Gut Bacteria and Obesity

DR.

ALAN WALKER: OK well Hello, everyone. My name is Dr. Alan Walker. I’m a scientist based at the University of Aberdeen, and I’m going to talk to you today about the potential ways in which the microbes that live inside our guts might impact on things like weight gain and on weight loss. And by the end of 15 minutes or so lecture, I hope that you’ll come away understanding what’s meant by the term, gut microbiota. Hopefully, you’ll be able to understand and describe some of the mechanisms the microbiota might use to play a role in weight gain and weight loss.

But I also want you to leave with a sense that this actually is, in many respects, quite a controversial area of research. There’s a lot still to be learned. And we still don’t really understand the extent and the nature of the microbiota’s role in diseases such as obesity. OK. So just to start, one of the main things I want to get across is that we all associate microbes with disease, the germs that cause a whole range of nasty diseases of humans, but this is actually a very tiny proportion of the number of microbes that live on the planet. 99.9% And above actually don’t cause disease and frankly don’t care about us whatsoever.

And indeed, our body actually is host to a huge number of microbes all the time. And so the collection of microbes that live inside our body as a whole is called the microbiota, and it’s a huge number. OK. So I want to go across this in this slide here, focusing just on the gut microbiota. That’s the species of microbes that live inside our guts. It’s a massive number. The picture on the left hand side there that’s a microscopic image showing microbes inside a faecal sample. And you have to dilute it 1 in 10 because if you don’t delete it, they’re all crammed in together so closely that it’s actually hard to make out some of these cells.

To try and visualise that in numbers, I often use this chart here. And so what’s up here? That’s the population of the UK. It’s about 65 million. On the same scale, the population of the world is about 7.5 billion. So, you know, it’s a big number. But again on the same scale, what just appeared here in brown that is the number of bacteria in just 1 gramme of what I’ve politely termed gut contents. It’s about 100 billion in just 1 gramme. And if you consider 1 gramme weighs roughly the same sort of average, small-sized paper clip, then obviously we have a lot more than that inside our guts. So that number could be even 1,000 times higher at that scale.

You might have 100 trillion bacteria living inside your guts. So imagine that brown section as 1,000 times higher, and then you’re starting to visualise just quite how many bacteria are sitting inside your guts as you listen to me speak. And so it’s important to note that the number of cells in our body varies depending on what side of the body we look at. And most microbes are living inside our colon or our large intestine, but there’s also a huge diversity of microbes in there too. There’s thousands of different species that can live in our gut. And so if I was to ask you, can you name me a gut bug? I suspect most people would see either E.

coli or they’ll say lactobacillus, a kind of probiotic type organism. But in fact, E. coli is less than 1% of most people’s microbiota in their gut, and lactobacilli are 0.1%. These are very much minority components. And instead, it’s species such as bacteroides, or faecalibacterium, roseburia these are the dominant groups in our gut these might be 5%, 10%, 15%, or 20% of our microbes. And this matters because our microbiota matters. We now know that it plays key roles in a whole range of different facets of human physiology, including nutrition. It defends us against invading pathogens and can also stimulate our immune system in various ways. And I’ll touch on these as I go through the rest of the lecture.

However, we also have to acknowledge that it seems the microbiota might also be playing a role in a range of human diseases. And it’s been seen when people compare the microbiota of people with disease, and I’ve listed a few of them in this image here, versus people who are healthy, there are differences observed in the microbiota. And obesity is one of these conditions. Now, I think it’s really important to add a caveat at this point that this is just a correlation. If you see a disease cohort and you see a healthy cohort and you compare them, there are differences. That doesn’t mean the differences are causal.

If you have obesity, you might have a different diet which might drive different microbes to be present. If you’ve got an inflammatory bowel disease, you’d have diarrhoea and that might cause the microbes to change. So it might not be causal. It might be an effect of the disease. So what is the evidence for the microbiota being important in obesity in particular. So as I say, there’s now numerous studies when they compare the microbiota of people who are lean versus people who are obese, and very often you see differences between the two groups. However as I say, that proves nothing in and of itself.

And so some of the best proof has come from rodent model studies, particularly the ones that I’ve shown an overview of on the left-hand side of the slide. And in this study, what they did is they took twins who were discordant for obesity, and by that I mean there was one twin who was obese, and the other twin was lean. And they took faecal samples from those people and they transplanted them into mice. And they found that the mice that received faecal transplants from an obese twin they gained a lot more weight than the mice who’d received the sample from a lean twin, therefore indicating that something about the microbes was causing these mice to gain more weight.

Now, it’s important to note that this is very much dependent on the background diet. So if you put a lean person’s microbiota into a mouse but fed it a bad diet, it still gained weight. It’s still increasing in adiposity. The microbes alone weren’t enough to protect it. It’s still diet dependent. That’s an important caveat. But what this work established was that at least in rodents, there was evidence that the type of microbes that are in the gut can impact the amount of weight that is gained by the animal. And so how might this happen? There’s a few potential mechanisms, and one of them is through enhanced energy harvest from our diet.

And so normally when we eat things like dietary fibre, our body actually lacks the enzymes to break that down. And so the fibre passes through our small intestine into the large intestine, and there, as you can see in the upper left-hand side, it becomes rapidly colonised by microbes. Those little dots that are on the surface of that fibre our microbes basically breaking it down into smaller monosaccharides, which it then ferments into what are called short chain fatty acids as part of their growth. It grows on these fibre. And basically what this does in return is provides us with energy because we actually absorb these short chain fatty acids across our gut.

And so the cells that line our colon they get about 70% of their energy needs from just one of these short chain fatty acids called butyrate. And so as I said on the slide, that basically increases our energy yield from the diet. We get energy from things like fibre, which we lack the ability to break down and get energy from ourselves via our microbes. And so that might account for perhaps up to 5% of our total calorie intake every day. And it’s also important to note the SCFAs in rodent models have been shown to impact things like satiety. So if you expose these rodents to short chain fatty acids, they actually feel fuller and they eat less.

So again, it’s another mechanism by which these SCFAs might, and it’s still to be proven conclusively in humans, but might be playing a role in weight gain. However, I need to add some caveats here. You’re talking a very small number of calories every day. Now, of course, over time that can add up. But you would expect the body to equilibriate. You don’t just continually gain weight over time just from a tiny amount of calories. In addition, I think it’s really important to get across that the faecal transplant experiment you saw in mice they don’t seem to be repeated very well in humans.

So faecal transplants have been taken from people that are lean, and they’ve been given to people who have obesity. And those individuals do not lose weight after their microbiota has been changed. So again, I think it’s controversial quite what impact our microbes are going to have on losing weight. And certainly most of that compelling evidence is coming from rodent models rather than from human studies. And again, three relatively recent studies have compared all of the different microbiota studies looking between obese and lean people, and actually they find there isn’t a consistent microbiota pattern that says, if you have that microbiota pattern in your gut, you’re going to be obese. And if you have that one, you’re going to be lean.

There isn’t such a thing. It doesn’t exist. And so is the microbiota really causing obesity? I think it’s plausible that it might have a role via some weight gain. But if we want to lose weight, I think there are clearly easier ways of doing it than trying to target our gut microbiota. I’m generally rather sceptical about the role this might play overall in weight loss. However, on the flip side, I am slightly more convinced of the role the microbiota might play in weight gain, particularly in context of children who are malnourished. And so a lot of people started looking into children in developing countries who may have poorer growth, stunting, malnourishment and looked at their microbiota.

And it was found that the kids that were malnourished, they certainly do seem to have a different microbiota. It’s slower to mature. It’s less diverse, and it has more opportunistic pathogens that could cause low level disease than children who have a normal weight gain trajectory. And so again, looking at faecal transplant experiments that have been carried out in mice and again taking micro faecal samples from children who are at a healthy weight, the mice gained a sort of set amount of weight based on that. But again, if you take faecal samples from children who are undernourished or have shown poor weight gain, then the mice actually gain less weight.

So again, it’s further evidence that the microbes are playing a role, at least to some extent, in weight gain. Now, some of that might be due to energy harvest, as I discussed previously, particularly in the context of low to middle income countries where there might be more consumption of fibre as a general rule. It’s certainly possible that more energy is coming from the microbiota in these populations than in a westernised type population. But however, it may be other mechanisms involved here too because it’s important to know that undernutrition is not always as a result of too little food. Children can have adequate calorific intake every day but still fail to thrive and gain weight properly.

And that’s thought to be linked to a range of other factors, such as poor sanitation, exposure to toxins and pathogens in the environment. And the microbiota can be plausibly linked to all sorts of these other factors in many different ways. And so just to briefly give you an example, one example is of a disease called environmental enteric dysfunction. And in this case, this is a disease that’s caused by continual exposure to contaminated food and water, so pathogens in the environment. And so what happens is that this causes low level intestinal inflammation, and that essentially leads to damage to the intestine over time. And you can see that on the right hand side there.

Panel A at the top that’s a normal cross section through a guts, and you can see the long villi there, which obviously are there to absorb nutrients from the body. But in panel B at the bottom, that’s EED. And that shows that the villi are stunted. They’re blunted. And by doing so, that impairs the absorption of food, vitamins, and minerals leading to poorer growth in the children even if they’re getting enough food, and things like development of malnutrition and stunting. And so in this respect, the microbiota is thought potentially to be protective because there’s a number of ways in which the microbes can stop this sort of condition happening in the first place.

So the first is that the gut microbiota actually outcompetes a whole range of pathogens. It stops them getting in, dividing, and causing disease in the first place. So by outcompeting and killing off the pathogens, that stops this low level inflammation occurring and this blunting of the villi. Secondly, they may also impact on host immunity. I told you the microbiota impacts on the host immune system. And so short chain fatty acids, for example, can dampen down inflammation, but they can also feed the gut epithelial barrier to strengthen it. And in the same way, that might stop pathogens getting in and causing damage, and again help the intestine to repair itself, and then absorb nutrition from the foods in more effective ways.

And so with that in mind, the microbiota is now being targeted in new therapies to try and improve the ability of children who are malnourished to absorb nutrition from their diets. And I’ve included a little link to a blog at the bottom there describing some pilot studies that have been done whereby microbiota is kind of a target of diets that are given to these children. It’s not just about getting calories into them. It’s about feeding them components that will promote the growth of beneficial gut bacteria. The idea being that it will protect their gut from conditions such as EDD and allow them to grow better and thrive better.

So just to summarise this lecture then, I hope that I’ve convinced you the microbiota may play a role in weight gain or loss, and certainly there’s lots of evidence for connections between what we eat, the microbiota, and our gut health. And there are a range of different mechanisms, things like enhancing our energy return from consumption of plant fibre, protecting our guts against invading pathogens that might cause wasting disease, and again things like immunostimulatory and satiety enhancing-effects. However, again just to make clear, a lot of these mechanistic links still need to be thrushed out with more research. However, the microbiota is emerging as a potential target, as a therapeutic intervention source.

But again, I would postulate that actually it’s more likely to be effective in helping weight gain in undernourished children than weight loss in obese and overweight adults in a Western setting, simply because there’s all these other confounding factors like poor sanitation where the microbiota can help more, which doesn’t really apply in most cases in westernised settings. OK. And so with that, I think the important message to take away is that you’ll see a lot of hype about the microbiota. If you go in the popular press and read the internet, there’s lots and lots of stuff on there about the microbiota. And I guess that’s because there’s a lot of promise.

We’re now understanding a lot more about the microbiota and why it might be important for health. But I think what I really want to get across in this short lecture is that quite often you have to take this with a pinch of salt. So again, you might go looking for probiotics and you might find– if you Google it, one of the things that comes up is, what’s the best probiotic for weight loss? There are no probiotics available that are effective in weight loss. The only microbes that are affected for weight loss are nasty pathogens that give you diarrhoea like norovirus. They work, but you don’t want to go anywhere near them obviously because they’re very bad for your health.

And so I think I would just end this lecture with a sort of caution. Try and watch out for hype. It’s a hugely exciting era of the microbiome, but science is slow. It can take years and decades to verify findings, and it’s really important to note a bit like the obesity story in mice, that results from animal studies may not be replicated when they’re tried in humans. And so again, just take things with a pinch of salt, be cautious, and always ask what’s the level of proof. Can I really believe what I’m reading? Is the microbiome really having such an effect?

And certainly, in obesity that’s one of those conditions where we do need a lot more research to really verify the role it’s playing. OK. With that, I’ll wrap up the lecture. Hopefully by the end of this, you have come away knowing what’s meant by the gut microbiota. Hopefully, you can describe some of the mechanisms that might play in weight gain and loss. And as I say, I’ve covered at the end there some of the controversy in the field about the exact extent and impact of the microbiota. And with that, I’ll end the lecture and say thank you very much for your attention. Thank you. Goodbye.