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Short-Chain Fatty Acids
Short-chain fatty acids (SCFAs) are an important class of biologically active substances produced in the gut, specifically by the action of gut bacteria on plant-derived foods containing fiber that is otherwise resistant to digestion, such as artichokes and legumes. SCFAs are emerging as important contributors to body metabolism and weight regulation, immunity, and mental health. They play roles in mood, sleep, and stress resistance. But the full scope of their roles is very much a developing story. It is safe to say that the more scientists discover, the more important SCFAs are becoming to general and mental health.
Fibrous foods pass through the stomach and small intestine intact but meet a special group of bacteria in the lower intestines, or colon, that work them over by fermenting them—releasing energy, gasses, and SCFAs. The major SCFAs are acetate, propionate, and butyrate.
SCFAs are one of the many ways the gut communicates with the brain. They serve as signaling molecules throughout the body—mobilizing hormones and activating nerve pathways and many types of cells to regulate appetite, energy balance, body weight, immunity, brain function, and mood states. Butyrate specifically helps protect the brain, shielding it from toxins and infectious agents by maintaining the integrity of the blood-brain barrier.
There’s evidence that lack of SCFAs is a hidden force behind the rising rates of obesity, diabetes, and such psychological ills as anxiety and depression. Studies show that depressed people have far less diversity of the microbiome than do people who are not depressed. When the diversity of the microbiome is narrowed, there’s a failure to produce molecules that have become essential to normal brain function, including the response to stress and the processing of emotional information.
Boosting production of SCFAs by diet and direct administration of SCFAs may have therapeutic applications in disorders ranging from anxiety and depression to neurodegenerative conditions.
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The full scope of the SCFAs' activities is very much under active investigation. For example, there’s evidence that at least some SCFAs invigorate a tumor-specific T-cell response, boosting the efficacy of cancer immunotherapy. A diet that promotes the abundance of such bugs—largely plant-based—may, in the future, become a standard part of cancer care.
What is known for sure is that all three major SCFAs play important roles in maintaining the health and integrity of the intestines—but they also cross the blood-brain barrier and are active in the brain. A still-evolving list of their activities includes:
- Dampening inflammation in the body and brain
- Regulating the body’s energy balance through an array of mechanisms, including appetite and satiety signals—even influencing cravings
- Determining cardiac health by modulating the metabolic response to diet—influencing, most notably, postprandial blood lipid and blood glucose levels
- Influencing sleep quality and duration
- Bolstering mental health through such varied channels as dampening the response to stress, influencing neurotransmitter levels, and stimulating the growth of brain cells. They affect emotional processing in the brain—they keep it from dwelling on negative stimuli, studies show.
All three SCFAs, researchers have discovered, curb secretion of the stress hormone cortisol. Studies show that in both low and high doses, they shut off the cortisol response to acute psychosocial stress. The greater the levels of SCFAs, the lower the cortisol response and the lower stress reactivity.
They also activate a channel of biochemical signaling between the gastrointestinal tract and the brain, and they increase levels of BDNF, or brain-derived neurotrophic factor, which promotes mental flexibility by stimulating the growth of new neurons. That is likely why animals fed a diet enriched with fiber-containing supplements for 10 weeks resisted the animal equivalent of behavioral despair when subjected to specific kinds of stress. The researchers conclude that fiber-containing supplements function like an antidepressant.
Acetate, produced by Bifidobacteria, Lactobacilli, Akkermansia, and species of Prevotella and Ruminococcus, regulates the acidity of the gut, which keeps pathogenic bacteria under control. It also boosts gut diversity by nourishing other bacteria in the gut and, through actions on cells lining the gut, helps regulate appetite. It also plays a larger role in energy regulation. Acetate has been found to influence cardiometabolic health by decreasing stores of visceral fat. Acetate continues its energy-regulation action in the brain as well, inhibiting specific neurochemicals in the hypothalamus that otherwise increase appetite and decrease metabolism.
An increase in acetate levels in mice fed a high-fiber diet not only lowered levels of inflammation in the hippocampus, a brain region important to mood and memory, but it also increased levels of brain-derived neurotrophic factor, stimulating the growth of neurons important in cognitive and behavioral flexibility.
Butyrate, produced by members of the Firmicutes family (such as Faecal Bacteria and Roseburia) of gut bacteria, is a local source of energy powering cells lining the colon. But it does much more. It is critical for maintaining the integrity of the intestinal barrier and preventing a condition known as “leaky gut,” implicated as a source of inflammation of many organs, including the brain. Butyrate stimulates intestinal wall cells to produce mucus and maintains the integrity of the intestinal barrier, keeping intestinal wall cells tightly joined so that bacteria and toxins from the gut do not leak into the general circulation. The same actions protect the intestine itself against inflammation.
The local effects of butyrate on the gut have major repercussions for brain operations. A leaky gut, for example, allows bacteria and toxins to pass through the intestinal wall into the bloodstream and be transported to the brain. In the brain, they can set off an inflammatory response, disrupting normal operations of the nervous system to pose the risk of depression, anxiety, cognitive difficulties, and even paranoia, psychosis and dementia.
Butyrate also influences mental health in other ways. It is active as a neurosignaling agent in the gut-brain axis, and it activates the vagus nerve. The vagus, the longest nerve in the human body, originating in the brain stem and extending into the abdomen, is often called the main mind-body highway; it is the primary channel of communication between the gut and the brain. The SCFAs directly activate the vagus nerve, stimulating and facilitating gut-brain communication. Studies show that butyrate increases the rate at which vagal neurons can transmit signals up to the brain, particularly satiety-related signals.
Operating by way of the vagus nerve, butyrate is also thought to communicate nutritional preferences to the brain. Researchers find that butyrate shapes food preferences by altering receptors for umami taste. It has multiple effects on appetite regulation, affecting metabolism of fats in multiple ways that suppress feeding as well as influencing action of several hunger-related hormones.
Studies show that butyrate crosses the blood-brain barrier and stimulates neuroplasticity in the brain. Animal studies show it raises levels of BDNF in the prefrontal cortex, paving pathways out of depression.
By its chemical nature, butyrate is an anti-inflammatory molecule, extinguishing inflammatory processes wherever they occur, including the brain. In the gut and in the brain, butyrate and its sister SCFA propionate target immune cells to regulate the inflammatory response. They steer the production of specific anti-inflammatory cells from precursor cells and reduce the production of proinflammatory cytokines. There is evidence that these actions protect the brain against both depression and chronic pain.
Propionate, produced both by Bacteroidetes and Firmicutes, is also anti-inflammatory, and it helps regulate appetite. It not only affects the release of gut hormones that influence appetite and promote weight loss but reduces abdominal fat and improves insulin sensitivity.
Beyond the influence of propionate on energy, neuronal receptors specific for propionate, when activated, turn up production of the neurotransmitter norepinephrine, important for inhibiting both neuropathic pain and depression. Along with butyrate, propionate contributes to the synthesis of several neurotransmitters— serotonin, dopamine, noradrenaline, and adrenaline—by regulating the expression levels of the enzymes involved in their synthesis.
Short-chain fatty acids, by themselves, are not supplied in abundance by diet. Instead, they are manufactured in the lower intestine from fiber in food—carbohydrate-based nutrients derived largely from the cell walls of plants, substances largely impervious to the digestive enzymes that break down most other food in the small intestine. Once in the colon, digestion-resistant carbohydrates are met by several distinct species of fiber-degrading bacteria that act on them by fermentation. Short-chain fatty acids are among the substances produced by bacterial fermentation of complex carbohydrates in the gut.
The fermentation of complex carbohydrates in the gut and the resulting release of short-chain fatty acids have multiple effects not only on general health and mental health but also on the makeup of the microbiome. They shift the composition of the microbiome, increasing the diversity of bacterial species inhabiting the gut.
Microbial diversity is so much a marker of health for so many body systems that it is linked to lowered levels of all-cause mortality. The bacterial population of the gut is also so responsive to what you eat that shifts in bacterial composition have been detected within 24 hours. Independent of diet, the composition of the microbiome is also influenced by physical exercise.
The fermentation of resistant starches specifically increases the gut population of such bugs as Bifidobacteria and Lactobacilli while decreasing known pathogens such as E. coli. As a result of consumption of fiber-rich foods, the microbiome of older animals resembles that of young animals and displays souped-up metabolic efficiency. Unfortunately, the microbiome of people consuming an American-type diet is depleted of fiber-fermenting microbes.
The makeup of the microbiome, on which production of SCFAs depends, is exquisitely sensitive to diet. Shifts in the relative abundance of SCFA-producing species of bacteria have been recorded in hours. Because diets high in fiber provide nourishment for and increase the abundance and activity of the beneficial bacteria turning out SCFAs, they are known as prebiotics.
There are many types of fiber in foods. High-fiber foods are deemed prebiotics when they nourish a healthy diversity of populations of bugs in the gut and specifically those producing SCFAs. Multiple studies show that diets rich in fiber or supplemented with prebiotic fiber have a favorable effect on the gut microbiota composition, with increased diversity and enhancement in short-chain fatty acids and the bacteria producing them. High-fat diets, particularly diets high in saturated fatty acids, such as the standard Western diet, have the opposite effect.
The U.S. Department of Agriculture recommends that adults consume 14 grams of fiber per 1,000 calories. (The average American male aged 20 to 59 consumes 2,500 or more calories per day, according to the U.S. Department of Health and Human Services; the average American female consumes approximately 2,000 calories per day.) It is believed that our human ancestors consumed about 100 grams of fiber daily. American adults currently consume a total of 17 grams of fiber per day, on average, while people in European countries consume slightly more, 18-24 grams per day. The difference between the amount of fiber people typically consume and the recommended amount—to say nothing of the optimal amount—is sometimes referred to as the fiber gap.
Large-scale analyses of fiber consumption show that the higher the intake of fiber, the greater the protection against death. While intake of 25 to 29 grams of fiber per day produced the greatest incremental risk reduction, researchers conclude that intakes of fiber above 30 grams a day “could confer even greater benefit to protect against cardiovascular diseases, type-2 diabetes, and colorectal and breast cancer.”
There are, however, many types of fiber, and they differ in important physicochemical properties—for example, some are soluble (pectin, inulins) and some are not—and in how they are handled by the body. Not all fiber is fermentable by gut bacteria. For example, psyllium husk, a naturally occurring polysaccharide fiber commonly marketed to promote intestinal regularity, is not fermentable; it is not a prebiotic and does not induce the production of SCFAs.
While a prebiotic-rich diet is advisable, there are no dietary guidelines establishing how much should be consumed. Adding prebiotic foods to the diet is best approached gradually by those not used to such foods. They can generate gas and abdominal discomfort.
The digestion-resistant complex-carbohydrate nutrients that act as prebiotics bear a variety of names reflecting their chemical constitution. They are concentrated in fiber-rich foods like leeks, onions, bananas, artichokes, cabbage, and asparagus, but they can also be extracted from foods and made available as supplements.
Prebiotics are generally classified by their chemical structure, bearing names such as fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) that reflect the number of sugar molecules that make up their “backbone.” Collectively, they are often referred to as polysaccharides. More than one type of fiber can be found in a food.
Oligosaccharides
Fructans
- Fructooligosaccharides(FOS), highly fermentable fiber found in fruits and vegetables, including asparagus, dandelion leaves, shallots, onions, leeks
- Inulins, highly fermentable fiber found especially roots or rhizomes in chicory root, from which is typically commercially extracted; Jerusalem artichokes; garlic; onions; globe artichokes; unripe bananas
Galactans
- Galactooligosaccharide (GOS) found in the milk of some mammals and in legumes such as chickpeas, lentils, soybeans
Pectins—moderately fermentable fiber found in pears, apples, quince, plums, gooseberries, oranges and other citrus fruits
Beta glucans—moderately fermentable fiber found in barley, mushrooms, oats, algae, yeasts
Xylooligosaccharides found in bamboo shoots, milk, honey
Resistant Starch
Moderately fermentable fiber found in brown rice, whole grains, lentils; also converted from starchy food like potatoes that have been cooked and cooled.
Independent of fiber-rich foods, omega-3 fatty acids have been found to increase the diversity of bacteria in the gut. Very specifically, they have been found to increase families of bacteria that produce SCFAs—Bacteroidetes and butyrate-producing bacteria belonging to the Lachnospiraceae family. Omega-3 fats are found in fatty fish like sardines, mackerel, and salmon.
In one study, researchers supplemented the diet of healthy adults with 500 mg of omega-3 fatty acids for six weeks. They found “significant changes” in the levels of short-chain fatty acids resulting from bacterial fermentation. The overall effects, they reported, were comparable to those achieved by supplementation with the food fiber inulin. Like inulin, say the researchers, omega-3 fats act as a prebiotic.
One of the first but most important changes that immigrants to the U.S. undergo is totally invisible to the naked eye—a shift in the bacterial makeup of the microbiome. The change in the composition of their gut microbiome will put them on a path to developing chronic disease—along with millions of other Americans. Their inner “Americanization” puts them at high risk for obesity and metabolic diseases such as diabetes, inflammatory bowel disease, psychiatric disorders like depression and anxiety, and neurodegenerative disorders such as Alzheimer’s and Parkinson’s.
In studies over the last couple of years, researchers have documented loss of bacterial diversity, extinction of whole strains of beneficial bugs (notably belonging to the Prevotella genus), and loss of ability to fully process carbohydrates and fiber. One prominent shift in dietary patterns with immigration to the U.S. is consumption of a high proportion of animal-derived protein relative to carbohydrate—it can alter the microbiome in one day.
Americanization of the microbiome reflects not only a shift to consumption of high-fat red meats and away from fiber-laden foods rich in complex carbohydrates. It also results from the consumption of ultra-processed foods. The industrial processing of food—it’s called junk food for a reason—does more than strip the bacteria-sustaining prebiotic fiber from food; it adds such components as texturizers and emulsifiers (carboxymethylcellulose and polysorbate 80 are two pervasive additives) that actually destroy gut microbial diversity, altering the entire microbial ecosystem and making it less receptive to whole populations of beneficial bacteria. Some scientists liken the loss of microbial species to a health threat on a par with climate change.
The American diet is notable for limited consumption of legumes, nuts, and seeds—three food groups especially rich in prebiotic fiber. It also leans more heavily on meats than on fruits and vegetables, also major sources of prebiotics.
One distinguishing feature of the Mediterranean diet is the predominance of such foods, and the production of SCFAs is believed to account for many of the mental and physical health benefits of the Mediterranean diet. It is closer than the highly processed American diet to what our ancestors ate for most of human history—a hardscrabble diet in which nuggets of nutrients came bundled in indigestible plant material. The human gut was adapted to a diet of more than 100 grams per day of fiber from foraged food—compared with the fewer than 15 grams of fiber a day supplied by the typical Western diet of highly processed, energy-dense foods.
