Two cups of coffee after learning may cure your forgetful streak

Like most junkies, I struggle to come up with excuses to justify my addiction. Lucky for me, increasing evidence is supporting my semi-hourly coffee habit: caffeine, the world’s favourite drug, not only keeps you awake and alert, but may also boost your memory.

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Here, have a memory-jolting Latte. Source:

Perhaps in an effort to excuse their own coffee addiction, many research groups have studied whether caffeine enhances memory. The results, unfortunately, are highly mixed. One study, for example, found that 200mg of caffeine – roughly the amount in two cups of drip coffee – consumed before a memory-taxing game enhanced working memory, the ability to flexibly maintain and manipulate information in your head to solve a problem. The catch? Only if you’re an extrovert. In a separate cohort of volunteers, 75mg of caffeine (roughly that in a cup of espresso) taken together with glucose on an empty stomach helped stabilize a new verbal memory. This is called “memory consolidation”, whereby new and unstable memories are moved into semi-permanent storage. However, in that study caffeine by itself had little effect on memory.

One problem with these previous studies is that caffeine was always given prior to learning or testing. This makes interpreting any improvements in performance difficult: is caffeine directly boosting memory or is it enhancing performance indirectly through increasing attention, vigilance and/or processing speed, thus giving the appearance of memory gain?

D Borota et al. Post-study caffeine administration enhances memory consolidation in humans. Nature Neuroscience, published online Jan 12, 2014. doi:10.1038/nn.3623 

To get to the bottom of this, researchers from University of California, Irvine* decided to see how caffeine consumed after learning affects memory consolidation. They recruited 160 uncaffeinated adults, a rare breed that drank less than 5 cups of coffee per week and showed no traces of caffeine or its metabolites in their saliva prior to the experiment. In fact, average caffeine intake of most of these “caffeine naïve” people lingered around 70mg a week, coming mostly from chocolate and soda rather than coffee per se. (*The research described in this post was done at Johns Hopkins before the lead author moved to UC Irvine)

The volunteers first looked at a series of images of various objects, such as a saxophone, a sea horse or a basket, and categorized them as either an indoor or outdoor object. Upon completing the task, they immediately popped a pill containing either 200mg of caffeine or a placebo and left the lab.

A day later, the volunteers returned. By now all traces of caffeine and its metabolites had washed out of their system; they were stone-cold sober. The researchers then showed them a new series of pictures, instructing them to identify whether they had previously seen the picture (“old”) or if it was new. To make things harder, researchers sneaked in several pictures extremely similar those shown before. For example, instead of the old picture of a svelte sea horse arching its back, they now presented a “lure” picture of the animal hunched over. This type of “pattern separation” task is considered to reflect memory consolidation to a deeper degree than simple recognition.

Regardless of caffeine intake, both groups had no trouble identifying the old and new pictures. However, as shown below, the caffeinated group outperformed their peers in picking out the lure, with a higher propensity of calling them out as “similar” rather than “old” (though the effect was small and barely reached significance, more on that later). In other words, caffeine seemed to help them retain minute details present in the original pictures. A similar boost in performance was seen when researchers repeated the experiment with 300mg of caffeine (~1 cup more than before), but the advantage disappeared when they dropped the dose down to 100mg. Remember that caffeine was administered after viewing the photos, hence the drug was not increasing attention to detail during the learning process.

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White bar is caffeine and grey bar is placebo. Notice the shorter white bar in the “Old” group (fewer lure images identified as old) and taller white bar in the “Similar” group (more images correctly identified as lure).

However, not everyone metabolizes the same 200mg caffeine pill to the same degree. When researchers accounted for individual differences in caffeine absorption and metabolism, they found that participants who broke down the largest amount of caffeine performed worse than those who metabolized slightly less. In other words, there is a sweet spot for caffeine’s memory enhancing powers – go either under or over and you loose that edge.

Finally, what if you waited too long after learning, only to remember to chug that Starbucks mocha the day after? In a separate study, researchers allowed 24hrs for volunteers to consolidate the memory of the initial picture stack before giving them the same caffeine pill, just one hour before the test. This time it didn’t work – these volunteers mixed up similar and old pictures just like the placebo control group. Whatever caffeine is doing, it has to be done during consolidation.

Researchers aren’t quite sure how caffeine induces memory gain, but they have a few ideas. The image discrimination task used here engages the hippocampus, a key brain area involved in learning and memory. It expresses high amounts of the caffeine receptor (adenosine A1 receptor) in its CA2 subregion, thus allowing caffeine to tweak (strengthen?) its function in memory consolidation. Caffeine can also indirectly boost the level of norepinephrine, a neurotransmitter that helps you lay down a memory for good.

While exciting, this study cannot end the debate on whether caffeine improves memory. The effect sizes were small, with some only scraping significance – that is, researchers were only barely able to say with some confidence that the effect is real. This doesn’t reflect the quality of the research, but most likely represents individual variance among the volunteers: different gene variants for faster caffeine metabolism, BMI, basal metabolic rate, oral contraceptives and so on. It would also be interesting to see if caffeine boosts memory reconsolidation: when you retrieve a memory, it temporarily becomes labile. Can coffee help the memory restablize?

Unfortunately, we don’t known if caffeine-induced memory gain applies to caffeine junkies like me. But to quote the lead author: one needs to do the experiment with habitual drinkers to find out, but my guess is that it’s why we’re so awesome!

Many thanks to the principal investigator @mike_yassa for patiently answering my questions over Twitter. You can check out our full conversation in my timeline.
Borota D, Murray E, Keceli G, Chang A, Watabe JM, Ly M, Toscano JP, & Yassa MA (2014). Post-study caffeine administration enhances memory consolidation in humans. Nature neuroscience PMID: 24413697

Christmas food for thought: Feed me, all 100 trillion of me

The morning before Christmas eve, I’m sitting here in the dining room munching happily on the bits and pieces of what’s left of our gingerbread house that was only erected to its full glory the night before. I have not consumed this amount of carbohydrates in over a year.

Inside, a few species of my extensive gut microbe community are screaming bloody murder.

E. coli bacteria

FEEEEED ME!!!! Source:

When you eat, you’re not only feeding your own fleshy vessel, but also the 100 trillion of microbugs that thrive in your intestines. Hardly “along for the ride”, these bugs not only help us digest foodstuff, ferment carbohydrates and proteins but also heavily impact our metabolism and general health. Depending on their composition, they tweak our risk of cardiovascular diseases, Type II diabetes and may even cause obesity in humans. There’s tantalizing evidence that their reach extends to the brain, influencing mood, anxiety and cognition in mice.

However, the gut microbiota* is a fluid, ever-changing beast. In one previous study, researchers transplanted gut-free mice with fresh or frozen human poop to inoculate them with a microbiome of known composition. When researchers switched these mice’s plant-based diet to a high-fat, high-sugar one, the structure of the established microbiome changed within a single day: some species dwindled in number, while others exploded onto the intestinal stage, bringing with them their particular metabolic tricks. (*The word “microbiome” refers to the set of genes in the gut bugs).

Similar diet-induced changes have been found in humans. When babies are weaned from their mothers’ milk and switch to solid food, their gut bug community simultaneously go through tumultuous changes. The gut bugs of African hunter-gatherers vastly differ from those in people grown on a Western diet. But these changes take weeks, even lifetimes. Just how fast can the microbiome adapt and change to a new diet?

In a new study, researchers recruited ten volunteers and put them on two drastically different extreme diets for 5 days – as you can see below, the plant-based diet was rich in grains, fruits and vegetables (high-carb and high-fibre), while the animal-based diet consisted of meats, eggs and cheeses (high-fat, high-protein and low/no-fibre). Each day, the volunteers handed in a poop sample for the researchers to monitor.

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In general, the animal-based diet had a greater impact on gut flora than the plant-based one. It significantly increased the diversity of gut flora, enriching 22 species whilst decreasing the fibre-intake associated Prevotella in a life-long vegetarian on this meaty diet. The plant-based diet, on the other hand, only increased the abundance of 3 species, mostly those associated with carbohydrate fermentation.

Many of the changes made sense. An animal-based diet enriched putrefactive microbes, shifting carbohydrate fermentation into amino acid digestion, thus helping the body break down the onslaught of heaps animal protein. Several strains of immigrant bacteria – particularly those used for cheese- and sausage-making –settled down and made themselves comfortable in the native gut flora community. The meat-heavy diet also triggered microbes to activate pathways that degrade cancer-causing compounds found in charred meats, and enhanced the synthesis of vitamins.

On the other hand, several strains of potentially health-negative bacteria also multiplied in the meat-eaters. On a high-fat diet, we excrete more bile – a bitter fluid that may ruin a good fish dish – to deal with the digestion of fat. Bile is toxic to many gutbugs, but not to the mighty Bilophila (“bile-loving”) wadsworthia – a bile-resistant bacterium stimulated by saturated fats in milk that may cause intestinal inflammation, at least in mice. The high-fat content in the animal-based diet also triggered increased levels of microbe-produced DCA, which is previously linked to liver cancer in mice. However, as of now there’s no evidence that these risks also apply to people, and researchers caution against making health-related judgments (although some can’t resist the temptation).

On the whole, plant- and animal-based diets induced changes in host microbiome gene structure that resembled those of herbivorous and carnivorous mammals within a few days. Furthermore, the volunteer’s microbiome reversed back to their previous composition only 2 days after the end of the experiment. Researchers believe we might be looking at a fast-forwarded movie of millions of years of co-evolution between humans and their microbugs: when animal food sources fell scarce, our ancestors were forced to switch to a plant-heavy diet; a flexible gut-bug community could quickly and appropriately shift their repertoire and function to help digestion, thus increasing the flexibility of human diets and chances of survival.

Thus, when you gobble down the vast selection of Christmas dishes this year, remember to thank the flexibility of your gut flora for your diverse digestive powers. And remember that we can’t say one diet is better than the other for our microbiota; the take-home message is that they are incredible flexible, more so than we previously thought. In the end, it still comes down to the age-old wisdom: you are what you eat.
David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, & Turnbaugh PJ (2013). Diet rapidly and reproducibly alters the human gut microbiome. Nature PMID: 24336217

#SfN13 Stressed out mice turn to carbs for comfort food

Poster ZZ3 Ghrelin protects against stress by promoting the consumption of carbohydrates.T. Rodrigues. Z. Patterson. A. Abizaid. Carleton University, Ottawa, ON, Canada

In this world nothing can be said to be certain, except death and taxes.– Benjamin Franklin

Personally, I’d add stress to that.

There’s no question that chronic stress is a killer. Handled badly, stress can lead to anxiety, memory impairments, cardiovascular disease and sleep disorders. We all have our own strategies for coping with stress, some healthier than others. Me? I turn to food.


Cavities galore or stress relief? Source: 

Apparently, so do bullied mice. Mice are social creatures; when housed together, larger and meaner ones will quickly assert dominance. The little guys have it rough, usually showing signs of anxiety, depression and increased body weight within weeks.

The reason for their weight gain can be traced back to an increase in ghrelin, a hunger-causing (orexigenic) hormone produced in the stomach. Once released, ghrelin travels to the brain and binds to its receptors to increase calorie consumption. But not all foods are equal; new research from Carleton University suggests that ghrelin promotes the intake of comfort foods – specifically, carbohydrates- because they decrease the level of circulating stress hormones such as corticosterone.

In the study, researchers first measured the amount of chow that mice ate per day for 21 days. They then chronically stressed out one group of mice by putting a dominant bully into every cage; the two mice were separated by a see-through glass wall to reduce violence. Every day, the mice had 24hr access to a standard, high-carb chow and a 4hr-window to a fattier alternative. Compared to non-stressed controls, the bullied mice drastically increased their total calorie intake, paralleled by an increase in ghrelin levels but surprisingly normal corticosterone levels.

When researchers broke down in the increase in calories by the type of food, they uncovered an unexpected result: stressed-out mice did not eat more fat, but instead opted for more high-carb chow. In fact, this high-carb binge almost entirely accounted for the increase in total calorie consumption.

However, mice chow does contain ~50% of protein and fat. To rule out a preference towards these two macronutrients in combination, researchers repeated the experiment, but with sucrose solution as the alternative to high-carb chow. As before, stressed-out mice increased their intake of chow, but this time, they also doubled their intake of sugar water compared to their unstressed peers. At the same time, their corticosterone levels were normal, suggesting that they were coping fairly well in the face of daily terror.

Why is ghrelin triggering a preference for carbs? The answer might be internal stress management. When researchers feed both bullied and control groups the same standard chow (~50% carbs), effectively restricting access to stress eating, the bullied mice suffered numerous negative health effects. Their ghrelin and corticosterone levels shot through the roof. They had abnormally low blood sugar levels, signalling the onset of metabolic problems. They even showed signs of depression, refusing to swim when dropped into a deep container filled with water.

These data suggest that under stress, ghrelin levels rise and tip food preference towards high-carb rather than high-fat foods. To see if this is indeed the case, researchers turned to a strain of mice genetically engineered to lack ghrelin receptors. Normally, compared to wild-types, these mutants show similar patterns of eating and hormone regulation, although they tend to be slightly smaller. Once stressed, however, they didn’t respond by switching to the high-carb comfort chow, instead increasing their nibbling of fatty foods. Behaviourally, these mice could not cope – in the swimming task, they spent most of their time immobile, succumbing to their fates.

Researchers aren’t yet sure why ghrelin-induced carb – but not fat – intake helps to manage stress. One reason could be bioenergetics: stress alerts the brain that more energy is needed (and soon!) through ghrelin, which in turn increases the preference for glucose – a fast and efficient energy source. Or it could just be a matter of comfort. These mice grew up on standard mice chow, which just happens to be high in carbs. Perhaps, just like you and me, mice simply prefer familiar and comforting foods after a long, stressful day.

The fat-fueled brain: unnatural or advantageous?

This post was originally published in Scientific American MIND Blogs.


It’s not bacon; it’s therapy! Source:

The ketogenic diet is a nutritionist’s nightmare. High in saturated fat and VERY low in carbohydrates, “keto” is adopted by a growing population to paradoxically promote weight loss and mental well-being. Drinking coffee with butter? Eating a block of cream cheese? Little to no fruit? To the uninitiated, keto defies all common sense, inviting skeptics to wave it off as an unnatural “bacon-and-steak” fad diet.

Yet versions of the ketogenic diet has been used to successfully treat drug-resistant epilepsy in children since the 1920s – potentially even back in the biblical ages. Emerging evidence from animal models and clinical trials suggest keto may be therapeutically used in many other neurological disorders, including head ache, neurodegenerative diseases, sleep disorders, bipolar disorder, autism and brain cancer. With no apparent side effects.

Sound too good to be true? I feel ya! Where are these neuroprotective effects coming from? What’s going on in the brain on a ketogenic diet?

Ketosis in a nutshell

In essence, a ketogenic diet mimics starvation, allowing the body to go into a metabolic state called ketosis (key-tow-sis). Normally, human bodies are sugar-driven machines: ingested carbohydrates are broken down into glucose, which is mainly transported and used as energy or stored as glycogen in liver and muscle tissue. When deprived of dietary carbohydrates (usually below 50g/day), the liver becomes the sole provider of glucose to feed your hungry organs – especially the brain, a particularly greedy entity accounting for ~20% of total energy expenditure. The brain cannot DIRECTLY use fat for energy. Once liver glycogen is depleted, without a backup energy source, humanity would’ve long disappeared in the eons of evolution.

The backup is ketone bodies that the liver derives primarily from fatty acids in your diet or body fat. These ketones – β-hydroxybutyrate (BHB)*, acetoacetate and acetone – are released into the bloodstream, taken up by the brain and other organs, shuttled into the “energy factory” mitochondria and used up as fuel. Excess BHB and acetoacetate are excreted from urine, while acetone, due to its volatile nature, is breathed out (hence the characteristically sweet “keto breath”). Meanwhile, blood glucose remains physiologically normal due to glucose derived from certain amino acids and the breakdown of fatty acids – voila, low blood sugar avoided!

*Chemically speaking, BHB is not a ketone – it’s a carboxylic acid)


Brain on ketones: Energetics, Oxidation and Inflammation

So the brain is happily deriving energy from ketones – sure, but why would this be protective against such a variety of brain diseases?

One answer may be energy. Despite their superficial differences, many neurological diseases share one major problem – deficient energy production. During metabolic stress, ketones serve as an alternative energy source to maintain normal brain cell metabolism. In fact, BHB (a major ketone) may be an even more efficient fuel than glucose, providing more energy per unit oxygen used. A ketogenic diet also increases the number of mitochondria, so called “energy factories” in brain cells. A recent study found enhanced expression of genes encoding for mitochondrial enzymes and energy metabolism in the hippocampus, a part of the brain important for learning and memory. Hippocampal cells often degenerate in age-related brain diseases, leading to cognitive dysfunction and memory loss. With increased energy reserve, neurons may be able to ward off disease stressors that would usually exhaust and kill the cell.

A ketogenic diet may also DIRECTLY inhibit a major source of neuronal stress, by –well- acting like a blueberry. Reactive oxygen species are unfortunate byproducts of cellular metabolism. Unlike the gas Oxygen, these “oxidants” have a single electron that makes them highly reactive, bombarding into proteins and membranes and wrecking their structure. Increased oxidants are a hallmark of aging, stroke and neurodegeneration.

Ketones directly inhibit the production of these violent molecules, and enhance their breakdown through increasing the activity of glutathione peroxidase, a part of our innate anti-oxidant system. The low intake of carbohydrates also directly reduces glucose oxidation (something called “glycolysis”). Using a glucose-like non-metabolized analogue, one study found that neurons activate stress proteins to lower oxidant levels and stabilize mitochondria.

Due to its high fat nature, keto increases poly-unsaturated fatty acids (PUFAs, such as DHA and EPA, both sold over-the-counter as “brain healthy” supplements), which in turn reduces oxidant production and inflammation. Inflammatory stress is another “root of all evil”, which PUFAs target by inhibiting the expression of genes encoding for pro-inflammatory factors.

Neurons on Ketones: Dampen that enthusiasm!

Excited neurons transmit signals, process information and form the basis of a functioning brain. OVER-excited neurons tend to die.

The brain teeters on a balance between excitation and inhibition through two main neurotransmitters, the excitatory glutamate and the inhibitory GABA. Tilt the scale towards glutamate, which occurs in stroke, seizures and neurodegeneration, and you get excitotoxicity. In other words, hyper-activity is toxic.

Back in the 1930s, researchers found that direct injection of various ketone bodies into rabbits prevented chemically-induced seizures through inhibiting glutamate release, but the precise mechanism was unclear. A recent study in hippocampal neurons showed that ketones directly inhibited the neuron’s ability to “load up” on glutamate – that is, the transmitter can’t be packaged into vesicles and released – and thus decreased excitatory transmission. In a model of epilepsy that used a chemical similar to glutamate to induce damage, the diet protected mice against cell death in the hippocampus by inhibiting pro-death signaling molecules. On the other end of the excitation-inhibition balance, ketones increase GABA in the synapses (where neurotransmitters are released) of rats and in the brains of some (but not all) epileptic humans subjects. This increase in inhibition may confer both anti-seizure effects and neuroprotection, though data is still scant.

Then there are some fringe hypotheses. The acidity of ketones may decrease the pH of certain brain microdomains, which might to be the mechanism of keto’s positive effect on Type II Bipolar disorder (lot’s of mays and mights, I know).  As keto affects the whole body, global changes due to calorie restriction and regulation of the satiety hormone Leptin are bound to alter brain function, and play a circumstantial role.

Neuroprotection? Show me the evidence!

All these molecular changes suggest that a ketogenic diet is protective against brain injury. But is there any REAL evidence?

A study with 23 elderly with mild cognitive impairment showed that a ketogenic diet improved verbal memory performance after 6 weeks compared to a standard high carbohydrate diet. In a double-blind, placebo-controlled study, 152 patients with mild- to moderate Alzheimer’s disease were given either a ketogenic agent or a placebo, while maintaining a normal diet. 90 days later, those receiving the drug showed marked cognitive improvement compared to placebo, which was correlated with the level of ketones in the blood.

In a pilot study in 7 patients with Parkinson’s disease, 5 were able to stick to the diet for 28 days and showed marked reduction in their physical symptoms. In an animal model of Amytrophic Lateral Sclerosis (ALS), a ketogenic diet also led to delayed motor neuron death and histological and functional improvements, although it did not increase life span; clinical trials are on the way.

Remarkably, a long-term ketogenic diet does not seem to be associated with significant side effects, although constipation, dehydration and electrolyte and micronutrient deficiencies are common complaints. More serious complications include increased chance of kidney stones, gallbladder problems and bone fractures, especially in children. Menstrual irregularities often occur in women, with potential impact on fertility. Although ketoacidosis – acidification of the blood due to pathological levels of ketones – was historically proposed as a side effect, nutritional ketosis simply cannot achieve the level of ketones required to induce this life-threatening state. Nevertheless, there are no studies directly monitoring the side effects of ketosis yet, hence it’s too early to conclude that the diet is completely safe for everyone.

Brain ❤ Bacon?

While promising, large-scale placebo-controlled clinical trials in patients with neurological disorders are still lacking. The existing data needs to be interpreted carefully to avoid generating false hope or encourage patients to “ditch drugs for diet”. Nevertheless, the possibility that we can reduce symptoms of untreatable neurological disorders through modifying dietary composition is quite incredible; that a ketogenic diet may benefit physical and cognitive performance in healthy individuals is an even more tantalizing idea.

As the science behind this age-old dietary therapy gradually comes to light, social issues such as low adherence and public prejudice will need to be resolved. In the meantime, to those neuroscientists interested in studying keto: pass the bacon and I VOLUNTEER!

The skinny on gutbug-transplanted obesity

For centuries, mankind has looked into the vast skies and wondered “are we alone?” We still don’t know. But if we turn our gaze inwards, towards our own bodies, then the answer is a definitive “NO!”


It’s a jungle in there. Source:

100 trillion microbugs thrive in our intestines, forming complex communities – called “microbiota”- that live with us in symbiosis. (The word “microbiome” that you often hear describes the set of GENES that a particular microbiota has). Our gut bugs munch on the foodstuffs that we inadvertently share with them, not only helping us digest carbohydrates and ferment fibre, but also heavily influencing our metabolism. In fact, depending on the composition of your microbiota, they may influence your risk of Type II diabetes, cardiovascular disease, and mood.

They may even help shape your waistline.

Numerous studies have shown that obese and lean people harbour divergent populations of gut microbes; when obese people lose weight on either a fat- or carbohydrate-restricted diet, their gut bug populations gradually shift to that of a lean person’s. A recent study surveying 292 Danes found that obese people have fewer and less diverse gut bacteria populations, constituting an impoverished state that correlated with increased inflammation and risk of future weight gain.

But these observational studies cannot tell us which came first: obesity or obesity-associated microbiota? In other words, can gut microbes CAUSE obesity?

Ridaura VK et al (2013). Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science doi:10.1126/science.1241214.

Researchers recruited four pairs of female human twins whom drastically differed in body composition (BMI difference >=5.5) and collected a sample of their microbiota. If you’re imagining long cartoonish needles, think again: since microbes heavily populate the large intestine, many hitch a hike with foodstuff and eventually gets shuffled out as poop – ready for collection. Researchers then transplanted the fecal samples into lean germ-free mice, fed them a standard low-fat diet and waited for the bugs to colonize the mice’s virgin guts.

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15 days later, the bodies of recipient mice morphed into their human donor’s composition and shape. As you can see above, while “lean” bug-receiving mice (left) retained their body fat levels, those getting “obese” bugs dramatically packed on the squishy pounds (right). When researchers inoculated a new group of mice with “pure” bacteria cultured from the original fecal samples, the same divergence in body fat gain was observed.

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Here’s a nifty summary. Source: Science 341 (6150): 1069-1070

The few extra pounds weren’t the big problem – mice receiving “obese” bugs also started metabolizing amino acids in a way often seen in insulin-resistant humans, suggesting that their metabolisms were becoming compromised.

The researchers next wondered if these negative changes in body composition could be prevented with a healthy dose of “lean” bugs in an epic “battle of the microbes”. Following “obese” germ-transplants, researchers fed the mice with standard low-fat chow and waited until the bugs stabilized in their guts. Before recipient mice showed apparent signs of weight gain, researchers dropped “lean” bug-inoculated mice into their home cages. Since mice regularly ate each other’s feces, housing the two together should hypothetically result in a hearty mingling of each other’s gut bugs.

Or so it seemed. Although the microbiota of “obese”-germ mice was infiltrated with that of “lean”-germ mice, the swap was a one-way street – “lean”-germ mice retained their original microbiota, as well as their svelte physique (red bar in the graph below). Co-housing saved “obese”-germ mice from their rotund fate; their fat gain dramatically slowed (Ob-ch, empty blue bar), as compared when housed alone (Ob-Ob, solid blue bar).

Screen Shot 2013-09-12 at 9.28.16 PMWhy this one-directional infiltration? Careful genomic analysis revealed the answer may be population diversity: because an obese germ community is less diverse than a lean one, it leaves many empty “niches” in the intestines – prime real estate for “lean” bacteria to move in. The fiercest invaders were from the Bacteroidetes family, whose overrepresentation in gut flora has previously been associated with leanness in mice.

If “lean” microbes tend to wipe out and replace “obese” ones, why is it that we have an obesity problem instead of a “lean” epidemic (I wish!)? The answer may partially lie in – you’ve probably guessed it – diet.  In the above experiments, all mice were fed the same low-fat high-fibre diet, regardless of the type of microbiota received. To see if diet changes anything, the authors cooked up two human diet based recipes, one high in fruits and vegetables but low in saturated fat, and one with the opposite composition.

Screen Shot 2013-09-12 at 9.31.26 PMScreen Shot 2013-09-12 at 9.31.39 PM

As you can see in the above left graph, when “obese”-germ mice gobbled the low-fat high-veg chow, they still gained more weight (Ob-Ob, solid blue bar) and showed signs of mild glucose intolerance, which was once again canceled by co-housing with their “lean”-germ peers (Ob-ch, empty blue bar. Compare it to the solid blue bar, see how there’s a trend towards decrease?) . However, on a diet high in fat but low in veg (right graph), “obese”-germ mice rapidly gained fat mass, regardless of whom they were housed with. In other words, a high fat diet barricaded any attempts that the “lean” germs might have made to invade the “obese” germ community (compare the solid and empty blue bars again).

Why is this the case? Bacteroidetes, the most successful invaders, are experts at breaking down dietary fibres into short-chain fatty acids, which can be used by the host as energy. Previous studies have shown – somewhat paradoxically – that these fatty acids promote leanness by inhibiting fat accumulation, increasing metabolism and enhancing the level of hormones that promote feelings of fullness. On a high-fat low-veg diet, the Bacteroidetes lacked the magic ingredient to work with and couldn’t establish themselves in the “obese”-germ mice. Any weight management benefits died off with the bacteria. The difference between high- and low-fat diet was only 11% by weight; it’s interesting to note that increasing fibre (as opposed to decreasing fat) may be more helpful in sculpting your waistline. I’d love to know what would’ve happened if the mice were fed a high-fat, high-fibre diet; would weight gain still be prevented by “lean” microbe transfer?

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Summary #2. Source: Science 341 (6150): 1069-1070

So how relevant are the findings for us humans? Results from studies looking at Bacteroidetes in humans have been mixed – they seem to increase in obese individuals in some studies. So the jury’s still out there. What I’m wondering is whether transplanting “obese” microbiota into ALREADY obese mice can REVERSE their weight gain. If so, it’s certainly possible to isolate a few important “lean” strains and develop them into probiotics with anti-obesity powers. That is, if you watch your diet.

In the meantime, I’ll still stick to the good old mantra: eat less, move more.
Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, & Gordon JI (2013). Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science, 341 (6150) PMID: 24009397

Note: I just realized wordpress has been putting ads in some of the posts sporadically – my apologies if you were assaulted. It’s been taken care of!

How a high-fat diet makes that stick of celery seem less rewarding

By shooting the gut fatty messenger, apparently.


Do brains dream of delectable treats? Source:

A longstanding debate in obesity research is whether compulsory eating is an “addiction”. The A word certainly brings baggage to the table – by calling overeating an addiction we’re essentially labelling the obese as mentally ill. Negative connotations aside, there certainly are strong parallels: just like drugs of abuse, rewarding foods stimulate the same brain circuits (most natural rewards do), triggering dopamine release in the striatum, which signals reward and motivates feeding behaviour.

It’s a great system optimized to keep us alive. But it tragically breaks down when we take gustatory decadence to the extreme. Chronic consumption of high fat & sugar goodies overwhelms the system, so that the individual becomes less sensitive to reward signals. One idea is that people then overeat to compensate for the lack of a fat/sugar high – just like addicts striving for the next hit, despite being fully aware of the health and social consequences.

While it seems like a good theory, one link is missing: excess food consumption happens in the intestinal tract, while dopamine rush occurs in the brain. What’s happening in between?

Luis A. Tellez et al. 2013. A gut lipid messenger links excess dietary fat to dopamine deficiency. Science 341: 800-802.

The messenger might be oleoylthanolamine (OEA, say it out loud I dare you), an appetite-suppressing lipid synthesized in the gut following food intake. Why point the crosshairs at OEA? The authors didn’t really say, but did note that OEA is one of the few factors that DECREASES in response to a high-fat diet (as opposed to leptin, insulin and glucose which all increase in the obese), and that supplementing OEA reduces body weight in obese mice.

The authors put 216 mice on either a very high-fat (60% fat, 20% protein and 20% carbs) or low-fat (10% fat, 20% protein and 70% carbs) diet and let them eat to their little hearts’ content. 15 weeks later, compared to low-fat fed mice, high-fat mice indeed had significantly lower levels of OEA in their small intestines. The mice also responded to fatty foods differently. As you can see below, when researchers delivered a “fat shot” (a flavorless fatty solution, ew) directly into the mice’s intestines, high-fat fed mice (HF, white line) showed a muted dopamine response compared to low-fat fed ones (LF, black line).

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However, when high-fat fed mice were given external OEA before the gut fatty infusion (blue arrow below), they once again experienced a dopamine rush (white line in graph B) – just like low-fat fed mice (A). OEA acts through a protein called PPARalpha, and transmits information through the vagus nerve, part of the peripheral nervous system, to the brain. OEA is certainly acting in the gut; if you directly give OEA into the brain, it looses its effect. Thus, the gut itself can sense the presence of rewarding fatty foods – even in the absence of taste and mouth feel – and that dopamine response to fat in the gut is muted in rats raised on a high-fat diet.

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A: low-fat fed mice; B: high-fat fed mice. In high-fat fed mice, administering OEA before fat infusion restores dopamine bump. (From Fig 1)

Sure, but do high-fat mice BEHAVE differently? The authors first wanted to see if a fatty diet alters feeding motivation. Intra-gastric feeding is a dopamine-dependent behaviour; dopamine is often associated with motivation. As you can see in the graph below, although high-fat mice (right) ATE the same amount of yummy fatty food as low-fat fed (left) mice, they showed far less interest in administering flavourless fats into their guts (compare the two black lines). When given an extra dose of OEA (shadowed areas and white lines), low-fat fed mice seemed to lose their appetite, self-administering far less high-fat solution than usual (left). This makes sense, as OEA is naturally produced in the gut to signal fullness and satisfaction.

Screen Shot 2013-08-24 at 1.18.51 PMHowever, high-fat mice perked up after OEA and pumped MORE fatty solution into their guts (right graph above, shadowed area and white line). Interestingly, the same dose of OEA caused both types of mice to infuse themselves with the same number of calories. In other words, OEA may create a “set-point” of calorie intake and once that level is reached, call out to the brain to either drive the mice to get more or less calories through dopamine signalling. In high-fat fed mice who hesitate to self-administer fatty liquids into their guts, OEA thus restored their deficient dopamine-dependent motivational circuits.

Wait, if supplementing OEA causes obese mice to tube-feed themselves MORE, how’s that a GOOD thing? One thing to take note is that intra-gastric feeding bypasses all the flavour and mouthfeel feedback to the brain which occurs during oral feeding, aka normal eating. While high-fat fed mice were reluctant to pump flavourless fat into their guts, they DID eagerly mow down on a delicious fatty slurpee orally, but turned their backs on a less enticing low-fat option. Mice raised on a low-fat diet, on the other hand, happily ingested both high and low-fat offerings.

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So how did OEA affect ORAL/normal eating? As you can see above, unlike intra-gastric feeding, OEA infusion caused BOTH low (left) and high (right)-fat fed mice to abhor eating more fatty food (shadowed area, white line). Especially intriguing is this: while OEA also DECREASED the amount of “diet” food low-fat fed mice ate, it seemed to INCREASE high-fat fed mice’s liking for low-fat food. The overall picture then, is that external OEA artificially boosted low-fat food’s reward value by increasing dopamine release in the brain, and rectifies motivational deviances that occur in a chronic high-fat diet.

First, I’d like to point out that the high-fat diet used in this study is actually a high-fat/moderate-sugar diet, so does not pertain to very low carb diets like the ketogenic diet. That out of the way, the authors make a good case for OEA as an intermediate link between fat consumption and dopamine response. I find it especially interesting that OEA affected feeding behaviour differently depending on the route of consumption – oral-sensory factors are definitely at play. Indeed, digestion happens long before swallowing. The sight, taste and smell of food are powerful triggers that initiate enzymatic and neurochemical responses to prepare the body for digestion. Which factors are more important in deciding the final level of motivation?

I would also love to know if in the ABSENCE of OEA, low and high-fat fed mice orally ingest fatty solutions differently. That is, whether “one piece of cream cake and lead to another” in obese mice trying to chase a heavenly fatty high. It’s interesting that high-fat fed mice were less willing to work for intra-gastric food; but what about delicious fatty food that they can taste? I also wonder if the decrease in OEA synthesis is reversible; that is, does it go back to normal after you put a high-fat fed mouse on a low-fat diet?
Tellez LA, Medina S, Han W, Ferreira JG, Licona-Limón P, Ren X, Lam TT, Schwartz GJ, & de Araujo IE (2013). A gut lipid messenger links excess dietary fat to dopamine deficiency. Science, 341 (6147), 800-2 PMID: 23950538

L-carnitine: good for brains, bad for hearts?

Remember this study from a week ago, where researchers showed L-acetyl carnitine rapidly alleviating depression symptoms by changing DNA expression? Well, a new study in Nature Medicine now identified a compound in red meat that can be metabolized by our gut microbiota into TMAO, which promotes atherosceleosis. And the culprit? L-carnitine, the parent compound of L-acetyl carnitine.

Koeth RA et al (2013): Gut microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. Advanced online publication, doi:10.1038/nm.3145

It’s long been suspected that cholesterol and saturated fats in red meat are bad for the cardiovascular system, although a recent meta-analysis did not show a statistically significant association. This prompted the idea that environmental factors such as concurrent salt-intake, cooking of the meat or food-gut interactions may also be at play. The authors decided to look at the last factor: are the micro-critters in our gut converting SOMETHING in red meat into compounds toxic to our hearts?


Gaah meat, Y U so good?

 Previously, they discovered that choline – found in egg yolks- can turn into TMAO by gut flora. TMAO is correlated with future risk of heart disease in humans, and can cause heart problems when fed to mice (probably one reason why egg yolks have such a bad rep). Since L-carnitine is structurally similar to choline and abundant in red meat, researchers hypothesized L-carnitine may also be taken up by gut bugs and transformed into TMAO.

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To test this, the authors fired up the grill and fed omnivore volunteers sirloin steaks together with an isotope-labeled L-carnitine capsule (an 8-ounce sirloin steak contains about 180mg of L-carnitine). Blood tests later revealed an increase in L-carnitine and TMAO radioactivity, meaning L-carnitine is being metabolized into TMAO. But by what? To pin this down, volunteers took broad-spectrum antibiotics to suppress gut flora for a week. They were then given another L-carnitine challenge. This time, there was virtually no TMAO in the blood and urine. After being off antibiotics for several weeks, allowing gut bacteria to grow back, the volunteers once again chowed down on steak and produced TMAO. This suggests the conversion only happens in the presence of gut bacteria.

However, your gut microbiome != my microbiome. Gut bacteria composition can be influenced by dietary habits. In fact, researchers found vegans and vegetarians produced markedly less TMAO after ingesting L-carnitine. A screen of their gut microbiome (extracted from poop) showed several gut bacteria types that were associated with lower ability to produce TMAO compared to meat-eating omnivores. This indicates that previous diet can be a major factor in gut flora composition and the ability to produce TMAO.

“Induction” is an important concept in biology. The more you consume some substances (like alcohol), the more your body increases the ability to break down that substance by switching necessary metabolism pathways into high gear (for example, by upregulating necessary enzymes and/or adjusting gut flora composition). To see if the ability to convert L-carnitine into TMAO is inducible, the researchers turned to mice. Indeed, specially raised germ-free mice were unable to produce TMAO initially, but gained the ability after living in conventional cages full of bacteria. In another group, mice supplemented with L-carnitine produced roughly ten times more TMAO compared to mice on a normal diet.

All of the above shows that in mice and men, gut flora is necessary to convert L-carnitine into TMAO and the composition determines the efficacy of the conversion. But is L-carnitine and/or TMAO actually BAD for heart health?

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Mice supplement with L-carnitine showed more plagues in their arteries than normal mice after 15 weeks, and this was rescued when mice were given broad-spectrum antibiotics. So L-carnitine isn’t toxic per se, but its conversion into TMAO stresses the carodiovascular system. A correlational study in humans also found an association between L-carnitine and cardiovascular risk, but further analysis pointed to TMAO concentration as the main driving force.

Is L-carnitine the reason red meat is bad for our hearts? At this point it’s hard to say, but it may be an important contributing factor. Many questions remain unanswered. How does L-carnitine (or TMAO) cause plague buildup? How much and how often can a person consume red meat before TMAO reaches high enough concentration to be a hazard? Can supplementing L-carnitine for fitness goals ironically cause poorer heart health? L-carnitine is also present in fish, which is linked to lower cardiovascular risk. Are the omega-3s in fish counteracting TMAO’s effect? How does the co-consumption of other food substances alter L-carnitine absorption and TMAO conversion? Finally, even the link between red meat consumption and cardiovascular risk is still contentious. If the anti-cholesterol campaign has taught us anything, it’s that we must be cautious when pointing our finger at a single food chemical as the devil.

It would be very interesting to see if manipulating L-carnitine consumption can influence cardiovascular risk in a clinical setting. If so, tinkering with gut flora may be a new and exciting way to lower heart disease (a vegan-to-omnivore fecal transplant comes to mind, hah). Whether it also changes your brain function though, is an entirely different story that’ll have to be looked at.
Koeth, R., Wang, Z., Levison, B., Buffa, J., Org, E., Sheehy, B., Britt, E., Fu, X., Wu, Y., Li, L., Smith, J., DiDonato, J., Chen, J., Li, H., Wu, G., Lewis, J., Warrier, M., Brown, J., Krauss, R., Tang, W., Bushman, F., Lusis, A., & Hazen, S. (2013). Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis Nature Medicine DOI: 10.1038/nm.3145