Of Mice, Men & Microflora II: Microflora & Energy Balance

Mostly based on studies like THIS (abstract only), there's a new whiff in the air around obesity researchers.  Some go so far as to call gut microflora an "unsung organ".  Some have picked up this ball and run with it to the point of making wild claims that microflora control how much energy we extract from our food and we have no control over "energy in".   
Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet.
Firstly, we have correlation here, not causation.
Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'.
Many have read this and jumped all over it to say this indicates the arrow of causation goes from microflora to obesity.   That seems reasonable until one considers what actually happened here.  Germ-free mice are smaller because they lack a major component in extraction of energy from their diet.  I discussed this in Of Mice, Men & Microflora I.  Basically, rodents are hindgut fermenters who rely on fermentation for a significant amount of energy extracted from food.  Their digestive systems are clearly different from the human digestive system.  If you colonize their guts with more bacteria that are efficient energy extractors, is it any surprise the animal gains more weight?  But this does not indicate causality because we do not know the microflora composition of the obese mice before they became obese.  My gut { pun alert } reaction on all this is that a nutrient dense intestine favors the growth of certain bacteria over others, and the direction of causality goes from hypercaloric diet to microflora + obesity.

I was totally unaware that human fecal transplants have been done since the 1980's, mostly as a "last ditch effort" to eradicate Clostridium difficile.  The pioneering physician using these has performed some 1500 such procedures.  I'm thinking that there is every reason to believe that many of the donor/recipient pairings were of different weights.  Although not for weight loss, I would think that somewhere along the line of all these procedures, some recipients would report significant gains or losses.  That we haven't seen reports of *mysterious* gains/losses, the microflora as cause of obesity theory and use of fecal transplants to treat obesity seem rather implausible.  

Indeed, when one group did fecal transplants from lean men into 18 obese men, they did not lose weight.  The changes in insulin sensitivity and triglycerides are quite interesting.  Clearly the microflora effects metabolic regulation in some manner, but again we can't draw the arrow of causation.  Indeed the triglyceride improvements at 6 weeks did not persist to 12 weeks.  

There's a fun "factoid" floating out there that we have 10X as many bacteria in our bodies than we have human cells.  Or, as one scientist put it in the Same poop different gut article, we're 10% human and 90% poo.  But this is horribly misleading.  Bacteria are single celled organisms with masses on the order of 10^-12g (that's one one trillionth).  They exist pretty much to grow and divide.  I've seen estimates that our bodies contain between 1-2kg: 2.2 - 4.4 lbs of bacteria, so maybe 3-3.5 lbs in the gut.  What do you think the metabolic needs of this "organ" are compared to, say, just the cells of an ~3lb human brain?  I've seen figures ranging from 100g-200g daily glucose requirements for just our brains.  This makes sense to me because neurons are constantly doing electrochemical work to generate nerve impulses, manufacture neurotransmitters, etc.  A single sensory neuron has a mass on the order of 10^-6g -- so for those not familiar with scientific notation and orders of magnitude, a sensory neuron weighs approximately as much as one million bacteria.  Consider our muscle cells, organ cells, etc.  Lots of energy stuff going on there to move, lift, etc.   I've seen "average" human cell masses on the order of 10^-9 g -- so that's about 1000 bacteria = 1 human cell.  Bottom line, playing with numbers of cells makes for a "neato" scientific soundbite, but it's pretty meaningless. On a mass basis we're talking low single digit percents in terms of mass, and the metabolic activity per mass just is not comparable.  Bacteria don't regulate their internal temperature, engage in significant locomotion compared to humans, etc.  So the metabolism of these couple percent of cells is likely quite small, and certainly not enough to be significant.

But, presuming it is significant, what of "energy extraction"?  Humans ingest relatively little in the way of foods that is indigestible.  The energy extractors could only significantly impact our metabolisms by increasing fermentation of undigestible matter, the stuff we call "fiber".  Of course we all know how the obese are notorious for consuming lots of fiber in their diets, and how in the immediate aftermath of dramatic increases in fiber intake eating meat and veggies on Induction, LC'ers are notorious for gaining weight.  R hhh iiiiigghhhhht.    If the bacteria are "eating" anything else, like undigested carbs for instance, they are utilizing that energy for their needs, not releasing energy.  IOW they're lowering your intake slightly presuming you would have eventually absorbed these nutrients, or if they utilize these in lieu of fibers that yield nutritive byproducts, again this would reduce "intake" slightly.  

Barring further convincing evidence in humans, and I await all the data from the Swedish study, I'm not going to spend much time worrying over my gut bacteria.   I've seen little evidence that we can predictably  manipulate it much anyway.  I'll probably throw up a few posts with references for "bookmarking" purposes.


Melchior Meijer said…
If gut bacteria play a role in body fat regulation – which I think they do – it’s probably not because they take some of our food. Our body would simply urge us to compensate for the energy deficit. It seems more plausible to me that the (assumed) effect is through host microbe cross talk. Just like gut bacteria work together (or are actually a part of) our immune system, they could very wel be talking to, let’s say’ the hypothalamus: “You might see a fatso in the mirror, but he, you’d better grab something to eat.” Another possibility could be that a certain type of gut flora causes systemic inflammation, thus making the hypothalamus deaf for leptin. In any case it’s mind bogglingly complicated and as you say, it’s very hard to change the gut flora. There are, however, some promising results from supplementing with prebiotics like inuline and oligofructose. Eat more onions ;-).
CarbSane said…
Hi Melchior, my hunch as regards obesity is a local inflammatory response with enterocytes leading to malfunction and whatnot. It is certainly possible, but I have a hard time accepting that such a simple organism can cross-talk with a higher order organism in any meaningful way. I can see that this would impact metabolic regulation (e.g. impaired incretin secretion --> impaired insulin augmentation, etc.) in an indirect manner as opposed to directly signalling the host organism. If proven wrong, I'll eat crow on that ... but it just seems highly implausible to me that bacteria can directly influence hosts in any significant manner.

The obesity link is proposed to be a caloric one - the obese have higher proportion of energy extracting bacteria. The implication being that greater energy extraction leads to more caloric intake. I highly question the arrow of causation there.
Melchior Meijer said…
Hi CarbSane,

After attending a lecture by the Finnish allergy/gut flora specialist Erika Isolauri a couple of years ago in Dublin, I assumed that intensive and 'intelligent' host microbe cross talk was an established fact, at least with regard to the human immune system.

I might be wrong. A quick search reveals that Isolauri is now into obesity too.


I don't buy the caloric link.
CarbSane said…
There's no doubt that our gut microbes interact with and are part of our immune systems. Also that there's "cross talk". The human immune system reacts to certain toxins they produce and I do believe, since the gut is also an endocrine organ secreting incretins amongst other things, that "bad bacteria" can wreak all sorts of havoc on metabolic regulation and gut integrity by impairing the cells of the gut. What I'm skeptical of is the bacteria actually sending signals to our brains. Make sense?

Thanks for that link. Vaca reading 8)
Anonymous said…
Gut microbiota is a VERY STRONG part of body fat regulation.