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By Madelaine Leitman

“There is always room for dessert!” Even after a full meal, the allure of a soft, mouth-watering chocolate chip cookie or a decadent slice of cake can be simply irresistible. We’ve all experienced the sweet whispers from dessert, tempting us to give into its indulgence. But what lies behind these cravings? The answer largely lies in the sophisticated relationship between our gut and brain.

In recent years, scientists have been uncovering a fascinating connection between our gut and brain often referred to as the “gut-brain axis.” As this interaction is not a linear process but involves a complex network of communication channels between the gut, the brain and the gut microbiome, a better name for these connections is the “brain gut microbiome system”. The gut microbiome refers to the trillions of microorganisms living in our gastrointestinal tract, including bacteria, viruses, and fungi. A growing body of evidence suggests that these tiny inhabitants of our gut play an instrumental role in various aspects of our health, including digestion, immunity, and even our brain function. To understand this system’s involvement in the complex regulation of feeding behavior, we must first distinguish between energy homeostasis and motivational processes.

Energy-homeostasis is regulated by a tiny structure deep within our brain called the hypothalamus, which can sense the body’s fat reserves and interpret gut’s satiety signals to modulate food intake and energy expenditure in order to maintain a constant body weight. This is an intricate process that our body has evolved to ensure we maintain a balanced energy state despite variations in food availability. The gut communicates vital nutritional information to the hypothalamus through the vagus nerve, which is one of the many ways that the gut microbiome communicates with the brain in a bidirectional manner. Vagal sensory nerves are activated when your stomach expands in response to food ingestion and a group of your gut’s hormonal (enteroendocrine) cells secrete satiety hormones which act on receptors on vagal nerve terminals. These vagal sensory neurons send this information to the hypothalamus which in turn reduces our motivation to eat more.

“The gut communicates vital nutritional information to the hypothalamus through the vagus nerve…”

However, living in a world in which we are constantly bombarded with food-related commercials, and as many of us have experienced, the feeling of “fullness” is not always enough to stop eating. In these situations, the hedonic aspect of eating overrides homeostatic mechanisms, e.g. the mechanisms assuring the right amount of food for our energy needs. In other words, the expected pleasant sensations of continued eating may be stronger than the body’s natural signals telling us that we are full, causing us to keep eating even when our bodies do not need more food. This occurs because the consumption of food, especially foods that are high in fats or sugar, stimulate the release of the neurotransmitter dopamine activating the mesolimbic dopamine pathway in the brain, or the brain’s reward circuit. This pathway involves the release of a neurotransmitter called dopamine from a brain region called the ventral tegmental area (VTA). At rest, dopamine neurons fire in a low-frequency mode. However, the frequency of these nerve oscillations increases during both rewarding and aversive experiences, allowing the brain to store the environmental stimuli associated with such events either for future realization of the pleasurable experience, or in order to avoid the aversive ones. The dopamine that is released from the VTA activates the nucleus accumbens and other brain regions. This can drive individuals to seek pleasure from compulsive eating patterns, which can ultimately lead to food addiction and obesity. Hyper-addictive drugs such as cocaine and opioids hijack the same pathway, causing an unnatural and excessive release of dopamine, leading to intense feelings of euphoria, shedding light on the shared neurological mechanisms that underlie both drug and food addictions.

“However, living in a world in which we are constantly bombarded with food-related commercials, and as many of us have experienced, the feeling of “fullness” is not always enough to stop eating.”

The struggle to resist food cravings is often seen as a lack of self-control, but another possibility is that our microbes are playing a larger role than once thought. There is an evolutionary mismatch between the host (e.g. us) and our gut microbes that have alternate interests in host eating behavior. Gut microbiota solely depend on their host for providing the nutrients necessary for their survival and growth, giving the microbes an incentive to influence host behavior for their own fitness, Microbial genes, which outnumber human genes with a 100 to 1 ratio, are responsible for carrying out crucial functions beneficial to the host organism, as well as participating in competitive interactions with other microbial species that share their “ecosystem.” A less diverse microbial population will likely have species with larger population sizes, allowing for these species to allocate more energy towards host manipulation, with the help of large-scale coordination. That is, low diversity may give way for the overgrowth by few species, giving these organisms more relative power to synthesize neurotransmitters or hormones such as dopamine that influence host behavior. In preclinical studies it has been shown that certain gut microbiota can modify dopaminergic transmission but the underlying mechanisms are not clear.

“A less diverse microbial population will likely have species with larger population sizes, allowing for these species to allocate more energy towards host manipulation, with the help of large-scale coordination.”

Dysbiosis can also lead to gut inflammation, and emerging research indicates that inflammatory signals originating in the gut can lead to immune activation in the brain. Specifically, molecules such as cytokines, produced as part of the immune response against pathogenic bacteria in the gut, can travel through the vagus nerve or the systemic circulation and cross the protective blood-brain barrier, gaining access to the brain. Once there, these inflammatory molecules can trigger a cascade of immune responses by the brain’s immune cells, leading to neuroinflammation, which can affect the brain’s mesolimbic dopamine pathway through the dysregulation of neurotransmitters such as dopamine. One study looking at how inflammation affects the reward circuitry in patients with depression found that increased inflammatory cytokines were associated with decreased connectivity within the nucleus accumbens and other brain regions associated with reward and addiction.

Another way in which gut microbiota may affect the brain’s reward network is through gut-derived metabolites, which are end products of bacterial metabolic processes. Circumstantial evidence of this relationship showed that those who are “chocolate desiring” contained distinct microbial metabolites in their urine compared to “chocolate indifferent” individuals, despite eating identical diets. One group of microbial metabolites that has been associated with food reward are tryptophan-derived indoles. Tryptophan is an essential amino acid in protein and neurotransmitter synthesis, but that the body cannot produce on its own, so it must be obtained through our diet. Within the gut, gut microbes metabolize tryptophan into indole metabolites, which are believed to impact food intake by enhancing the functional connectivity of the nucleus accumbens—an integral part of the brain’s reward system. As we consume foods rich in tryptophan, such as chicken, fish, milk, and oats, our gut microbiota process this amino acid and generate the indole metabolites, enhancing the communication within the nucleus accumbens, creating a more responsive reward system.

“One group of microbial metabolites that has been associated with food reward are tryptophan-derived indoles.”

Past research has investigated how nutritional state (fasted vs. fed) and different food stimuli (appetizing vs. bland, high-caloric vs. low-caloric) influence the brain reward systems through studying brain activity in fMRI scans. The researchers found that fasting selectively increased activation in response to pictures of high-caloric food in the reward processing regions of the brain. This heightened responsiveness displays the interplay between gut-derived hunger and satiety hormones, such as ghrelin, leptin, CCK, PYY, and GLP-1, in shaping our food choices and the brain’s reactivity to different food cues. It makes sense that the hungrier we are, the more excited we get for calorie-dense foods. However, disrupted homeostatic controls over appetite and eating, meaning our nutritional needs and perceived status of satiety become skewed, can influence hedonic intake.

Understanding how the microbiome can shape our reward responses to food offers new avenues for addressing issues like overeating, food addiction, and even mood disorders. While ongoing research continues to unravel the intricate details of how gut microbiota directly influence our hedonic food intake, the existing evidence already highlights clear connections between these two vital elements of our physiology.

Madelaine Leitman is an undergraduate student at UCLA, with a major in Computational and Systems Biology. Her passion for her ongoing research at the Goodman-Luskin Microbiome Center is fueled by her strong belief that the brain gut microbiome system plays a crucial role in overall wellbeing and health. Her ultimate goal is to contribute valuable insights to the scientific community and disseminate knowledge to the wider public. Beyond her academic pursuits, she enjoys traveling, running, practicing yoga, and playing volleyball.