The Role of the Gut-Brain Axis in Metabolism and Energy Homeostasis

Key Learning Objectives

• Learn how special cells in the gut modulate energy balance 
• Find out how the gut microbiota influences metabolism
• Understand the importance of the gut microbiota in metabolic health
• Discover how the microbiota may be targeted to support metabolic health

The extent of our relationship with gut bacteria is only beginning to be unraveled, but it’s already clear that the gut microbiota has a tremendous influence on many aspects of human health. We know that a healthy intestinal flora is supported by a healthy diet and that, together, they are essential for the maintenance of energy homeostasis, metabolism, and healthy weight.

Energy Homeostasis and Healthy Weight

Energy homeostasis is the balance the body achieves from all the processes involved with the energy we take in (e.g., calories) and use. It is the result of a dynamic control of energy intake, via the regulation of appetite and satiety, and energy expenditure, via basal metabolism, heat generation, and physical activity. In a simplified sense, when we maintain energy homeostasis our weight stays about the same over time.

To maintain energy homeostasis, the brain needs to know when our energy reserves are low so it can tell us to feed; likewise, it needs to be informed of what and how much we ingest so it can tell us to stop eating. To be able to do so, the brain needs to receive input from other organs informing it of the body's energy state and energy reserves. The brain maintains homeostasis by integrating this neural and chemical input and adjusting our energy intake and expenditure accordingly.

The gastrointestinal (GI) tract is the major source of information about our energy intake. Thus, it plays a key role in the regulation of energy homeostasis. As we’ve seen in What is the Gut-Brain Axis?, the brain, the gut, and the microbiota are linked by a bidirectional neuronal, endocrine, and immune communication system known as the gut-brain axis.[1] 

In this article, we will take a look at the role of the gut microbiota and the gut-brain axis in metabolism and energy homeostasis. We will learn how food-derived chemical signals—nutrients and microbial metabolites—are translated in the gut into endocrine and neural signals that convey information about the caloric load and composition of a meal to the brain. We will also discuss the impact of diet on the gut microbiota and on the mechanisms of energy homeostasis, particularly the regulation of appetite.

Energy homeostasis is maintained through the dynamic control of energy intake and energy expenditure.

How Enteroendocrine Cells Sense The Gut

Scattered throughout the lining of the GI wall, in contact with the gut lumen (i.e., the space inside the GI), a type of gut-specific endocrine cells called enteroendocrine cells (EECs) can be found. EECs are important because they have a sensory apparatus at their surface that allows them to sense the gut lumen. They sense gut nutrient levels—sugars, fats, and proteins—and microbial metabolites, and communicate those levels by producing signaling molecules called gut hormones or gut peptides.[2]

EECs produce over 20 different gut peptides. Each gut peptide is released in response to specific stimuli (e.g., nutrient composition of a meal, caloric load of a meal) and collectively they act as a code that (1) signals what and how much we have eaten, and (2) triggers adequate metabolic and behavioral responses.[3,4] 

Following their secretion, gut peptides can activate nearby neurons of the vagus nerve or the enteric nervous system (ENS), the gut’s own nervous system. Enteric and vagal neurons can sense nutrients directly, but because neuronal innervation does not extend to the gut lumen, direct nutrient sensing is restricted to absorbed nutrients and local metabolic products. The input from gut peptides is then sent to the brain via the vagus nerve. Gut peptides can also reach the systemic circulation and act directly on the brain. [1,3,5]

Chemical signals from nutrients and microbial metabolites are translated in the gut into neuroendocrine signals that convey information about the caloric load and composition of a meal to the brain.

Source: Bliss and Whiteside, 2018; 10.3389/fphys.2018.00900. License: CC BY 4.0

How Gut Peptides Influence Energy Homeostasis

Neuronal inputs from the gut are conveyed to energy regulation centers in the brain, where they are integrated with energy reserve signals (such as leptin and insulin, for example) and other hormonal and neurochemical inputs to regulate appetite and energy expenditure. Blood-borne gut peptides also stimulate satiety centers in the brain directly to decrease appetite.[2,4,6]

Gut peptides act locally as well. For example, they change gastrointestinal motility and secretion and increase gastric distension, which helps create that feeling of fullness that stops us from overeating. They also modulate insulin and leptin secretion to adjust glucose and fatty acid utilization.[3,4,6]

Appetite-inhibiting gut hormones also act by decreasing the secretion of appetite-promoting gut hormones, the most prominent of which is ghrelin—actually known as the hunger hormone. Ghrelin secretion, which occurs mostly in the stomach, is determined by absorbed nutrients and by neural and hormonal signals. Ghrelin secretion rises when the nutritional status is low to stimulate hunger and food intake; its levels fall rapidly after a meal in part due to the action of gut peptides.[7]

Besides decreasing energy intake, gut-derived neuroendocrine signals within the gut-brain axis also influence energy expenditure.[1,6] Gut peptides can increase energy expenditure by increasing motor output, basal metabolic rate, and brown adipose tissue (BAT) thermogenesis (i.e., heat generation).[6,8] 

In table 1, you can see a few examples of appetite-inhibiting gut peptides, what stimulates their secretion, and what their actions are.

Table 1 - Effects of gut peptides on energy intake and expenditure [6]

Gut hormones signal the nutrient composition and caloric load of a meal and trigger physiological responses that modulate appetite and energy expenditure.

How The Gut Microbiota Influences Energy Homeostasis

We have a mutually beneficial symbiotic relationship with the gut microbiota. This means we cooperate and help each other. We help bacteria by feeding them what we eat. In return, they help us digest and extract energy from food, transforming nutrients we wouldn’t be able to absorb into other forms that can be taken up by the gut into the blood. 

Metabolites produced by the gut microbiota include short-chain fatty acids (SCFAs), secondary bile acids, choline metabolites, phenolic compounds, indole derivatives, vitamins, neurotransmitters, and neurotransmitter precursors, and bioactive lipids. Through these metabolites, the gut microbiota can influence the activity of EECs, gut hormone secretion, appetite, and energy storage.[9,10] Many of these microbial metabolites are essential for our health. 

Short-chain fatty acids (SCFAs), which include the molecules acetate, propionate, and butyrate, are particularly relevant in the crosstalk between microbial and human metabolism. SCFAs are mostly produced from the breakdown of nondigestible fibers and starches and they account for up to 10% of human energy requirements. The SCFA butyrate is the primary energy source for epithelial cells in the colon, propionate is used by the liver to produce glucose, and acetate is transported in the blood to other tissues, where it can be oxidized and used as a substrate for energy metabolism.[1,11,12] 

But beyond being a source of energy, SCFAs are also signaling molecules. SCFAs bind to receptors expressed by EECs, influence nutrient-sensing, and regulate gut hormone secretion.[1,6,9] SCFA receptors are also expressed in neurons of the vagus nerve and ENS and in immune cells.[13,14] Thus, SCFAs can regulate and have a significant impact on the gut-brain axis, and consequently, on appetite, food intake, metabolism, and energy homeostasis.[15–17] 

SCFAs also act on liver and muscle cells, where they regulate glucose utilization and energy expenditure, and on adipose cells, where they regulate fat storage.[13,14] SCFAs can also regulate energy homeostasis by stimulating leptin production in fat cells.[9] Leptin is a hormone produced by adipose tissue that signals the state of fat stores to the brain and inhibits hunger.[18]

Secondary bile acids are another type of microbial metabolite that also act as signaling molecules. Secondary bile acids result from the degradation by gut microbes of a fraction (5 to 10%) of bile acids (or bile salts) produced in the liver from cholesterol and secreted in bile. [Bile acids are molecules that facilitate the metabolism of dietary fat and the absorption of fat-soluble vitamins and cholesterol.] Microbiota-derived secondary bile acids influence signaling pathways involved in energy and lipid metabolism, production of fatty acids, and triglyceride storage.[9]

Microbial metabolites influence nutrient-sensing, the production of gut hormones, and the gut-brain axis. Thus, the gut microbiota influences energy intake and energy storage in our body.

How Dysbiosis Affects Weight Gain

The composition and diversity of the gut microbiota, which determines the levels of  SCFAs and secondary bile acids, for example, is known to be one of the factors that influence our feeding behaviors and appetite.[19,20] In turn, the composition and diversity of the gut microbiota are determined by the diet.[1]

Overnutrition and high-sugar and high-fat diets can have a particularly negative impact on the gut, creating imbalances in microbial composition and diversity, referred to as dysbiosis. Unhealthy diet-induced dysbiosis can have a significant impact on energy homeostasis: it can alter microbial signaling, gut nutrient-sensing, gut peptide sensitivity, and endocrine, immune, and neuronal signaling to the brain.[21,22] These dysfunctions in the gut-brain axis will result in abnormal appetite control, leading to further overeating.[1,6,23]

The composition and diversity of the gut microbiota is one of the factors that determines appetite and feeding behaviors.

Animal studies have given us a glimpse of the extent of the metabolic impact of the gut microbiota. For example, colonization of germ-free mice with a gut microbiota from obese mice was shown to induce more weight gain than with a microbiota from lean mice. This increased weight gain was attributed to the composition of the gut microbiota of obese mice. It was shown that obese mice have a microbiome (the genetic pool of the microbiota) enriched in genes involved in the extraction of calories from indigestible carbohydrates and in the stimulation of fat production and fat accumulation, for example.[24] 

It’s likely that a similar process occurs in humans. Because of differences in the composition of the gut microbiota induced by unhealthy diets, overweight individuals may become more effective at extracting energy from food and at storing and accumulating fat.[24]

Furthermore, one of the immediate consequences of overeating or high-fat and/or high-carbohydrate diets is the excessive production of some gut peptides. If this behavior becomes customary, tolerance to gut peptides develops over time and their satiety-promoting effect consequently decreases. This creates a crescendo of overeating and tolerance that, along with dysbiosis, can lead to significant weight gain.[25]

Diet-induced changes in gut microbiota composition and diversity contribute to the dysregulation of energy homeostasis associated with excessive weight gain.

Adapted from Bliss and Whiteside, 2018; 10.3389/fphys.2018.00900. License: CC BY 4.0

How Diet May Impact Metabolic Health

Excessive weight and fat accumulation are often associated with a number of parameters that are indicative of generalized poor health, including insulin resistance, atherosclerosis, and other cardiometabolic dysfunctions.

The gut microbiota may play a key part in this process of health impoverishment.[26,27] For example, high-fat diets favor the growth of a type of bacteria that produce an endotoxin called lipopolysaccharide (LPS), a proinflammatory molecule. A chronic high-fat diet may increase plasma LPS concentrations two- to threefold.[28] This type of diet-induced change in the gut microbiota can lead to gut barrier dysfunction (known as leaky gut). As a consequence, microbial products, such as LPS or other inflammatory molecules, may reach the blood and activate proinflammatory processes throughout the body, particularly in white adipose tissue.[29–31]

This state of generalized chronic low-grade inflammation induced by changes in the microbiota is known as metabolic endotoxemia. Gut dysbiosis and changes in intestinal barrier permeability have been implicated in what is known as cardiometabolic syndrome, a combination of symptoms associated with chronic low-grade inflammation—hypertension, insulin resistance, impaired glucose tolerance, dyslipidemia (high-fat content in the blood), and abdominal adiposity—that can have massive detrimental effects on health.[32–34]

Changes in gut microbiota composition can lead to a state of chronic low-grade inflammation that contributes to poor cardiometabolic health.

Source: Petschow et al 2013, 10.1111/nyas.12303. License: CC BY-NC 3.0

How The Gut Microbiota May Support Metabolic Health

The gut microbiota can influence gut nutrient sensing and gut peptide release. Thus, gut microbiota manipulation is a potential tool to target the gut–brain axis and influence energy homeostasis to support metabolic health.[1]

Raising the levels of SCFAs by, for example, increasing the dietary intake of indigestible starches and fibers is known to confer metabolic benefits. In animals with genetic obesity, dietary supplementation with SCFAs was shown to decrease weight gain, improve insulin sensitivity, and increase energy expenditure.[35] The metabolic benefit of chronic SCFA administration was associated with activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and increased mitochondrial function, indicating that it can influence cell nutrient sensing and metabolic pathways.[17,36]

The composition of the gut microbiota can be altered using probiotics and prebiotics. Probiotics are “live microorganisms, which when consumed in adequate amounts, confer a health effect on the host.”[37] A prebiotic is a “nondigestible compound that, through its metabolization by microorganisms in the gut, modulates composition and/or activity of the gut microbiota, thus conferring a beneficial physiological effect on the host.”[38] Studies using probiotics and prebiotics have shown that these products are able to modify the gut microbiota in such a way that improves gut nutrient-sensing mechanisms and reduces food intake.[1]

Also in animal studies, it was shown that probiotics increase the levels of satiety hormones, causing a reduction in food intake that suppresses body weight gain and improves metabolic parameters such as insulin sensitivity.[39–41] Similarly, studies in mice fed high-fat diets showed that prebiotics decreased food intake, weight gain, fat mass, and insulin resistance. [39,42,43]

In humans, probiotic administration has also been shown to support weight loss, an effect that was associated with reductions in circulating leptin levels.[44] Likewise, prebiotic administration was shown to increase satiety and reduce hunger and the desire to eat, an effect most likely due to an increased release of satiety-signaling gut hormones.[45,46] In overweight adults, prebiotics induced weight loss and improved glucose regulation.[47]

Probiotics and prebiotics modulate the composition and diversity of the gut microbiota and can be used to support metabolic health.

As our knowledge about the influence of the gut microbiota on our metabolism expands, it becomes increasingly clearer that a healthy diet supports a healthy gut microbiota, and that both are key factors in maintaining a healthy metabolic function. Likewise, it is becoming clearer that interventions designed to support a healthy gut microbiota may be highly beneficial in supporting a healthy metabolism and cardiometabolic function.[1] 

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