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The gut microbiome is known as the "final frontier". Some of the most cutting-edge research focus on studying the ins and outs of the gut microbiome, simply because we know so little about it.

Yet, there is strong evidence suggesting that it is hugely important for our overall health & wellbeing. Let's take a look at some of these studies with help from Dr. Brianna Stubbs.

We'll be diving into three papers that studied the effects of diet and intermittent fasting on the gut microbiome.

1. Diet Rapidly and Reproducibly Alters the Human Gut Microbiome
2. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet
3. Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota

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Transcription

Overview

I’m your host Dr. Brianna Stubbs, and today we will be getting down and dirty with the creepy crawlies colonizing your insides - the cast of critters making up your gut microbiome.

The word microbiota represents an ensemble of microorganisms that resides in a previously established environment. Gut microbiota (formerly called gut flora) is the name given today to the microbe population living in our intestine

Our gut microbiota contains tens of trillions of microorganisms, including at least 1000 different species of known bacteria with more than 3 million genes (150 times more than human genes). Microbiota can, in total, weigh up to 2 kg. One third of our gut microbiota is common to most people, while two thirds are specific to each one of us. In other words, the microbiota in your intestine is like an individual identity card.

While each of us has a unique microbiota, it always fulfills conserved physiological functions, that all have a direct impact on our health. Some of the functions include: Helping the body to digest certain foods that the stomach and small intestine have not been able to digest, helping with the production of some vitamins (B and K), helping to combat aggressions from other microorganisms, maintaining the wholeness of the intestinal mucosa, playing an important role in the immune system & performing a barrier effect.

Taking into account the major role gut microbiota plays in the normal functioning of the body and the different functions it accomplishes, experts nowadays consider it as an “organ". However, it is an “acquired" organ, as babies are born sterile; that is, intestine colonization starts right after birth. The balance of bacteria can be affected during the aging process and, consequently, the elderly have substantially different microbiota to younger adults.

While the general composition of the intestinal microbiota is broadly speaking, similar in most healthy people, the species composition is highly personalized and largely determined by our environment and our diet. The composition of gut microbiota may become accustomed to dietary components, either temporarily or permanently. Japanese people, for example, can digest seaweeds (part of their daily diet) thanks to specific enzymes that their microbiota has acquired from marine bacteria.

Although it can adapt to change, a loss of balance in gut microbiota may arise in some specific situations. This is called dysbiosis. Dysbiosis may be linked to health problems such as functional bowel disorders, inflammatory bowel disease, allergies, obesity and diabetes.

So without further ado, why don’t you pop a squat and let’s dive in and I’m going to apologize now in advance for a small splattering of toilet humor and also for any terrible pronunciation of bacterial species...

Diet Rapidly and Reproducibly Alters the Human Gut Microbiome

In this study, researchers based at UCSF took ten healthy American participants, all of one of whom ate a mixed ‘omnivorous’ diet and asked them to make extreme changes to their diets for 5 days straight, and then they took stool samples measured the changes to their microbiome. Everyone’s microbiome fingerprint was studied before they changed their diet, and subjects were followed for 6 days after each diet to see if any changes were reversible and if so, how quickly did this happen.

The two diets studied here were a plant based diet and a diet containing only meat, eggs and cheeses. Subjects on the plant-based diet ate cereal for breakfast and precooked meals made of vegetables, rice and lentils for lunch and dinner with fresh and dried fruits were provided as snacks. Subjects on the animal-based diet ate eggs and bacon for breakfast, and cooked pork and beef for lunch. Dinner consisted of cured meats and a selection of four cheeses. Snacks on this diet included pork rinds, cheese and salami.

While both diets affected the abundance of certain gut microbes, switching to animal-based diets had the bigger overall effect. The researchers saw big shifts in diversity 1-2 days after the diet was started. One of the most surprising things here is that most of those changes happened within a day of starting the diet. Once people stopped the animal based diet, their microbes settled back into an omnivorous profile within a day or two.

Previous research had indicated that stability is the norm for the human microbiome. But these other studies have taken single microbiome snapshots or a series of microbial profiles spaced months apart, as soon as you start to measure on shorter timescales, you see increasing variability around a somewhat stable baseline."

When volunteers switched to the animal-based diet, bacteria including Bilophila wadsworthia, Alistipes putredinis and species in the genus Bacteroides quickly rose to prominence. Those bacteria can withstand bile, which the body releases after a person eats fat. On the meat diet, Alistipes and Bacteroides bacteria also began pumping out short-chain fatty acids. Some of the fatty acids have been associated with inflammation in animal studies, although this study did not measure long-term health effects. Interesting to contemplate who this observations fits with the stories of suppressed inflammation on the carnivore diet that have been discussed in some recent H.V.M.N. Podcasts.

For me, one of the key takeaways here is that the microbial changes are really very transient. This means if you want to really alter your microbiome you need to make changes and stick to them. The authors of the study hypothesize that this might have played a role in human evolution, saying that “consumption of animal foods by our ancestors was probably volatile, depending on season and foraging success, with readily available plant foods offering a fall-back source of calories and nutrients. Microbial communities that could quickly, and appropriately, shift their functional repertoire in response to diet change would have subsequently enhanced human dietary flexibility.”

The Gut Microbiota Mediates the Anti-Seizure Effects of Ketogenic Diet

So, as we’ve discussed before in the H.V.M.N. Podcast, the ketogenic diet has numerous health benefits, including reducing seizures for children with epilepsy who do not respond to anti-epileptic medications. It's actually been used to treat the disease for over 100 years, before the discovery of modern anti epileptic drugs. However, there has been no clear explanation for exactly how the diet aids children with epilepsy.

In this study, UCLA scientists identified that specific gut bacteria play an essential role in the anti-seizure effects of the high-fat, low-carbohydrate ketogenic diet. This study is the first to establish a causal link between seizure susceptibility and the gut microbiota.

The research team conducted a comprehensive investigation using a mouse model of seizures . Firstly, they put mice on the ketogenic diet and confirmed that it was protective against seizures. Like in our first paper, the researchers found that the ketogenic diet substantially altered the gut microbiota in fewer than four days.

To test whether these diet induced changes in the microbiota was important for protection against seizures, the researchers analyzed the effects of the ketogenic diet on two types of mice: those reared as germ-free in a sterile laboratory environment - meaning that they had never had a gut microbiome, and mice treated with antibiotics to deplete gut microbes.

In both cases, the ketogenic diet was no longer effective in protecting against seizures, even though the mice had elevated ketones, which have been hypothesized to have an anti seizure effect themselves. This suggests that the gut microbiota is required for the diet to effectively reduce seizures and ketones alone might not cut it.

The biologists used DNA sequencing to identify two types of bacteria that were elevated by the diet and play a key role in providing this protection: Akkermansia muciniphila and Parabacteroides species.

With this new knowledge, they studied germ-free and antibiotic treated mice that were supplemented with these bacteria. Interestingly, they found that they could restore seizure protection if we gave these particular types of bacteria together. Either of the species given alone did not protect against seizures; this suggests that these different bacteria perform a unique function when they are together.

Finally, doing a fecal transplant (or, less scientifically, “re-poopulating”) the gut microbiome from mice fed the ketogenic diet into mice fed a control diet also was protective against seizures. That’s a bit of an unorthodox use for poop..

So what could the bacteria hiding out in the gut be doing to actually stop the mice having seizures? The researchers measured levels of hundreds of biochemicals in the gut, blood and hippocampus, a region of the brain that plays an important role in spreading seizures in the brain. They found that the bacteria that were elevated by the ketogenic diet alter levels of biochemicals in the gut and the blood in ways that affect neurotransmitters in the hippocampus.

It's very interesting that the microbiome by itself could have such profound effects on the body. One cautionary note is that lab animals have very different exposure to germs than wild mice and also to humans, so its not clear if this mechanism is as important in humans, although these results show we should certainly consider it.

Also I’d say that the conclusion that changes to the gut microbiome, not the the increase in ketones is the main effector mechanism of the ketogenic diet is certainly supported by the data here, but its not entirely consistent with other work which has shown that ketones themselves can protect against seizures in both cell culture and animal models. One of the examples that springs to mind is Dom D’Agostino’s work using an acetoacetate ketone diester, which showed that giving exogenous ketones increased seizure latency in central nervous system oxygen toxicity by 100%.

All in all, interesting results, watch this space to see if similar kind of findings can be found in humans.

Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota

There are two types of fat in your body: Brown fat and white fat. The brown fat is a type of fat that BURNS energy. The white fat is a type of fat that STORES energy. Brown fat is not common in modern adult humans.

Is there a way to turn our white fat brown? There aren't many options that we know of. But, as some of you biohackers may know, exposure to cold will stimulate the production of brown fat cells in our bodies. We call this "shivering thermogenesis". Scientists are working hard to find a weight loss drug that can help "brown" our white fat cells, but more natural strategies may be the key.

Intermittent fasting is one such natural intervention. It’s another one of the research areas that we like to follow here at H.V.M.N. because fasting has very low barriers to entry with a low risk reward ratio and can be adjusted to fit in with most people’s lifestyles. Intermittent fasting raises ketones, decreases inflammation, triggers autophagy and production of new brain cells. Guess what else it does? It can turn your white fat tissue brown!

In this landmark Cell Metabolism paper, we are going to look at every other day fasting (EODF) in mice. The intervention group (the one that gets to feed and fast) (EODF) did 15 cycles of this, for a total of 30 days and was compared to a control group that could eat at will.

The first eye opening finding was that both groups ate the same amount of food, and the fasting group weighed LESS than the control group. The fasting mice had a higher total energy expenditure compared to the control group but this wasn’t due to differences in exercise.

This was because the fasting mice had more "thermogenesis". And indeed, they did generate more heat that the control mice, as measured by rectal thermometers (poor mice). Thermogenesis was being fueled by fat burning, shown by measuring the respiratory exchange rate of the two groups.

The researchers went to the microscope, and found that the fasting group had MORE brown fat and turned some of their the white subcutaneous fat BROWN. These transformed fat cells had two prominent features of brown fat cells: More lobules to them (Think fat cells with baby fat cells attached to them.), and higher amounts of an uncoupling protein called UCP-1. This protein uncouples the protons moving down the mitochondrial gradient from the synthesis of ATP, allowing the energy to be dissipated as heat in a process called "nonshivering thermogenesis"

Now it's time to look at the microbiome. The researchers did the usual before and after sequencing to see if fasting changed the microbiome, and sure enough it did- with the abundance of Firimicutes a Bacteroides being the most changed between the fasting and control group. They also did metabiolic profiling and saw that two metabolites whose levels increased in those mice, namely acetate and lactate, are known beiging inducers from previous research.

Having identified these changes, they then did a microbiome repoopulation from the fasting mice into the control mice and also mice with metabolic syndrome- and saw that this triggered many of the changes that had been seen in fasting mice- white fat beiging and increased uncoupling protein expression. To confirm their findings, they looked at the effects of fasting in germ free mice, and without the microbiome, fasting did not trigger the beneficial changes.

So, its not just WHAT you eat, but also when or how often you eat, that can drive some powerful changes to the bacteria in your gut.

Conclusion

I want to wrap up with some general thoughts that apply to all of these studies. Over the last few years scientists have called the gut microbiome the ‘new final frontier’ which is ironic as it is close to home for all of us.. It's clear that there are complex, deep rooted links between what we eat, the bacteria we are exposed to in our environment and many aspects of our health- our brains, our metabolism - and much more. It's amazing to think that there are thousands of bugs living inside of us, talking to the huge cluster of nerves in our guts (called the enteric nervous system) and having effects throughout the body.

That said, gut microbiome is a trendy topic right now, and as with all trendy topics I suspect there will be some conditions where it is a key contributing factor and others where there are changes that correlated but don’t drive the change in condition. And many of the early promising findings from animal studies need to be tested out in humans, and I think the picture will become far far more complex.

We still don’t understand how changing our diet affects us as individuals, because we all have an individual microbiome either changing your diet or supplementing with probiotics or prebiotics to try and change your microbiome might work better for some people than others. At the moment, one of the only ways that is scientifically proven to successfully manipulate the gut microbiome is by re-poopulating people who have had a bad infection with a bacteria called C. Dificile - this treatment can restore their microbial diversity and improve health. There is much more controversy about ways to use the microbiome to help in other conditions. I wouldn’t advocate finding yourself a poop donor just yet - but watch this space as science starts to get to (wait for it) bottom of things.

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