The gut microbiota plays a key role in modulating host physiology and behavior, particularly feeding behavior and energy homeostasis. There is accumulating evidence demonstrating a role for gut microbiota in the etiology of obesity. In human and rodent studies, obesity and high-energy feeding are most consistently found to be associated with decreased bacterial diversity, changes in main phyla relative abundances and increased presence of pro-inflammatory products. Diet-associated alterations in microbiome composition are linked with weight gain, adiposity, and changes in ingestive behavior. There are multiple pathways through which the microbiome influences food intake. This review discusses these pathways, including peripheral mechanisms such as the regulation of gut satiety peptide release and alterations in leptin and cholecystokinin signaling along the vagus nerve, as well as central mechanisms, such as the modulation of hypothalamic neuroinflammation and alterations in reward signaling. Most research currently focuses on determining the role of the microbiome in the development of obesity and using microbiome manipulation to prevent diet-induced increase in food intake. More studies are necessary to determine whether microbiome manipulation after prolonged energy-dense diet exposure and obesity can reduce intake and promote meaningful weight loss.
The gut microbiota is a collection of over 10 13 microorganisms, including bacteria and fungi, that inhabit the gastrointestinal (GI) tract and plays a key role in regulating host physiology, particularly GI function and energy homeostasis. The microbiome is a relatively stable community of microbes in the individual. In response to the burgeoning obesity epidemic, research has focused on personal and environmental factors that might influence weight status. The discovery that in both humans and rodent models, obese individuals have a distinct microbiome profile compared to their lean counterparts, with an increased capacity to harvest energy from ingested food, has fueled over 15 years of research. Microbiota is vital for proper GI function, as it is implicated in vitamin synthesis, digestion and metabolism of carbohydrate and other dietary components, and development and function of the GI immune system. Gut microbes have also been shown to influence the function of other peripheral organs, as well as the central nervous system (CNS), throughout development and the lifespan. The importance of the gut microbiota in regulating host biology is evident from gnotobiotic studies: animals born germ-free (GF) present with altered intestinal, metabolic, and neural physiology.
Recently, advances in sequencing technologies have allowed us to more comprehensively and thoroughly assess microbiota composition and its relation with disease states. Adverse changes in composition have been associated with an array of pathologies, including autoimmune diseases, neurological conditions, and metabolic disorders such as obesity and diabetes. It is, however, important to note that any environmental modification is likely to impact microbiome composition, and differences in bacterial makeup associated with pathologies do not equate to a causal link between microbial changes and pathological development.
There is accumulating evidence supporting a role for an individual’s microbiota in regulation of food intake through both peripheral and central mechanisms. Peripherally, bacteria and their metabolites interact with vagal afferent neurons (VANs), which transmit information about intestinal contents to the nucleus of the solitary tract (NTS). The microbiome influences gut–brain satiety signaling via modulation of gut peptide release as well as sensitivity to satiety peptides (such as cholecystokinin, or CCK) and the energy storage hormone leptin. Changes in microbiome composition have also been reported to affect the structural integrity of the gut–brain axis. Centrally, unfavorable microbiome composition is associated with inflammation of key regions involved in the regulation of feeding, particularly the NTS and the hypothalamus. Further, there is emerging evidence that certain taxa of bacteria play a role in modulating reward circuitry and motivation. The purpose of this review is to describe the microbiota’s influence on food intake through the aforementioned mechanisms, including recent developments in the relationship between microbiome, reward, and eating behavior.
Chronic intake of energy-dense food has been linked to excessive weight gain. Despite homeostatic signals that act protectively against food overconsumption, chronic intake of palatable, high-energy diets alters the physiological response to food and favors overeating. Ultimately, this results in increased body weight (BW) and fat deposition. Specifically, sensitivity to hedonic cues is altered, while homeostatic signals of meal termination are dampened.
The vagus nerve is a direct pathway that carries post-ingestive feedback from the gut to the brain. Mechano- and chemosensitive VANs respond to the nutrient composition of ingested food to regulate meal size. VANs terminate in the NTS, where postprandial signals increase neuronal activity. In addition, VANs project to limbic brain regions, and this gut–reward circuit is sufficient and necessary for meal termination. Chronic consumption of a high-fat (HF) diet reduces VAN sensitivity to tension, satiation hormones (e.g., CCK), and intestinal nutrients. As such, diet-induced disruption of vagal signaling coincides with the onset of hyperphagia. In addition, diet-induced obese (DIO) rats also exhibit significantly decreased postprandial neuronal activation in the NTS compared to lean animals.
Other neuronal networks involved in the regulation of feeding are also altered by chronic HF consumption. Leptin is a key adiposity signal, with amounts produced proportional to the amount of fat stored in the body. Hypothalamic leptin signaling is disrupted during chronic HF feeding, with increased expression of suppressor of cytokine signaling 3 (SOCS3) and decreased phosphorylated signal transducer and activator of transcription 3 (STAT3) in the arcuate nucleus. Pro-opiomelanocortin (POMC) neurons in the hypothalamus in a normal physiological state are activated by leptin to ultimately decrease food intake via the production of α-melanocyte-stimulating hormone (α-MSH). Thus, HF-induced disruption of leptin can directly alter hypothalamic inhibition of food intake. Another neuronal system altered by HF intake is the dopaminergic reward system. Food’s hedonic value is an important factor in food consumption, and increased motivation for food intake is linked to obesity. Palatable foods initially have a higher reward value, while as obesity progresses, reductions in reward signaling emerge and lead to compensatory overeating. Among regions involved in the mesolimbic dopaminergic system, the nucleus accumbens (NAc) and striatum exhibit decreased dopamine release in rodents with long-term exposure to a HF diet.
Dietary intake is a major and easily modifiable determinant of an individual’s microbiota composition; other factors include age and genetics. In humans, both short- and long-term intake of specific macronutrients, as well as fibers and other plant foods, are correlated with abundance distribution of specific bacterial taxa present in the GI tract. Obesity is associated with changes in microbiome composition. While the vast majority of the composition is specific to the individual, small-scale studies have found that obesity has been associated with an increased ratio of Firmicutes to Bacteroidetes, the two main phyla present in the GI tract. Conversely, weight loss through caloric restriction has led to an increase in Bacteroidetes abundance, whether that restriction was through a carbohydrate- or fat-restricted diet plan. Similar results are observed in rodent models of DIO, with the addition of a bloom in the pro-inflammatory Proteobacteria sometimes reported in humans with obesity or type 2 diabetes. In rats, 8 weeks of 45% HF-feeding is associated with decreased bacterial α-diversity, a measure of the variety of bacterial taxa colonizing the gut, and increased relative abundances in the Firmicutes orders Clostridiales, in particular, the Dorea genus, and Erysipelotrichiales (Erysipelotrichaceae family). Three weeks of 60% HF-feeding has a similar effect on microbiome composition in rats, with increases in relative abundances of several Firmicutes families, including Streptococcaceae, Erysipelotrichaceae, Lachnospiraceae (Dorea genus), Peptococcaceae, and Staphylococcaceae, as well as Proteobacteria families Desulfovibrionaceae and Enterobacteriaceae. In rats, a mere 7 days of 60% HF-feeding is associated with decreased abundance of the Bacteroidetes orders Bacteroidales (Prevotella genus) and Sphingobacteriales, and increased Firmicutes order Erysipelotrichales, and several Proteobacteria orders, includin
