentation process. This must be true, otherwise the sense of taste, smell and all of those gut receptors are without purpose.


Anonymous said...

"perception"... in the gut
well, suppose i think / fantasize about eating a cake without actually eating it - will it affect my metabolism in any way?

donny said...

It may. But if your body is in hormonal balance, (which seems to equate with nutrient balance, from what I can tell so far) you probably won't spend much time thinking and fantasizing about cake in the first place.