The Long Reach Of Short-Chain Fats

You know by now that the gut and the billions of microbes inhabiting it have a powerful effect on the operations of many other organs of the body, including the brain—perhaps most especially on the brain. But if you want to understand how it all works, pay attention to three substances collectively known as short-chain fatty acids (SCFAs): acetate, propionate, and butyrate.

They appear to be the major messengers to your brain from your gut, and they affect brain physiology and behavior both directly and indirectly, including through the immune system. They influence your energy level, your appetite, your response to stressful events, your mood states, and more.

Unlike most fats the body needs, the three SCFAs are not directly supplied by food. Rather, they are produced by specific species of bacteria partial to dietary fiber so impervious to digestive enzymes that it reaches the colon intact. There, provided you’ve eaten right, brave bacteria lie in wait to ferment the fiber, releasing energy, gases, and a few metabolites, the SCFAs.

The amount of SCFA produced in your gut depends on how much fiber-rich food you’ve consumed to maintain the bacteria that feed on it. Acetate is the most abundant SCFA, composing 60 percent of the total, with propionate at 25 percent and butyrate at 15 percent.

SCFAs are consumed as an energy source by cells lining the intestine. They also stimulate local production of mucus and keep intestinal-wall cells tightly joined so that substances from the gut do not leak into the bloodstream.

It’s important to know about the local effects on the gut because they have many implications for brain operations. A leaky gut, for example, allows bacteria and toxins to escape through the intestinal wall and reach the brain, where they are able to set off an inflammatory response that can disrupt nerve function and pose a risk of depression, anxiety, paranoia, cognitive difficulties, even psychosis and dementia.

Intestinal housekeeping is just part of the still-unfolding job description of the SCFAs. Acting locally, propionate also stimulates the release of appetite-regulating hormones in the gut like peptide YY, which slows down stomach emptying and makes you feel fuller faster. In addition, SCFAs influence lipid metabolism. Butyrate, for its part, affects systemic metabolism by increasing insulin sensitivity, diminishing the risk of diabetes.

All three SCFAs enter the bloodstream from the gut, then cross the blood-brain barrier and gain direct access to the brain. There, they expand their effects on metabolism by acting on neurons in the hypothalamus to regulate energy balance. Butyrate, in particular, has a few special talents. It can do for the brain what it does for the gut—maintain barrier integrity, keeping out bad actors. And by its chemical nature, it is an anti-inflammatory molecule, tamping down inflammation.

In the gut and in the brain, SCFAs butyrate and propionate target immune cells to regulate the inflammatory response. They steer the production of anti-inflammatory cells and reduce the production of pro-inflammatory cytokines. This action, evidence suggests, protects the brain against both depression and chronic pain.

Further, neuronal receptors specific for propionate, when activated, turn up production of the neurotransmitter norepinephrine, important for inhibiting both neuropathic pain and depression. Butyrate increases levels of brain-derived neurotrophic factor in the prefrontal cortex, stimulating the growth of neurons to open pathways of behavior out of depression.

Once in the bloodstream, the SCFAs take important action against stress hormones. Studies show that they “significantly attenuate” the cortisol response to acute psychosocial stress. The greater the levels of SCFAs, the lower the cortisol response and the lower your stress reactivity.

Yet, it may be by way of the vagus nerve that SCFAs have their biggest effect on the brain and behavior. The longest nerve in the body, the vagus originates in the brainstem and extends into the abdomen, carrying signals to—and from—the viscera; it enables organs to adjust instantly to the demands of the internal and external environment. The vagus appears to be the main mind-body highway, the primary channel of communication between gut and brain; the SCFAs are likely its long-haul truckers.

For starters, they 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 via vagus pathways, butyrate also appears to communicate nutritional preferences to the brain, altering receptors for umami and possibly other tastes and shaping food preferences.

Because the microbes of the gut must subsist on the food we consume, the human diet directly affects the composition of bacteria in the biome. The colon-inhabiting bugs that produce SCFAs have very specific dietary requirements: fiber and digestion-resistant starch, stuff found in the cell walls of plants. A diet rich in fiber increases the number of bacteria turning out SCFAs.

Because they stimulate the growth of beneficial bacteria, substances like fiber are also known as prebiotics (just as the SCFAs are sometimes referred to as postbiotics). The most extensively documented prebiotics include the
digestion-resistant starches inulin, abundant in chicory root, unripe bananas, garlic, artichokes, and oats; fructo-oligosaccharides (FOS), found in fruits and onions, cabbage, and asparagus; and galacto-oligosaccharides (GOS), found in cow’s milk and legumes. These promote the growth of various species of Lactobacillus or Bifidobacterium that turn out SCFAs.

Unfortunately, a defining feature of the Western diet is a lack of fiber. The effect on gut microbial composition is seen as a hidden force behind rising rates of obesity, diabetes, colorectal cancer, and such psychological ills as anxiety, depression, and neurodegenerative disorders. On the other hand, consumption of fiber is linked to a reduction of all-cause mortality. SCFA production from the plant-rich Mediterranean diet is believed to account for many its mental and physical health benefits.

Adding prebiotic-rich foods to the diet is seen as one of the most bang-for-the-buck measures available for promoting both mental and physical health. But prebiotics are also extracted from foods and made available as supplements. Scientists are currently exploring disorder-specific prebiotic formulas for depression, anxiety, stress, sleep disorders, and Alzheimer’s disease, but that doesn’t stop general-purpose ones from boosting brain health now.

Fat Facts

• Physical exercise has been shown to increase levels of SCFA-producing bacteria in the gut.
• SCFAs enhance endurance exercise capacity, at least in mice.
• A high-fat diet shifts gut composition, decreasing SCFA-producing bugs and gut-brain signaling.
• Lack of SCFAs hinders the brain from clearing out debris linked to neurodegenerative diseases.
• Sleep deprivation depletes SCFA-producing bacteria, promoting inflammation and impairing cognition.
• In the gut, SCFAs keep pathogenic bacteria in check and tame their virulence.