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Brain-Gut Microbiota Interactions in Obesity

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Prebiotics and Probiotics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 88540

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Dr. Arpana Gupta

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Guest Editor

G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Interests: brain-gut microbiome axis; ingestive behaviors; metabolic syndrome; sex differences; obesity; food addiction; early life adversity; resilience; psycho-cultural environmental factors

Dr. Jonathan Jacobs

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Guest Editor

1. The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
2. Division of Gastroenterology, Hepatology and Parenteral Nutrition, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
Interests: intestinal microbiome; host-microbiome interactions; brain-gut-microbiome axis; intestinal inflammation; obesity; diet and microbiome
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Special Issue Information

Dear Colleagues,

Obesity rates have been steadily rising in the US, and with their complications have become one of the most prevalent and most expensive health problems. A growing body of evidence supports the concept of bidirectional signaling between the brain, the gut microbiome, and the immune system: Top-down signaling from the brain influences many gastrointestinal processes, or bottom-up signaling from the gut microbiota can alter neural signatures in the brain, induce systemic immune activation by interacting with gut-based immune cells, or get direct access to brain circuits by achieving sufficient systemic concentrations to reach nuclei within the hypothalamus, or cross the blood-brain barrier. Thus alterations within the brain-gut microbiome-immune axis may reveal novel therapeutic targets for the treatment of obesity. However, it is ultimately the complex balance between gut-derived satiety mechanisms, gut microbial metabolites, inflammatory mediators, and the motivational drive generated by the central reward system and prefrontal cortical inhibitory mechanisms that determines the dysregulated brain-gut microbiome interactions in obesity. It is also this imbalance within this brain-gut microbiome system that leads to increased alterations in maladaptive ingestive behaviors and an increased propensity towards or maintenance of obesity. Growing knowledge about this systems biological model of brain gut microbiome interactions provides novel treatment targets and approaches, either at the brain or gut level, for obesity.

The aim of this Special Issue is to bring together researchers, academics, clinicians, nutritionists, neuroscientists, microbiologists, and other health professionals, and experts in the fields of obesity and metabolism to increase our knowledge of the underlying physiology of obesity based on alterations in the brain-gut microbiome axis and to increase evidence for obesity-related treatments targeted at any level of the axis.

Dr. Arpana Gupta
Dr. Jonathan Jacobs
Guest Editors

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Keywords

brain-gut microbiome interactions
obesity
reward network
metabolites
brain or gut targeted treatments
altered ingestive behaviors

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Published Papers (9 papers)

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22 pages, 1795 KiB

Open AccessArticle

Understanding the Heterogeneity of Obesity and the Relationship to the Brain-Gut Axis

by Tony K. W. Hung, Tien S. Dong, Zixi Chen, David Elashoff, Janet S. Sinsheimer, Jonathan P. Jacobs, Venu Lagishetty, Priten Vora, Jean Stains, Emeran A. Mayer and Arpana Gupta

Nutrients 2020, 12(12), 3701; https://doi.org/10.3390/nu12123701 - 30 Nov 2020

Cited by 11 | Viewed by 3536

Abstract

Obesity is best understood as a multifactorial metabolic imbalances disorder. In a cross-sectional study, we aimed to explore sociodemographic and dietary determinants of obesity in relation to brain-gut homeostasis among overweight and obese individuals. Multivariate logistic regression models were used to examine obesity and its association with sociodemographic and dietary factors. Biological variables examined included the gut microbiome, fecal amino acid metabolites and brain structural volumes. Among 130 participants, there were higher odds of obesity if individuals were Hispanic (adjusted odds ratio (aOR) 1.56, p = 0.014). Compared to non-Hispanics, Hispanics differed in gut microbial composition (p = 0.046) with lower microbial species richness (Chao1) (p = 0.032) and evenness (Shannon) (p = 0.0029). Fourteen of the twenty fecal amino acids including branch-chain- and aromatic- amino acids were increased among Hispanics (q < 0.05). Brain structural volumes in reward regions were decreased in Hispanics (pallidum, q = 0.036; brainstem, q = 0.011). Correlation patterns suggest complex brain-gut interactions differ by Hispanic ethnicity. In conclusion, Hispanics expressed a unique brain-gut microbial signature, which was associated with obesity despite sociodemographic and dietary differences. Addressing ethnic disparities guided by biologic phenotypes may unlock novel understanding of obesity heterogeneity and treatment strategies. Full article

(This article belongs to the Special Issue Brain-Gut Microbiota Interactions in Obesity)

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17 pages, 4214 KiB

Open AccessArticle

Metabolic Responses to Butyrate Supplementation in LF- and HF-Fed Mice Are Cohort-Dependent and Associated with Changes in Composition and Function of the Gut Microbiota

by Sunhye Lee, Trina A. Knotts, Michael L. Goodson, Mariana Barboza, Elyse Wudeck, Grace England and Helen E. Raybould

Nutrients 2020, 12(11), 3524; https://doi.org/10.3390/nu12113524 - 16 Nov 2020

Cited by 11 | Viewed by 3502

Abstract

The gut microbiota and associated metabolites have emerged as potential modulators of pathophysiological changes in obesity and related metabolic disorders. Butyrate, a product of bacterial fermentation, has been shown to have beneficial effects in obesity and rodent models of diet-induced obesity. Here, we aimed to determine the beneficial effects of butyrate (as glycerol ester of butyrate monobutyrin, MB) supplementation on metabolic phenotype, intestinal permeability and inflammation, feeding behavior, and the gut microbiota in low-fat (LF)- and high-fat (HF)-fed mice. Two cohorts (separated by 2 weeks) of male C57BL/6J mice (n = 24 in each cohort, 6/group/cohort; 6 weeks old) were separated into four weight-matched groups and fed either a LF (10 % fat/kcal) or HF (45% fat/kcal) with or without supplementation of MB (LF/MB or HF/MB) at 0.25% (w/v) in drinking water for 6 weeks. Metabolic phenotypes (body weight and adiposity), intestinal inflammation, feeding behavior, and fecal microbiome and metabolites were measured. Despite identical genetic and experimental conditions, we found marked differences between cohorts in the response (body weight gain, adiposity, and intestinal permeability) to HF-diet and MB. Notably, the composition of the gut microbiota was significantly different between cohorts, characterized by lower species richness and differential abundance of a large number of taxa, including subtaxa from five phyla, including increased abundance of the genera Bacteroides, Proteobacteria, and Parasutterella in cohort 2 compared to cohort 1. These differences may have contributed to the differential response in intestinal permeability to the HF diet in cohort 2. MB supplementation had no significant effect on metabolic phenotype, but there was a trend to protect from HF-induced impairments in intestinal barrier function in cohort 1 and in sensitivity to cholecystokinin (CCK) in both cohorts. These data support the concept that microbiota composition may have a crucial effect on metabolic responses of a host to dietary interventions and highlight the importance of taking steps to ensure reproducibility in rodent studies. Full article

(This article belongs to the Special Issue Brain-Gut Microbiota Interactions in Obesity)

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15 pages, 1469 KiB

Open AccessArticle

A High Protein Calorie Restriction Diet Alters the Gut Microbiome in Obesity

by Tien S. Dong, Kayti Luu, Venu Lagishetty, Farzaneh Sedighian, Shih-Lung Woo, Benjamin W. Dreskin, William Katzka, Candace Chang, Yi Zhou, Nerea Arias-Jayo, Julianne Yang, Aaron Ahdoot, Zhaoping Li, Joseph R. Pisegna and Jonathan P. Jacobs

Nutrients 2020, 12(10), 3221; https://doi.org/10.3390/nu12103221 - 21 Oct 2020

Cited by 46 | Viewed by 15096

Abstract

Background: High protein calorie restriction diets have shown clinical efficacy for obesity, but the mechanisms are not fully known. The intestinal microbiome is a mediator of obesity and preclinical data support an effect of high protein diet (HPD) on the gut microbiome of obesity, but there are few studies in humans. Methods: To address this, we conducted a dietary intervention trial of 80 overweight and obese subjects who were randomized to a calorie-restricted high protein diet (HPD) (30% calorie intake) or calorie-restricted normal protein diet (NPD) (15%) for 8 weeks. Baseline dietary intake patterns were assessed by the Diet History Questionnaire III. Longitudinal fecal sampling was performed at baseline, week 1, week 2, week 4, week 6, and week 8, for a total of 365 samples. Intestinal microbiome composition was assessed by 16S rRNA gene sequencing. Results: At baseline, microbial composition was associated with fiber and protein intake. Subjects on the HPD showed a significant increase in microbial diversity as measured by the Shannon index compared to those on the NPD. The HPD was also associated with significant differences in microbial composition after treatment compared to the NPD. Both diets induced taxonomic shifts compared to baseline, including enrichment of Akkermansia spp. and Bifidobacterium spp. and depletion of Prevotella spp. Conclusion: These findings provide evidence that weight loss diets alter the gut microbiome in obesity and suggest differential effects of HPDs compared to NPDs which may influence the clinical response to HPD. Full article

(This article belongs to the Special Issue Brain-Gut Microbiota Interactions in Obesity)

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16 pages, 1694 KiB

Open AccessArticle

Improvement in Uncontrolled Eating Behavior after Laparoscopic Sleeve Gastrectomy Is Associated with Alterations in the Brain–Gut–Microbiome Axis in Obese Women

by Tien S. Dong, Arpana Gupta, Jonathan P. Jacobs, Venu Lagishetty, Elizabeth Gallagher, Ravi R. Bhatt, Priten Vora, Vadim Osadchiy, Jean Stains, Anna Balioukova, Yijun Chen, Erik Dutson, Emeran A. Mayer and Claudia Sanmiguel

Nutrients 2020, 12(10), 2924; https://doi.org/10.3390/nu12102924 - 24 Sep 2020

Cited by 22 | Viewed by 5147

Abstract

Background: Bariatric surgery is proven to change eating behavior and cause sustained weight loss, yet the exact mechanisms underlying these changes are not clearly understood. We explore this in a novel way by examining how bariatric surgery affects the brain–gut–microbiome (BGM) axis. Methods: Patient demographics, serum, stool, eating behavior questionnaires, and brain magnetic resonance imaging (MRI) were collected before and 6 months after laparoscopic sleeve gastrectomy (LSG). Differences in eating behavior and brain morphology and resting-state functional connectivity in core reward regions were correlated with serum metabolite and 16S microbiome data. Results: LSG resulted in significant weight loss and improvement in maladaptive eating behaviors as measured by the Yale Food Addiction Scale (YFAS). Brain imaging showed a significant increase in brain volume of the putamen (p.adj < 0.05) and amygdala (p.adj < 0.05) after surgery. Resting-state connectivity between the precuneus and the putamen was significantly reduced after LSG (p.adj = 0.046). This change was associated with YFAS symptom count. Bacteroides, Ruminococcus, and Holdemanella were associated with reduced connectivity between these areas. Metabolomic profiles showed a positive correlation between this brain connection and a phosphatidylcholine metabolite. Conclusion: Bariatric surgery modulates brain networks that affect eating behavior, potentially through effects on the gut microbiota and its metabolites. Full article

(This article belongs to the Special Issue Brain-Gut Microbiota Interactions in Obesity)

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27 pages, 9045 KiB

Open AccessArticle

Obesity Worsens Gulf War Illness Symptom Persistence Pathology by Linking Altered Gut Microbiome Species to Long-Term Gastrointestinal, Hepatic, and Neuronal Inflammation in a Mouse Model

by Dipro Bose, Punnag Saha, Ayan Mondal, Brian Fanelli, Ratanesh K. Seth, Patricia Janulewicz, Kimberly Sullivan, Stephen Lasley, Ronnie Horner, Rita R. Colwell, Ashok K Shetty, Nancy Klimas and Saurabh Chatterjee

Nutrients 2020, 12(9), 2764; https://doi.org/10.3390/nu12092764 - 10 Sep 2020

Cited by 25 | Viewed by 6607

Abstract

Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese phenotype of the deployed GW veterans. The host microbial profile in the Western diet-fed GWI mice showed a significant decrease in butyrogenic and immune health-restoring bacteria. The altered microbiome was associated with increased levels of IL6 in the serum, Claudin-2, IL6, and IL1β in the distal intestine with concurrent inflammatory lesions in the liver and hyperinsulinemia. Microbial dysbiosis was also associated with frontal cortex levels of increased IL6 and IL1β, activated microglia, decreased levels of brain derived neurotrophic factor (BDNF), and higher accumulation of phosphorylated Tau, an indicator of neuroinflammation-led increased risk of cognitive deficiencies. Mechanistically, serum from Western diet-fed mice with GWI significantly increased microglial activation in transformed microglial cells, increased tyrosyl radicals, and secreted IL6. Collectively, the results suggest that an existing obese phenotype in GWI worsens persistent gastrointestinal and neuronal inflammation, which may contribute to poor outcomes in restoring cognitive function and resolving fatigue, leading to the deterioration of quality of life. Full article

(This article belongs to the Special Issue Brain-Gut Microbiota Interactions in Obesity)

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17 pages, 2794 KiB

Open AccessArticle

Gut Microbiota Associations with Metabolic Health and Obesity Status in Older Adults

by Xiaozhong Zhong, Janas M. Harrington, Seán R. Millar, Ivan J. Perry, Paul W. O’Toole and Catherine M. Phillips

Nutrients 2020, 12(8), 2364; https://doi.org/10.3390/nu12082364 - 7 Aug 2020

Cited by 38 | Viewed by 6497

Abstract

Emerging evidence links the gut microbiota with several chronic diseases. However, the relationships between metabolic syndrome (MetS), obesity and the gut microbiome are inconsistent. This study aimed to investigate associations between gut microbiota composition and diversity and metabolic health status in older adults (n = 382; median age = 69.91 [± 5 years], male = 50.79%) with and without obesity. Gut microbiome composition was determined by sequencing 16S rRNA gene amplicons. Results showed that alpha diversity and richness, as indicated by the Chao1 index (p = 0.038), phylogenetic diversity (p = 0.003) and observed species (p = 0.038) were higher among the metabolically healthy non-obese (MHNO) individuals compared to their metabolically unhealthy non-obese (MUNO) counterparts. Beta diversity analysis revealed distinct differences between the MHNO and MUNO individuals on the phylogenetic distance scale (R² = 0.007, p = 0.004). The main genera contributing to the gut composition among the non-obese individuals were Prevotella, unclassified Lachnospiraceae, and unclassified Ruminococcaceae. Prevotella, Blautia, Bacteroides, and unclassified Ruminococcaceae mainly contributed to the variation among the obese individuals. Co-occurrence network analysis displayed different modules pattern among different metabolic groups and revealed groups of microbes significantly correlated with individual metabolic health markers. These findings confirm relationships between metabolic health status and gut microbiota composition particularly, among non-obese older adults. Full article

(This article belongs to the Special Issue Brain-Gut Microbiota Interactions in Obesity)

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Review

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14 pages, 1108 KiB

Open AccessReview

Brain–Gut–Microbiome Interactions and Intermittent Fasting in Obesity

by Juliette Frank, Arpana Gupta, Vadim Osadchiy and Emeran A. Mayer

Nutrients 2021, 13(2), 584; https://doi.org/10.3390/nu13020584 - 10 Feb 2021

Cited by 35 | Viewed by 21842

Abstract

The obesity epidemic and its metabolic consequences are a major public health problem both in the USA and globally. While the underlying causes are multifactorial, dysregulations within the brain–gut–microbiome (BGM) system play a central role. Normal eating behavior is coordinated by the tightly regulated balance between intestinal, extraintestinal and central homeostatic and hedonic mechanisms, resulting in stable body weight. The ubiquitous availability and marketing of inexpensive, highly palatable and calorie-dense food has played a crucial role in shifting this balance towards hedonic eating through both central (disruptions in dopaminergic signaling) and intestinal (vagal afferent function, metabolic toxemia, systemic immune activation, changes to gut microbiome and metabolome) mechanisms. The balance between homeostatic and hedonic eating behaviors is not only influenced by the amount and composition of the diet, but also by the timing and rhythmicity of food ingestion. Circadian rhythmicity affects both eating behavior and multiple gut functions, as well as the composition and interactions of the microbiome with the gut. Profound preclinical effects of intermittent fasting and time restricted eating on the gut microbiome and on host metabolism, mostly demonstrated in animal models and in a limited number of controlled human trials, have been reported. In this Review, we will discuss the effects of time-restricted eating on the BGM and review the promising effects of this eating pattern in obesity treatment. Full article

(This article belongs to the Special Issue Brain-Gut Microbiota Interactions in Obesity)

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22 pages, 2625 KiB

Open AccessReview

Gut Microbiota in Hypertension and Atherosclerosis: A Review

by Barbara J. H. Verhaar, Andrei Prodan, Max Nieuwdorp and Majon Muller

Nutrients 2020, 12(10), 2982; https://doi.org/10.3390/nu12102982 - 29 Sep 2020

Cited by 229 | Viewed by 20457

Abstract

Gut microbiota and its metabolites such as short chain fatty acids (SCFA), lipopolysaccharides (LPS), and trimethylamine-N-oxide (TMAO) impact cardiovascular health. In this review, we discuss how gut microbiota and gut metabolites can affect hypertension and atherosclerosis. Hypertensive patients were shown to have lower alpha diversity, lower abundance of SCFA-producing microbiota, and higher abundance of gram-negative bacteria, which are a source of LPS. Animal studies point towards a direct role for SCFAs in blood pressure regulation and show that LPS has pro-inflammatory effects. Translocation of LPS into the systemic circulation is a consequence of increased gut permeability. Atherosclerosis, a multifactorial disease, is influenced by the gut microbiota through multiple pathways. Many studies have focused on the pro-atherogenic role of TMAO, however, it is not clear if this is a causal factor. In addition, gut microbiota play a key role in bile acid metabolism and some interventions targeting bile acid receptors tend to decrease atherosclerosis. Concluding, gut microbiota affect hypertension and atherosclerosis through many pathways, providing a wide range of potential therapeutic targets. Challenges ahead include translation of findings and mechanisms to humans and development of therapeutic interventions that target cardiovascular risk by modulation of gut microbes and metabolites. Full article

(This article belongs to the Special Issue Brain-Gut Microbiota Interactions in Obesity)

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21 pages, 1341 KiB

Open AccessReview

Gut Microbiota, Probiotics and Psychological States and Behaviors after Bariatric Surgery—A Systematic Review of Their Interrelation

by Jessica Cook, Christine Lehne, Alisa Weiland, Rami Archid, Yvonne Ritze, Kerstin Bauer, Stephan Zipfel, John Penders, Paul Enck and Isabelle Mack

Nutrients 2020, 12(8), 2396; https://doi.org/10.3390/nu12082396 - 10 Aug 2020

Cited by 10 | Viewed by 4819

Abstract

The gastrointestinal (GI) microbiota plays an important role in health and disease, including brain function and behavior. Bariatric surgery (BS) has been reported to result in various changes in the GI microbiota, therefore demanding the investigation of the impact of GI microbiota on treatment success. The goal of this systematic review was to assess the effects of BS on the microbiota composition in humans and other vertebrates, whether probiotics influence postoperative health, and whether microbiota and psychological and behavioral factors interact. A search was conducted using PubMed and Web of Science to find relevant studies with respect to the GI microbiota and probiotics after BS, and later screened for psychological and behavioral parameters. Studies were classified into groups and subgroups to provide a clear overview of the outcomes. Microbiota changes were further assessed for whether they were specific to BS in humans through the comparison to sham operated controls in other vertebrate studies. Changes in alpha diversity appear not to be specific, whereas dissimilarity in overall microbial community structure, and increases in the abundance of the phylum Proteobacteria and Akkermansia spp. within the phylum Verrucomicrobia after surgery were observed in both human and other vertebrates studies and may be specific to BS in humans. Human probiotic studies differed regarding probiotic strains and dosages, however it appeared that probiotic interventions were not superior to a placebo for quality of life scores or weight loss after BS. The relationship between GI microbiota and psychological diseases in this context is unclear due to insufficient available data. Full article

(This article belongs to the Special Issue Brain-Gut Microbiota Interactions in Obesity)

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