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: http://edbites.com/

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.

ResearchBlogging.org
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

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

By shooting the gut fatty messenger, apparently.

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Do brains dream of delectable treats? Source: http://www.yalescientific.org/

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?

ResearchBlogging.org
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