| Obesity has a great impact on human health.Epidemiological studies showed that the incidence of obesity and overweight has increased by 13%.Obesity has become a global health problem.The latest data show that the obese population of China is more than 90 million,which is the country with the largest obese population in the world.It is worth noting that the prevalence of obesity and overweight in children and adolescents is more than 18%,which will further worsen the prevention and treatment of obesity.Bariatric surgery is currently the only treatment with long-term and significant weight-loss effect.It not only significantly reduces weight,but also improves metabolic syndrome including type II diabetes,hypertension,and greatly reduces the mortality of obese patients.Our group collaborating with Xijing Gastrointestinal Hospital affiliated with Air Force Military Medical University carried out the neural mechanism study of regulating weight by sleeve gastrectomy(LSG),showing significant weight loss and an average extra weight loss ratio of more than 70% one year post-surgery.Existing studies have shown that bariatric surgery significantly reduced craving for highcalorie food cues and amount of food intake in obese patients,and played an important role in postoperative weight loss.Appetite and eating behavior are regulated by two primary systems including the homeostasis system which mainly consists of the hypothalamic and hedonic system including reward and cognitive circuitries.A variety of peripheral hormones which are related to metabolism regulation and food intake modulate brain function and dietary behavior by interacting with the two systems.Recent studies have shown that microbiota and its metabolites can regulate brain function and eating behavior though the vagal and immune nervous system or by impacting hormone/intestinal peptide secretion.LSG changes the structure of the stomach,and regulates gut-brain axis interaction.Therefore,we hypothesized that LSG regulates the central nervous system(CNS)playing an important role in weight loss and improve eating behavior,probably by changing the microbiota-gutbrain axis interactions in obese patients.Considering the complexity of human brain cognition and the limitations of animal model research,it is a very ideal human model to understand the neural mechanisms of intestinal intervention and explore the interaction between the gut and brain,and it is also a good research model to understand the impact of brain on behaviors;thus,it is a hot topic in brain science.This study will provide a new theoretical basis for revealing the surgery-induced microbiota-gut-brain axis interactions,and provide improvement in corresponding treatment strategies.Weight loss is the inverse process of obesity.Studying obesity is helpful to understand the regulatory mechanism of bariatric surgery.The well-established experimental paradigms and analytical methods in obesity studies also shed light on the neural mechanisms of bariatric surgery.The current obesity study employed food cue reactivity to examine brain responses,and results showed that abnormal activation in the brain regions was associated with food reward processing in obese patients and their correlation with abnormal eating behavior.However,due to the differences in experimental design and analysis methods,there is great heterogeneity between different research results,which seriously limits the credibility of existing research conclusions.First of all,we used a meta-analysis based on activation likelihood estimation to test the spatial location of abnormal brain regions found in the 22 published papers with the food cue reactivity task.Meta-analysis showed abnormal brain responses to food cues in regions involving reward value prediction(ventral tegmental area,caudate nucleus),emotion and memory(hippocampus,amygdala,insula,anterior cingulate gyrus),appetite homeostasis regulation and inhibition control(inferior frontal gyrus,superior frontal gyrus,orbital frontal gyrus),and parietal lobe(anterior cuneiform,anterior central gyrus,posterior central gyrus and auxiliary motor area).Those abnormal brain activations were significantly correlated with food craving and body mass index(BMI).Based on the findings of imaging studies,scholars established the theoretical model of imbalance between reward/drive and inhibitory control,but lacked the investigation on longterm resting state brain activity.Abnormal resting state function reflects the impact of obesity on baseline brain functions,which is also of great significance to study,especially the relationship between resting state activity and abnormal brain activations under food stimulation;this is helpful to reveal and understand the neural mechanisms of food stimulation in obese patients.In addition,the existing studies mostly compared obese subjects with normal weight individuals,without including the overweight group which is in the midst of obesity development and could provide valuable pathological information.Therefore,in the current study,we employed functional magnetic resonance imaging(f MRI)with a food cue reactivity task and resting-state MRI(RS-f MRI)to assess brain abnormalities in 44 obese subjects,37 overweight subjects and 37 normal weight subjects.One-way ANOVA and post-hoc test showed abnormal brain activations in the hippocampus/amygdala,anterior cingulate cortex(ACC),right precentral gyrus(Pre Cen),right inferior frontal gyrus,supplementary motor area(SMA)and bilateral insulae during resting-state in obese patients.Hippocampus and amygdala showed abnormal activity and activation in both resting-state and when exposed to food stimuli that were correlated with BMI.The resting-state activity of the hippocampus/amygdala in overweight subjects was increased and showed a trend at the level of obese subjects,while the regional activation stimulated by food pictures was consistent with that of normal subjects,indicating that the resting state activity in the hippocampus/amygdala was more sensitive to weight gain.The relationship between BMI and hippocampus/amygdala activation to high-calorie food stimulation was fully mediated by the their resting-state activity in obese patients.The findings indicated that obese patients not only showed acute brain functional abnormality in response to food cues,but also showed long-term abnormal baseline activity.The abnormal baseline activity of the hippocampus/amygdala has a great impact on abnormal brain responses to food cue stimulation in obese patients.Based on the aforementioned findings of abnormal brain functions caused by obesity,the current study employed f MRI with food-cue reactivity and RS-f MRI to investigate LSGinduced changes in brain activations in obese patients.LSG-induced effective and long-term weight loss not only depended on the reduction in food intake,but also on the reduction in food craving and improvement in diet structure and eating behavior in obese patients postsurgery,suggesting that LSG improves brain function related to food intake control.Based on the test-retest experimental design,30 obese patients who received LSG surgery and 26 non-surgical obese control subjects were examined with the food cue reactivity task and RSf MRI scan pre-and one-month post-surgery,and eating behaviors and psychological state were also assessed.Repeated two-way ANOVA and post-hoc test showed that LSG not only significantly reduced BMI,food addiction and craving for high-calorie food,but also significantly reduced activation of the dorsolateral prefrontal cortex(DLPFC)in response to high-calorie food picture stimulation,which was significantly related to the reduction in food craving.LSG reduced the resting activity of the hippocampus and orbitofrontal gyrus,and increased the resting activity of the posterior cingulate gyrus(PCC)and DLPFC.Functional connection density mapping(FCDM)analysis showed that LSG significantly changed the FCD value in the ventromedial prefrontal cortex,PCC/precuneus,dorsal ACC/medial DLPFC,DLPFC and insula.Functional connectivity analysis showed improvement in the "top-down" regulatory circuit was not only in response to food picture stimuli,but also during the resting-state.After surgery,the functional connectivity between the orbitofrontal cortex(OFC)and the limbic system was decreased,and the functional connectivity between the hypothalamus and hippocampus was enhanced.At the same time,the improvement in resting brain activity was also shown in the middle line area involved with self-referential processing,enhancement of the interaction between the salience network and the defaultmode network,and enhanced connections between the insula and hippocampus involved with homeostasis regulation.Improvement in the OFC,hippocampus and DLPFC was significantly related to the reductions in food craving and BMI.These findings indicate that LSG enhances the functions of inhibitory-control,interoception,self-referential processing and homeostasis which are regions involved with food intake control,reversing brain dysfunction caused by obesity,and playing an important role in improving eating behavior and weight loss after surgery.LSG removes the fundus of the stomach,changes the structure of the gastrointestinal tract,and causes changes in peripheral hormones and microbiota.However,it lacks evidence on the interaction between gut and brain interactions.Therefore,we tested the samples of blood and feces pre-and one-month post-surgery in 16 obese patients.Results showed that LSG significantly reduced the levels of plasma insulin,leptin and ghrelin,and increased the diversity of the microbiota.The analysis of flora composition showed that LSG reduced the phylum and increased the relative abundance of Bacteroides.The results showed that the abundance of Bacteroides,Parabacilli and Acanthomycetes was increased,while that of Shigella,Clostridium and Weisseria was decreased.It was found that the reduced ghrelin levels were positively correlated with decreased DLPFC activation and resting-state hippocampal activity.At the same time,we also found that the changes in peripheral hormones and microbiota were significantly related to the changes in functional activities in the superior frontal gyrus,middle frontal gyrus,inferior frontal gyrus,orbital frontal gyrus,anterior cuneiform lobe,inferior parietal lobule and hippocampal gyrus.Previous studies have shown that the changes in central function are closely related to the improvement in eating behavior and weight loss.Thus,we speculated that the improvement in appetite and eating behavior depends on the changes in the gut-brain interaction induced by LSG.The findings of this study provide a theoretical basis for non-surgical intervention and improvement in clinical treatment strategies such as neural modulation and fecal microbiota transplantation. |
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