Credit:Microbiota-gut-brain axis drives overeating disorders.
Overeating disorders (ODs), encompassing conditions like binge eating disorder (BED) and bulimia nervosa (BN), are prevalent in modern society, affecting millions of individuals worldwide. Characterized by an inability to control excessive food intake and a preoccupation with food, ODs can have profound effects on physical and mental health, leading to obesity, metabolic disorders, and psychological distress. The etiology of ODs is complex and multifactorial, with both genetic and environmental factors contributing to their development.
Recently, Fan et. al. investigated the intricate connection between the gut microbiota, the gut-brain axis, and the development of overeating disorders (ODs). Their study, published in Cell Metabolism, delved into the underlying mechanisms of these disorders, offering potential therapeutic strategies for a condition that plagued contemporary society.
The researchers employed a mouse model of ODs, mimicking the combination of dieting and stress experienced by humans. This model involved two phase: dieting phase and refeeding phase. In the first phase, the mice were subjected to a period of food restriction, where they had limited access to a standard chow diet. This phase simulated the calorie restriction that occurred during dieting in humans. Following the dieting phase, the mice were provided with unlimited access to high-calorie, palatable foods such as Oreo cookies. This phase simulated the refeeding behavior that can occur after dieting, leading to excessive intake of high-calorie foods. In addition, the mice were exposed to stress-inducing foot shocks during the refeeding phase. This simulated the stress experienced by individuals with ODs, which can further exacerbate overeating behaviors. In the current study, the researchers observed a progressive development of a preference for these foods and an increase in caloric intake, akin to human ODs.
To probe the role of the gut microbiota in this process, the researchers administered a cocktail of broad-spectrum antibiotics to deplete the gut microbiota. This led to a significant increase in the preference for palatable foods and caloric intake, suggesting that the gut microbiota played a crucial role in regulating dietary preferences and intake. Furthermore, the transplantation of fecal microbiota from healthy mice to OD mice effectively prevented overeating behaviors, further emphasizing the importance of gut microbiota in ODs.
Next, the researchers conducted a thorough analysis of the gut microbiota in OD mice using 16S rDNA sequencing. They found significant changes in the microbial composition, with a reduction in beneficial bacteria like Lactobacillus and an increase in potentially harmful bacteria like Bacteroides. These changes were mirrored in the gut microbiota of patients with BN, a type of OD.
To understand the neural circuitry involved in ODs, the researchers used c-Fos, a marker of recent neural activity, and identified increased c-Fos expression in several brain regions, including the paraventricular nucleus of the thalamus (PVT), which was known to be involved in addiction and energy balance.
To further explore the role of the PVT, the researchers used chemogenetic and optogenetic techniques to manipulate PVT neurons. They found that activating or inhibiting PVT neurons influenced the preference for palatable foods and caloric intake in both healthy and OD mice, suggesting that the PVT was a key regulator of these behaviors.
To map the neural connections between the gut and the brain, the researchers used retrograde tracing techniques and found that the PVT was connected to the nucleus of the solitary tract (NTS), a key component of the gut-brain axis. They also observed increased neural activity in NTS neurons in OD mice, further supporting the link between the gut and the brain in ODs.
The researchers then focused on kynurenic acid (KYNA), a metabolite produced by the gut microbiota, and its potential role in ODs. They found that KYNA levels were significantly reduced in OD mice and that supplementing KYNA could restore normal eating behaviors. This suggested that KYNA played a critical role in regulating the gut-brain axis and preventing overeating.
Finally, the researchers examined the gut microbiota and KYNA levels in patients with BN and found similar changes to those observed in the mouse model, further supporting the findings from the animal studies.
In summary, this research provides compelling evidence that the gut microbiota plays a crucial role in the development of ODs by influencing the gut-brain axis. Specifically, the loss of beneficial bacteria and the fluctuation of KYNA levels contribute to the hyperactivation of PVT neurons and subsequent overeating behaviors.
The study identifies several potential therapeutic strategies for ODs:
Fecal Microbiota Transplantation (FMT): Transplanting beneficial bacteria from healthy donors could restore normal gut microbiota and alleviate OD symptoms.
Probiotic Supplementation: Increasing the abundance of beneficial bacteria through probiotics or prebiotics could also be an effective strategy.
KYNA Administration: Supplementing KYNA could restore normal gut-brain axis function and prevent overeating.
Targeting PVT Neurons: Manipulating PVT neurons through chemogenetic or optogenetic techniques could be another potential therapeutic approach.
While further research is needed to translate these findings into clinical applications, this study offers valuable insights into the complex interplay between the gut microbiota, the gut-brain axis, and ODs. It opens doors for novel treatments that target the underlying mechanisms of these disorders, potentially leading to better outcomes for patients with ODs.
Reference:
Fan S, Guo W, Xiao D, Guan M, Liao T, Peng S, Feng A, Wang Z, Yin H, Li M, Chen J, Xiong W. Microbiota-gut-brain axis drives overeating disorders. Cell Metab. 2023 Nov 7;35(11):2011-2027.e7.
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