The interaction between microbiome and host central nervous system: the gut-brain axis as a potential new therapeutic target in the treatment of obesity and cardiometabolic disease

Introduction: The role of the intestinal microbiota in host cardiometabolic health and disease has gained significant attention over recent decades. Previous studies have shown effects on metabolic health through gut microbiota modulation; this suggests diverse interaction pathways that constitute the communication between gut microbiota and host central nervous system, the so-called gut-brain axis. Areas covered: This article provides an overview of the various mechanisms that may mediate the gut-brain axis. It places an emphasis on cardiometabolic health, including effects of short-chain fatty acids (SCFA), alterations in neurotransmitters and gut peptides and microbial effects on chronic inflammation and immune function. Moreover, this paper sheds light on whether these mechanisms afford therapeutic targets to promote metabolic health. To this end, a PubMed search with the terms ‘gut microbiota,’ ‘obesity’ and ‘insulin sensitivity’ was performed. Expert opinion: Many properties of the human gut microbiome are associated with the central regulation of appetite and metabolic status. Some of these relationships are causal and there are positive effects from certain intervention methods. Microbial manipulation may offer a means to prevent or treat obesity and associated co-morbidities. However, to establish direct causal relations between altered gut microbiota and metabolic disease, clinical intervention studies are necessary

Combination therapy with exenatide decreases the dapagliflozin-induced changes in brain responses to anticipation and consumption of palatable food in patients with type 2 diabetes: A randomized controlled trial

Aims: Sodium-glucose cotransporter-2 inhibitors induce less weight loss than expected. This may be explained by sodium-glucose cotransporter-2 inhibitor-induced alterations in central reward- and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists reduce appetite and body weight because of direct and indirect effects on the brain. We investigated the separate and combined effects of dapagliflozin and exenatide on the brain in response to the anticipation and consumption of food in people with obesity and type 2 diabetes. Materials and Methods: As part of a larger study, this was a 16 week, double-blind, randomized, placebo-controlled trial. Subjects with obesity and type 2 diabetes were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice-daily 10 μg with dapagliflozin-matched placebo, dapagliflozin plus exenatide, or double placebo. Using functional magnetic resonance imaging, the effects of treatments on brain responses to the anticipation of food and food receipt were assessed after 10 days and 16 weeks. Results: After 10 days, dapagliflozin increased activation in right amygdala and right caudate nucleus in response to the anticipation of food, and tended to decrease activation in right amygdala in response to actual food receipt. After 16 weeks, no changes in brain activation were observed with dapagliflozin. Dapagliflozin plus exenatide reduced activation in right caudate nucleus and amygdala to the anticipation of food, and decreased activation in the right amygdala in response to food receipt after 16 weeks. Conclusions: The dapagliflozin-induced changes in brain activation may contribute to the discrepancy between observed and expected weight loss with dapagliflozin. Exenatide blunted the dapagliflozin-induced changes in brain activation, which may contribute to the additional weight loss with combined treatment

Personalized Dietary Advice to Increase Protein Intake in Older Adults Does Not Affect the Gut Microbiota, Appetite or Central Processing of Food Stimuli in Community-Dwelling Older Adults: A Six-Month Randomized Controlled Trial

Expert groups argue to raise the recommended daily allowance for protein in older adults from 0.8 to 1.2 g/kg/day to prevent undernutrition. However, protein is thought to increase satiety, possibly through effects on gut microbiota and central appetite regulation. If true, raising daily protein intake may work counterproductively. In a randomized controlled trial, we evaluated the effects of dietary advice aimed at increasing protein intake to 1.2 g/kg adjusted body weight/day (g/kg aBW/day) on appetite and gut microbiota in 90 community-dwelling older adults with habitual protein intake <1.0 g/kg aBW/day (Nintervention = 47, Ncontrol = 43). Food intake was determined by 24-h dietary recalls and gut microbiota by 16S rRNA sequencing. Functional magnetic resonance imaging (fMRI) scans were performed in a subgroup of 48 participants to evaluate central nervous system responses to food-related stimuli. Both groups had mean baseline protein intake of 0.8 ± 0.2 g/kg aBW/day. At 6 months’ follow-up this increased to 1.2 ± 0.2 g/kg aBW/day for the intervention group and 0.9 ± 0.2 g/kg aBW/day for the control group. Microbiota composition was not affected, nor were appetite or brain activity in response to food-related stimuli. Increasing protein intake in older adults to 1.2 g/kg aBW/day does not negatively impact the gut microbiota or suppress appetite

Gut microbial characteristics in poor appetite and undernutrition: a cohort of older adults and microbiota transfer in germ-free mice

Background: Older adults are particularly prone to the development of poor appetite and undernutrition. Possibly, this is partly due to the aged gut microbiota. We aimed to evaluate the gut microbiota in relation to both poor appetite and undernutrition in community-dwelling older adults. Furthermore, we studied the causal effects of the microbiota on body weight and body composition by transferring faecal microbiota from cohort participants into germ-free mice. Methods: First, we conducted a cross-sectional cohort study of 358 well-phenotyped Dutch community-dwelling older adults from the Longitudinal Aging Study Amsterdam. Data collection included body measurements, a faecal and blood sample, as well as extensive questionnaires on appetite, dietary intake, and nutritional status. Appetite was assessed by the Council of Nutrition Appetite Questionnaire (CNAQ) and undernutrition was defined by either a low body mass index (BMI) (BMI 5% body weight loss averaged over the last 2 years. Gut microbiota composition was determined with 16S rRNA sequencing. Next, we transferred faecal microbiota from 12 cohort participants with and without low BMI or recent weight loss into a total of 41 germ-free mice to study the potential causal effects of the gut microbiota on host BMI and body composition. Results: The mean age (range) of our cohort was 73 (65–93); 58.4% was male. Seventy-seven participants were undernourished and 21 participants had poor appetite (CNAQ < 28). A lower abundance of the genus Blautia was associated with undernutrition (log2 fold change = −0.57, Benjamini–Hochberg-adjusted P = 0.008), whereas higher abundances of taxa from Lachnospiraceae, Ruminococcaceae UCG-002, Parabacteroides merdae, and Dorea formicigenerans were associated with poor appetite. Furthermore, participants with poor appetite or undernutrition had reduced levels of faecal acetate (P = 0.006 and 0.026, respectively). Finally, there was a trend for the mice that received faecal microbiota from older adults with low BMI to weigh 1.26 g less after 3 weeks (P = 0.086) and have 6.13% more lean mass (in % body weight, P = 0.067) than the mice that received faecal microbiota from older adults without low BMI or recent weight loss. Conclusions: This study demonstrates several associations of the gut microbiota with both poor appetite and undernutrition in older adults. Moreover, it is the first to explore a causal relation between the aged gut microbiota and body weight and body composition in the host. Possibly, microbiota-manipulating strategies will benefit older adults prone to undernutrition

Identifying Gut Microbiota associated with Gastrointestinal Symptoms upon Roux-en-Y Gastric Bypass

Abstract: Purpose: Roux-en-Y gastric bypasses (RYGB) are frequently accompanied by long-term gastrointestinal (GI) symptoms. Direct mechanistic insight into the causation of these symptoms is lacking, but changes in the intestinal microbiome have been proposed to play a role. With this study, we aimed to investigate whether a microbial predisposition exists before RYGB which is associated with GI symptoms during follow-up and to evaluate which microbial groups are involved. Materials and Methods: In total, 67 RYGB patients were included. Shotgun metagenomic sequencing was performed on fecal samples obtained just before and 1 year after surgery. To assess GI symptoms, patients filled out Gastrointestinal Quality of Life Index (GIQLI) questionnaires and were divided into groups based on their total GIQLI score and change in score (postsurgery versus baseline). Extremely randomized tree predictor models were used to identify the most distinctive microbial species associated with postoperative GI symptoms. Results: Beta diversity differed significantly between baseline and 1-year post-surgery samples, with the post-surgery microbiome resembling a more dysbiotic profile. The most predictive species regarding total GIQLI (AUC 0.77) or delta GIQLI score (AUC 0.83) were identified. Many of these species are known butyrate producers or species known to support them and/or species with anti-inflammatory properties, including Coprococcus eutactus, Faecalibacterium prausnitzii, and Ruminococcus callidus. Conclusion: Beneficial commensal gut microbiota related to a high GI score were associated to adequate intestinal fermentative capacity, suggesting these species might have protective properties against postoperative GI malfunctioning. Graphical Abstract: [Figure not available: see fulltext.

Personalized Dietary Advice to Increase Protein Intake in Older Adults Does Not Affect the Gut Microbiota, Appetite or Central Processing of Food Stimuli in Community-Dwelling Older Adults: A Six-Month Randomized Controlled Trial

Expert groups argue to raise the recommended daily allowance for protein in older adults from 0.8 to 1.2 g/kg/day to prevent undernutrition. However, protein is thought to increase satiety, possibly through effects on gut microbiota and central appetite regulation. If true, raising daily protein intake may work counterproductively. In a randomized controlled trial, we evaluated the effects of dietary advice aimed at increasing protein intake to 1.2 g/kg adjusted body weight/day (g/kg aBW/day) on appetite and gut microbiota in 90 community-dwelling older adults with habitual protein intake intervention = 47, Ncontrol = 43). Food intake was determined by 24-h dietary recalls and gut microbiota by 16S rRNA sequencing. Functional magnetic resonance imaging (fMRI) scans were performed in a subgroup of 48 participants to evaluate central nervous system responses to food-related stimuli. Both groups had mean baseline protein intake of 0.8 ± 0.2 g/kg aBW/day. At 6 months’ follow-up this increased to 1.2 ± 0.2 g/kg aBW/day for the intervention group and 0.9 ± 0.2 g/kg aBW/day for the control group. Microbiota composition was not affected, nor were appetite or brain activity in response to food-related stimuli. Increasing protein intake in older adults to 1.2 g/kg aBW/day does not negatively impact the gut microbiota or suppress appetite

Personalized Dietary Advice to Increase Protein Intake in Older Adults Does Not Affect the Gut Microbiota, Appetite or Central Processing of Food Stimuli in Community-Dwelling Older Adults: A Six-Month Randomized Controlled Trial

Expert groups argue to raise the recommended daily allowance for protein in older adults from 0.8 to 1.2 g/kg/day to prevent undernutrition. However, protein is thought to increase satiety, possibly through effects on gut microbiota and central appetite regulation. If true, raising daily protein intake may work counterproductively. In a randomized controlled trial, we evaluated the effects of dietary advice aimed at increasing protein intake to 1.2 g/kg adjusted body weight/day (g/kg aBW/day) on appetite and gut microbiota in 90 community-dwelling older adults with habitual protein intake <1.0 g/kg aBW/day (N intervention = 47, N control = 43). Food intake was determined by 24-h dietary recalls and gut microbiota by 16S rRNA sequencing. Functional magnetic resonance imaging (fMRI) scans were performed in a subgroup of 48 participants to evaluate central nervous system responses to food-related stimuli. Both groups had mean baseline protein intake of 0.8 ± 0.2 g/kg aBW/day. At 6 months’ follow-up this increased to 1.2 ± 0.2 g/kg aBW/day for the intervention group and 0.9 ± 0.2 g/kg aBW/day for the control group. Microbiota composition was not affected, nor were appetite or brain activity in response to food-related stimuli. Increasing protein intake in older adults to 1.2 g/kg aBW/day does not negatively impact the gut microbiota or suppress appetite

Oxidative stress and brain morphology in individuals with depression, anxiety and healthy controls

Oxidative stress is a biological process, caused by an imbalance between reactive oxygen species (ROS) and antioxidants, in favour of the ROS. This imbalance leads to oxidative damage to lipids, proteins and DNA and ultimately cell death. Studies in rodents have shown that the brain, particularly the amygdala and hippocampus, is sensitive to oxidative stress, although studies on the association between oxidative stress and brain morphology in humans are lacking. Oxidative stress has also been associated with major depressive disorder (MDD) and may be related to volumetric abnormalities in the amygdala and hippocampus in MDD and anxiety disorders. In this study we aimed to examine the association between two robust measures of oxidative damage in plasma (8-OHdG and F2-isoprostanes) and volume of the hippocampus and amygdala in a large sample of individuals with and without MDD and/or anxiety (N = 297). In secondary analyses, we examine whether this association is similar in patients and controls. 8-OHdG and F2-isoprostanes plasma levels were determined using liquid chromatography tandem mass spectrometry and volume of the hippocampus and amygdala and hippocampal subfields was determined using Freesurfer. We found no association between plasma markers (or interaction with MDD and/or anxiety disorder diagnosis) and subcortical volume, suggesting that peripheral oxidative stress damage is not associated with subcortical brain volume. (C) 2017 Published by Elsevier In