Can a bacterium help you lose weight ?

Yes, it's called Cholera. There, story over. Nothing to see here.

All right, I'll try to leave the snark aside for this story.  It's just that every time I look at a story extolling the virtues of a new weight loss treatment based only on data from mice, I get slightly sceptical. But let's take a look at this new piece of research published in PNAS this week and give the research a fair hearing.

The bacterium that is the focus of this research is Akkermansia mucinophila. This bacterium was discovered in 2004 in the guts of humans, where it was suspected to degrade gut mucus. It is one of the "friendly" commensal bacteria which live in the diverse ecosystem of your gut.
A question that has interested a number of researchers worldwide is whether the type of bacteria that inhabit your gut ecosystem affect your weight.
I have mentioned in one of my earlier posts about how researchers can study obesity, through the use of genetically modified mice which don't produce a hormone (called Leptin) which acts to signal to them when they have too much fat and tells them to stop eating. With this gene turned off, mice eat uncontrollably and become fat. Early studies showed that these "Super" fat mice had a different gut ecosystem to the normal mice. Interestingly, if you were to take the "gut ecosystem" of a fat mouse, and gave it to a thin mouse, the thin mouse would start to gain weight. Unfortunately, the researchers didn't show the reverse effect occurring. But it was a promising start.
In other work using humans, the gut ecosystem of a fat person has been shown to be different to the ecosystem of a thin person. In these studies, one bacterium tended to stand out. Akkermansia mucinophila, whilst a key component in the healthy digestive system, is rarely found in obese people.
What is it about this bacterium ?

The researchers found that Akkermansia had a lower population within the gut of  Leptin deficient mice compared to healthy mice. I mentioned in the previous research that people looked at leptin deficient mice. Whilst these mice are fat, they aren't like most fat humans. Only ten people have ever been shown to have a genetic leptin deficiency. So these leptin deficient mice (called ob/ob) aren't like normal overweight humans.
 A more relevant model would be to feed mice fattier food. The equivalent of moving a human from salads to hamburgers. So they moved mice from the normal standard diet to a high fat diet, which tends to make them gain weight. As a result, the numbers of Akkermansia in these mice was lower than mice fed on a healthy diet.
But what would happen if you tried to increase Akkermansia numbers within the gut of a mouse when you start to feed it high fat food ?

They mixed in a prebiotic compound with the high fat diet to nswer this question. The compound they used was Oligofructose. This compound is known to increase the amount of mucus producing cells in the gut. Thus, it increases the amount of mucus. Since Akkermansia eats mucus, increasing the amount of food available for it causes its population to increase in the gut.

The mice fed on the high fat diet with the prebiotic added did not gain as much weight as the mice on a diet without the prebiotic.
Further more, the researchers noted that there were less inflammatory signals from the intestines from mice fed on the prebiotic than mice which were not. Why were the researchers interested in this ?

They were interested, because of something called Metabolic Endotoxemia.
The story goes like this :

• Fat cells play an important role in regulating the energy balance of the body, telling you when you have had too much to eat, or when you have had too little. 
• In a number of studies, Obese people have been shown to  have muscle and fat cells that send out unhealthy levels of inflammatory signals.
• The increased levels of fat in the blood can be helpful to the immune system during infection, but if the fat levels in the blood remain high for too long, they keep the immune system activated, which leads to chronic inflammation.
• This inflammation leads to the cells of the immune system to send out signals to eachother. The signalling between cells that regulate the immune system and those that regulate your metabolism often interact with eachother in normal situations. But in this case, the signals interfere with eachtoher, leading to some cells to stop producing insulin, which leads to diabetes.

Metabolic Endotoxemia can lead to the cells responsible for regulating the energy balance of you body to become less effective. It not only ruins a persons ability to control their own blood sugar, it also affects their ability to regulate their body fat and energy expenditure.

So with that, we have to look a the next experiment the researchers did. They took groups of mice, and fed them concentrated cultures of Akkermansia every day for four weeks. Mice were either fed on a healthy diet, or the High fat diet. 

They found that once again, mice fed with a high fat diet and Akkermansia gained less weight,and reduced the signs of inflammation caused by a rapid increase in weight. But how do we know whether this is the right kind of weight loss ? What if the mice are losing weight just because these treatments are making them ill ?

To work this out, they had to look at where exactly the mice are losing weight from. Were the fat stores being depleted, or were the mice losing muscle mass instead? So they used a neat piece of technology known as a body composition analyser. The body composition analyser is a tool to analyse the different chemical forms of fat and muscle within the body. They can put a live mouse in the machine and get a reading for the levels of fat in proportion to "lean tissue", and then take it out unharmed. So you can watch exactly what type of fat is accumulating within the mouse throughout the experiment. On all of these scales, the mice who were fed Akkermansia not only put on less fat, but had a body composition similar to healthy mice.

Unfortunately, I don't exactly know what a sick or starving mouse's body composition would look like to compare with these graphs. In fact, despite the fact that they allegedly took measurements every day, they only display the final time points, and seem to show the kind of data that could only be obtained from dissection rather than the use of a body composition analyser.

But fat in itself isn't the most damaging part of obesity. As I've indicated before, Metabolic Endotoxemia can lead to diabetes. They showed that inflammation can occur after this high fat diet. But did the mice show any signs of developing diabetes.

This is why they tested fasting hyperglycaemia. What is fasting hyperglycaemia, and why do we care about it ?
 In normal people you see hyperglycaemia occurring immediately after they have eaten. If a person has not consumed any food for a significant amount of time and is still hyperglycaemic, then it indicates that they cannot control the levels of sugar in their blood. In essence, it is a key sign of diabetes.

So they starved mice on these diets, and then tested to see whether they were still hyperglycaemic after a set amount of time. Mice provided with a high fat diet tended to show fasting hyperglycaemia, but the introduction of Akkermansia changed this. It appeared to lower the amount of sugar in the blood of mice fed on the high fat diet, although not the the levels of healthy mice.

So how were the mice suddenly able to control the levels of glucose in their blood ?
It comes down to insulin. When the liver senses this hormone, it soaks up the excess glucose from the blood, and converts it to glycogen. When there is a drop in the blood glucose levels, the liver converts glycogen back into glucose. In unhealthy animals, the conversion of glycogen into glucose is less well regulated, and leads to more glucose being released into the blood.
They tested the mice to see how well they reacted to insulin. Mice that don't react at all tend to become diabetic. So it is a good sign that the inclusion of Akkermansia  into a high fat diet tended to give the mice a better reaction to insulin than if mice were fed with a high fat diet only.
All of these bits of evidence seem to show that Akkermansia  can somehow prevent weight gain and hamper the progression of diabetes in mice fed with fatty foods.

So the next part of this research is where is gets complicated. You see, the storage of fat in your body is a dynamic process. You have special fat storing cells known as adipocytes, which can differentiate and change and adapt to changes to the way you eat. The amounts of lipids they manufacture, just for the day to day uses in the body, change depending on diet. If you have a high fat diet, they don't manufacture as much fat.  They also can oxidise the fats they store, and break them down. So the researchers took cells from the fat layers of the mice, and tested them to examine what they were doing.
The adipocytes of mice fed a high fat diet tend to differ from those fed a healthy diet. But when you add Akkermansia into the mix, in nearly all cases, it make the adipocytes behave as if they were in a healthy mouse, even if the mouse they are residing within is eating a high fat diet. So somehow, Akkermansia can controlling the way fat is stored within the body.

The researchers suspected it may have something to do with the way the intestine defends itself from infection. Some cells within the intestine can produce chemicals to kill off bacteria, known as Antimicrobial peptides. But they found no statistical differences between any of the treatment groups in terms of antimicrobial compounds.
They looked at the cells that produce these compounds, and found that they were more highly activated in mice fed on a healthy diet when exposed to Akkermansia.  But Akkermansia  produced no such effect in mice fed on a high fat diet.

There is a theory that the gut microbiota can regulate fat levels by communicating with the intestine via compounds known as endocannabinoids.

They examined the levels of three different endocannabinoids, 2-palmitoylglycerol (2-PG) 2-oleoylglycerol (2-OG) and 2-Arachidonoylglycerol (2-AG). These endocannabinoids are signalling compounds which can change the way the intestine absorbs certain compounds.
  The levels of these compounds were much higher in the mice which were fed Akkermansia in groups fed on the healthy and the fat diet. This suggests that the Akkermansia is in communication with these cells in the intestine, and somehow changes the way they absorb molecules.

They then looked inside the gut itself. They wanted to see whether the Akkermansia affected the thickness of the mucus layer within the gut. This acts as a barrier to pathogens, and protects the living cells on the guts surface, whilst still allowing nutrients through. The increase in mucus thickness could impair the guts ability to absorb nutrients. This layer is thinner in mice fed on a high fat diet, but when those mice are instead given Akkermansia, the  mucus layer becomes thicker.

So this draws us to the final set of experiments. They know that Akkermansia is needed to for all of these things to occur, but does it need to be alive ? This a chance for them to test how active Akkermansia is in regulating fat deposits. They repeated all of their previous tests, but this time with an additional control group. One group were fed a high fat diet, with dead Akkermansia  as the supplement. The dead bacteria did nothing.

Paper Readability
I would heartily recommend you read this paper, because why should I be the only one the suffer ? The main problem with this paper is that has been horribly compressed to fit the space allocated to it by the journal, and that a lot of the juiciest results are in the supplementary section. It is because of this that it is really difficult to understand what the researchers did. The methods section has been chopped up between the supplementary section and the actual paper. They only mention the whole body fat analyser in passing, and its unclear whether any of the data they show comes from using that piece of equipment.
It is a complex paper, and it really needs more space than it was given.

Conclusions
There is a great story at the centre of this article.

Once upon a time there was a bacterium in your gut called Akkermansia mucinophila. It lives in the protective mucus lining of your gut, and feeds on it. It always made sure there was enough delicious mucs by telling the cells of your gut to keep making it. This made the mucus layer nice and thick, which was not just good for Akkermansia, it was good for you. That thick mucus layer stopped harmful bacterial components entering your body, and reduced the amount of fat entering your blood stream.
But then you decided to eat your own weight in milkshakes every day for nine years, and everything went downhill from there. The poor Akkermansia couldn't survive in these conditions, and eventually became extinct in your gut. The protective mucus layer in your gut that it had so diligently maintained, became thinner. Harmful bacterial components entered your blood stream, alongside big globs of fat, giving you metabolic endotoxemia. Your fat cells and you immune system couldn't cope, and went to war. The cells that produce insulin were killed in the crossfire. That is when you became diabetic, and it is why you died after one particularly grotesque Oreo milkshake binge. Witnesses say that your last words were "Totally worth it"

The researchers have shown that Akkermansia  could reduce some of the negative outcomes. They have shown that in mice at least, it can reduce insulin sensitivity, and possibly slow down the progression to diabetes. It does this through maintaining the mucus layer in your gut wall for completely selfish reasons.
Hypothetically, this causes the gut to be less absorbent to fats to bacterial compounds.
But whilst this paper produces an interesting case that there is some communication occurring between the bacteria and the gut, it doesn't tell us anything about how this happens. We still don't know what the signals are between the bacteria and the gut wall, and even the immune system.

So, can Akkermansia help you lose weight ?

No. There is no evidence in this paper to suggest this. All of the tests looked at the reduction in weight gain. Changing the amount of weight you gain is quite different from weight loss. But Akkermansia is still an interesting example of how the bacteria that coexist within us act for both their own selfish reasons, and for our benefit.


Everard A., Belzer C., Geurts L., Ouwerkerk J.P., Druart C., Bindels L.B., Guiot Y., Derrien M., Muccioli G.G. & Delzenne N.M. & Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.1219451110