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Saturday, December 4, 2010

Of Mice, Men & Microflora I: The microflora transplant study

A while back I listened to an interview with Steven Guyenet of Whole Health Source blog where he mentioned a study where the gut bacteria were transplanted from obese mice to normal mice that had no endogenous bacteria.  The normal mice gained more weight.  Microflora differences have been identified between normal and obese humans and normal and anorexic humans.   This has led to much speculation that changes in microflora could be a causative agent in obesity.

I look at such studies and consider them to be interesting, but of all the alternate theories out there, I'm probably most skeptical of this one as being a significant cause of obesity.  I'll deal with the energy balance aspects and some related math in future post.   This post will focus on the differences between rodent and human digestion that lead me to believe that the observations in mice may well not translate to humans.

This Scientific American article is probably referencing a similar or the same study as my link above.  (Sorry, being lazy here).
Germ-free rodents have to consume nearly a third more calories than normal rodents to maintain their body weight, and when the same animals were later given a dose of bacteria, their body fat levels spiked, even if they didn't eat any more than they had before.
What might explain this?  A little research led me to discover that rodents are hindgut fermenters.

Hindgut fermenters
Horses, rabbits, rodents and other herbivores use cellulose and other fermentable plant material in much the same way as ruminants. However, as they only have a single stomach compartment, fermentation and digestion of cellulose primarily occurs in the large intestine and cecum. 
Digestive tract anatomy of hindgut fermenters
The stomach and small intestine of hindgut fermenters are similar in form and function to other non-ruminant herbivores. Food passes down the oesophagus and into the stomach (which does much the same job as the ruminant abomasums). However, monogastric species do not regurgitate their cud so all mastication occurs when food is taken into the mouth. Acid and enzymatic digestion begins in the stomach, and then partially digested food moves from the stomach into the small intestine where further breakdown and absorption of nutrients occurs. Like the ruminant system, the small intestine empties its contents into the caecum through the ileocecal orifice.
However, unlike other monogastric herbivores, the caecum and large intestine of hindgut fermenters is very large and anatomically complex. The caecum and colon in much the same way as the reticulorumen of ruminant animals; slowing down the throughput of food and allowing time for the fermentation of cellulose and other plant material bysymbiotic bacteria. Food leaves the caecum through an opening called the cecocolic orifice and moves into the ascending colon. Here regular muscle contractions in the colon wall efficiently mix the digested food and allow absorption of water, salts and the nutrients produced through fermentation. Food moves only slowly through the colon – in horses it takes 2-3 days to pass the length of the colon. The lower colon absorbs water and concentrates waste material before this is egested as faeces through the rectum.
Scientists believe that hind-gut fermentation is comparatively less efficient than rumination when it comes to extracting nutrients from cellulose-rich plant material. This has driven the evolution of a number of behavioural and physical adaptations in monogastric animals that maximise the energy they extract from their high-fibre diets.
I don't have access to the full text, but the cecum of mice (and rats) has a complex anatomy.   The cecum harbors microflora that can ferment cellulose. Rodents and other hindgut fermenters are also known to engage in corophagy -- eating feces -- to extract more fermentation products than those absorbed in the hindgut.  The human equivalent to the cecum is thought to be the appendix (the first part of the large intestine is called the cecum, but differs from the pouchy anatomy of the cecum in a hindgut fermenter).

In most vertebrates, the caecum is a large, complex gastrointestinal organ, enriched in mucosal lymphatic tissue (Berry 1900), and specialized for digestion of plants (see Figure 2Kardong 2002, pp. 510-515). The caecum varies in size among species, but in general the size of the caecum is proportional to the amount of plant matter in a given organism's diet. It is largest in obligate herbivores, animals whose diets consist entirely of plant matter. In many herbivorous mammals the caecum is as large as the rest of the intestines, and it may even be coiled and longer than the length of the entire organism (as in the koala). In herbivorous mammals, the caecum is essential for digestion of cellulose, a common plant molecule. The caecum houses specialized, symbiotic bacteria that secrete cellulase, an enzyme that digests cellulose. Otherwise cellulose is impossible for mammals to digest.
Does it come as any surprise that when bacteria are replenished in formerly germ-free mice, they get more caloric nutrition from their food and gain weight?  Not to me!!

Because of this key difference between rodents and humans, in my opinion, the utility of germ free mice to elucidate the role of intestinal microflora in humans is limited, at best.

Finally, in Digestive enzymes in the germ-free animal (NOTE: link downloads pdf) differences between germ free and normal animals are discussed.

Summary: The digestive physiology of the germ-free animal has a number of characteristics (cecal hypertrophy, slower small intestine cell renewal, slower gastric emptying and intestinal transit) which distinguish it from that of the conventional animal. If the germ-free model is to be used to determine the role of gastrointestinal microflora in the nutrition of the conventional animal, it is essential to complete the study of these characteristics by data on digestive enzymes in the germ-free. The present paper analyzes these data.  There is little information on salivary amylase and none on gastric proteolytic enzymes and intestinal peptidases. More complete data on exocrine pancreas enzymes and intestinal disaccharidases show that the digestive equipment is similar in germ-free and conventional animals. Bile salts, not considered as digestive enzymes, are qualitatively and quantitatively different, depending on the digestive tract bacterial environment.  In general, the germ-free animal has some characteristics which should permit better utilization of the diet ingested. Measurements of apparent digestibility do not confirm this hypothesis since results obtained in germ-free and conventional animals of the same species are contradictory.

However, a number of experiments in the germ-free animal have shown that it cannot be considered simply as a conventional animal, deprived of gastrointestinal microflora, since certain characteristics of its digestive physiology distinguish it from the conventional animal (see reviews by Gordon et al.,1966 ; Combe et al., 1976). 
A knowledge of these characteristics is essential when determining the part due to bacteria in the digestion of an ingested diet.  The germ-free state in rodents and lagormorphs leads to a substantial increase in cecal sac contents and size (Glimstedt, 1936 ; Wostmann and Bruckner-Kardoss, 1959 ; Wostmann, Bruckner-Kardoss and Knight, 1968 ; Pleasants, 1959). The same observation was made in the rat (Lee and Moinuddin, 1958), mouse (Meynell, 1963) and guinea-pig (Jervis and Biggers, 1964) after antibiotic treatment.


gn said...

the sheer insignificance of caecum in humans would be a very good point against vegetarians let alone vegans!

CarbSane said...

It would seem so, but OTOH, we have molars and the rest of our digestive systems resemble those of herbivores rather than carnivores. I've stumbled across some studies that mice can sense the nutrient content of different foods, and even though they're hindgut fermenters, they select foods they can actually digest.

John said...

... and the rest of our digestive systems resemble those of herbivores rather than carnivores

Does it? Not according to the following articles by Barry Groves:
Comparison Between the Digestive Tracts of a Carnivore, a Herbivore and Man
Should all animals eat a high-fat, low-carb diet?

Typical hindgut fermenting herbivores seem to have short small intestine, long caecum, and long large intestine.
Humans have the opposite: long small intestine, ultra short caecum, and short large intestine.


CarbSane said...

Thinking on this a bit more gn, it might also point to humans seeking/consuming more energy (sugar/starch) dense vegetation and less of the leafy greens so as not to rely on cellulose fermentation (especially given its bulk) for calories.

Sanjeev said...

Add me to the skeptics list ... I forget the specific symptoms that prompted it but I once considered taking those pro biotic supplements.

The papers I read at the time (to check the advertising claims) basically concluded that gut organisms are highly tenacious and it's extremely difficult to significantly change the overall makeup, at least in humans.

I suppose one could force the issue with aggressive antibiotics to kill what's there followed by ingesting beneficial species ... but how to predict which ones will take hold?

gn said...

i thought you might be interested in a series of articles at Hyperlipid about gut microflora:

and info in this one may explain 'weight loss' on a high fat diet:

Sanjeev said...

>> point to humans seeking/consuming more energy
>> (sugar/starch) dense vegetation

Denise Minger wrote on too much of it is similar to your post but with interesting additional detail

Sanjeev said...

google mangled my pst ...

... Denise Minger wrote on this too; much ...

CarbSane said...

This seems so counterintuitive as well. The obese tend to eat less fiber and veggies, most low carbers report eating more veggies than they did before and lose weight. Veggie matter is the main food (soluble and insoluble fibers to a lesser extent) for these bacteria. A change in the types of bacteria may be the result of excessive intake feeding more bacteria rather than more energy extraction by bacteria leading to obesity.

Also in several studies trying to examine various factors in weight stable states where TDEE is measured and then matched with caloric intake seem to be pretty successful in maintaining weight (perhaps sometimes slight losses are seen likely an artifact of more structured eating). If microflora differences were significant to energy extracted from food, we should see much more variability in tightly controlled studies.

Razwell said...

Mice share any pathways similar to humans. This study is yet ANOTHER BLACK SWAN to the caloric hypothesis.

WATCH Urgelt's obesity video. Read the comments from him . YOu have ALOT to learn

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