Akkermansia muciniphila, the Weight Loss Bug

"These results provide a rationale for the development of a 

treatment that uses this human mucus colonizer [A. muciniphila]

for the prevention or treatment of obesity and its associated

metabolic disorders."

- A. Everard et. al., Proc. Natl. Acad. Sci. USA, 2013, 110(22), 9066-9071

Looking over my recent posts, it appears that I've been focusing on all of the reasons why we should be afraid of bacteria.  They're in your food, and they're antibiotic resistant.  Tuberculosis is a world wide scourge.  Killer MRSA strains are lurking everywhere, and they're practically invincible.  Be afraid, be very afraid!  And to think that a few days ago, I complained about the news media always trying to scare the hell out of everyone.  Back in my July 3rd post, I promised I'd discuss something that would make us all feel a little bit better about the bugs we live with, and today, I'm finally going to make good on that promise.

I'd like to introduce you to a bug named Akkermansia muciniphila (IJSEM, 2004, 54(5), 1469-1476).  A. muciniphila is a rod shaped bug.  It's so intolerant of oxygen that it dies if it encounters any.  It secretes a sticky layer of molecular goo all over the surface of its cells.  It survives by eating mucus (yum!).  Oh, and by the way, it's living in your intestine.  Well, according to a report that came out in May in the journal Proceedings of the National Academy of Sciences of the USA (A. Everard et. al., 2013, 110(22), 9066-9071, I at least hope it's living in your intestine.  We'll get to why I hope that in a moment, but first, a little bit about your intestine.  Readers of this blog know that the human gastrointestinal (GI) tract is populated, top to bottom, with many 100s of different species of bacteria - the collective bacterial population is known as the human microbiota.  Our bacterial cohabitants cover our inner surfaces and they fill the spaces in the middle.  The vast majority do not cause disease and are actually supposed to be there.  They help us digest and absorb food and nutrients, they share resources with each other, they stimulate our immune system, and sometimes they even protect us from disease causing microbes.  It is now commonly accepted in the research community that the composition of our microbiota (what bugs are there?, where are they?, how many of them are there?) is dependent upon diet.  For a healthy adult, studies have shown that A. muciniphila comprises no less than 3-5% of the bacteria residing in the human gut.  This bug certainly makes its presence known.  It lives in the layer of mucus that lines the surface of the gut.  In every day parlance, "mucus" usually elicits a "yuck!" response, but the mucus lining of the GI tract is exceptionally important.  It plays a large protective role for the delicate tissue underneath and it is important for nutrient absorption into the rest of the body.  The researchers in this impressive study were able to show that A. muciniphila is far more abundant in lean, healthy mice compared to obese and/or diabetic mice.  More interestingly, feeding obese/diabetic mice live cultures of A. muciniphila helped reverse the effects of obesity, diabetes, and the low-level systemic inflammation associated with these disorders.  Lastly, they were able to show that a high percentage of A. muciniphila was correlated with a healthier, thicker mucus layer.  Given these results, the popular scientific press as well as high visibility research journals couldn't help but slyly suggest that A. muciniphila could be the next big weight loss therapy or treatment for adult onset diabetes.  Like good microbiota researchers, the authors asserted similar sentiments (see quote at top), but delivered their message along side a solid dose of, "... but there's still a lot that we don't know, so let's not get carried away."  Let's look at some details, shall we?

Mice are the model organisms for microbiota research.

The most headline worthy result was that administering live Akkermansia muciniphila cells to obese and diabetic mice counteracted many of the deleterious issues associated with these disorders.  Reductions in fat tissue, body weight, toxic metabolic byproducts, glucose tolerance (diabetes symptoms), and improved mucus layer health were all observed by providing living A. muciniphila cultures orally (i.e. the mice "ate" the bacteria).  None of this was observed by administering nonviable ("dead") A. muciniphila in the same fashion.  Thus, the positive effects are only observed if a diseased individual is populated with some threshold level of living, metabolizing, A. muciniphila cells, and not simply from chemical factors that would have been present from the dead cells passing through the GI tract.  To get the benefits, you need a viable population of this microbial symbiont!

Giving diseased mice a healthy dose of live bacteria seems like a very obvious thing to test, right?  After all, probiotics - cultures of living "good" bacteria that you take like medicine - are kind-of all the rage right now (think Activia*, for example).  But the beauty of this paper is that it demonstrates more subtlety than meets the eye, at least from our discussion thus far.  Recall one very important thing: A. muciniphila comprises 3-5% of a healthy microbiota.  The obese and diabetic mice aren't missing the bug, they just have less of it.  Given that the composition of the microbiota, and many of the negative effects associated with obesity and diabetes, are impacted directly by diet, the researchers explored the possibility of rehabbing the microbiota directly.  What would happen if you fed mice something that would favor the regrowth of A. muciniphila to the levels associated with a healthy mouse gut?  To answer this question, the group fed obese mice a diet rich in oligofructose, a mixture of short-chain sugar polymers that avoid digestion in the upper GI tract and that A. muciniphila can tap as a preferential food source.  The team found that feeding the mice oligofructose resulted in the restoration of healthy levels of A. muciniphila, and they observed a concomitant reversal of the adverse effects of obesity and diabetes - just like feeding the mice live cultures of the bug.  This suggests that diet alone can help reverse the most common problems associated with these health disorders.  You might read this and think, "Well, duh!  You're telling me all I have to do to lose weight is change my diet!"  And you might say this because you aren't thinking like a drug manufacturer or purveyor of dietary supplements.  Here's the vision you ought to be having:  1 pill, consisting of 50% A. muciniphila and 50% oligofructose, a bright shiny label reading, "The #1 All Natural Weight Loss Probiotic-Prebiotic on the Market!", and full page adds and billboards declaring, "Buy 1 bottle for $24.99, get the second one Absolutely Free!".  Yeah, that's what I'm talking about.  Snake oil peddling aside, the link the researchers made here is important and interesting.  It ties a specific probiotic bacterium, A. muciniphila, to a very specific prebiotic - the stuff you can eat that favors the growth of your "good" bugs.  Oligofructose anyone? (Hint: this shows that the high-fiber "hype" may not be all hype.)

Anti-inflammatory endocannabinoids

The chemically minded reader my now be asking, "So, what are the mechanisms here?  It sounds like this bug is altering metabolism, so what are the chemical details of this system?"  It's a good question, and to be honest, many of the chemical issues still need to be worked out.  However, this study did look at the effect A. muciniphila had on a suite of anti-inflamatory compounds called endocannabinoids.  Specifically, the inflammation fighting compounds 2-arachidonoylglycerol (2-AG), 2-oleoylglycerol (2-OG), and 2-palmitoylglycerol (2-PG) were found to be produced at higher levels by intestinal cells when the A. muciniphila population was maintained at healthy levels.  The factors stimulating the production of these natural anti-inflamatory compounds needs to be investigated further, but this paper now gives chemists a viable system and target to study.  This should come as welcome news to patients suffering from inflammatory bowel disorders, who currently must undergo surgery to affect long-term fixes to any of a number of given disease states.

If anything, this study once again demonstrates the centrality of human bacterial symbionts - our microbiota - in maintaining good health.  A. muciniphila now has its claim to fame as a jack-of-all-trades bug that can potentially be used to combat a lengthy list of metabolic issues that negatively impact huge portions of the western population.  Whether or not this bug can or will be sold as a panacea remains to be seen.  Well informed scientists would caution that we still have much to learn about our microbial symbionts.  That the ecosystem we call our gut is very complex and that we've barely scratched the surface.  Indeed, the overblown promises of the human genome project ("Sequence the genome, and cancer and diabetes will be a thing of the past!") are fresh in the minds of all stripes of biological scientist.  Nevertheless, this study is important in its detailed looked at a microbe that is clearly consequential to human health.  This ought to illustrate that, even though the media usually hypes the bad bugs, we have a lot of friends in the microbial world.

- @EJDimise

(* Not an endorsement of Activia and/or the health/nutritional benefits claimed by the manufacturer.)