Effect of the Gut Microbiota on Obesity and Its Underlying Mechanisms: an Update

The field of the gut microbiota is still a relatively young science area, yet many studies have already highlighted the translational potential of microbiome research in the context of human health and disease. However, like in many new fields, discoveries are occurring at a fast pace and have provided new hope for the development of novel clinical applications in many different medical conditions, not in the least in metabolic disorders. This rapid progress has left the field vulnerable to premature claims, misconceptions and criticism, both from within and outside the sector. Tackling these issues requires a broad collaborative effort within the research field and is only possible by acknowledging the difficulties and challenges that are faced and that are currently hindering clinical implementation. These issues include: the primarily descriptive nature of evidence, methodological concerns, disagreements in analysis techniques, lack of causality, and a rather limited molecular-based understanding of underlying mechanisms. In this review, we discuss various studies and models that helped identifying the microbiota as an attractive tool or target for developing various translational applications. We also discuss some of the limitations and try to clarify some common misconceptions that are still prevalent in the field.

Download Full-text

Gut Microbiome and Metabolome Profiles Associated with High-Fat Diet in Mice

Metabolites ◽

10.3390/metabo11080482 ◽

2021 ◽

Vol 11 (8) ◽

pp. 482

Author(s):

Jae-Kwon Jo ◽

Seung-Ho Seo ◽

Seong-Eun Park ◽

Hyun-Woo Kim ◽

Eun-Ju Kim ◽

...

Keyword(s):

Gut Microbiota ◽

Relative Abundance ◽

High Fat Diet ◽

Amplicon Sequencing ◽

Gas Chromatography Mass Spectrometry ◽

Control Group ◽

Rrna Gene ◽

High Fat ◽

Underlying Mechanisms ◽

Insight Into

Obesity can be caused by microbes producing metabolites; it is thus important to determine the correlation between gut microbes and metabolites. This study aimed to identify gut microbiota-metabolomic signatures that change with a high-fat diet and understand the underlying mechanisms. To investigate the profiles of the gut microbiota and metabolites that changed after a 60% fat diet for 8 weeks, 16S rRNA gene amplicon sequencing and gas chromatography-mass spectrometry (GC-MS)-based metabolomic analyses were performed. Mice belonging to the HFD group showed a significant decrease in the relative abundance of Bacteroidetes but an increase in the relative abundance of Firmicutes compared to the control group. The relative abundance of Firmicutes, such as Lactococcus, Blautia, Lachnoclostridium, Oscillibacter, Ruminiclostridium, Harryflintia, Lactobacillus, Oscillospira, and Erysipelatoclostridium, was significantly higher in the HFD group than in the control group. The increased relative abundance of Firmicutes in the HFD group was positively correlated with fecal ribose, hypoxanthine, fructose, glycolic acid, ornithine, serum inositol, tyrosine, and glycine. Metabolic pathways affected by a high fat diet on serum were involved in aminoacyl-tRNA biosynthesis, glycine, serine and threonine metabolism, cysteine and methionine metabolism, glyoxylate and dicarboxylate metabolism, and phenylalanine, tyrosine, and trypto-phan biosynthesis. This study provides insight into the dysbiosis of gut microbiota and metabolites altered by HFD and may help to understand the mechanisms underlying obesity mediated by gut microbiota.

Download Full-text

Lactobacillus casei LC89 exert antidiabetic effects through regulating hepatic glucagon response and gut microbiota in type 2 diabetic mice

Food & Function ◽

10.1039/d1fo00882j ◽

2021 ◽

Author(s):

Yongli Zhang ◽

Tao Wu ◽

Wen Li ◽

Yunjiao Zhao ◽

Hairong Long ◽

...

Keyword(s):

Gut Microbiota ◽

Molecular Mechanism ◽

Lactobacillus Casei ◽

Diabetic Mice ◽

Antihyperglycemic Activity ◽

Underlying Mechanisms ◽

Type 2 Diabetic ◽

Antidiabetic Effects

Previous study suggests Lactobacillus casei exhibit antihyperglycemic activity, however, the molecular mechanism has rarely been elucidated. Here, the anti-diabetic effects and underlying mechanisms of Lactobacillus casei LC89 were investigated in...

Download Full-text

The Relationship between Frequently Used Glucose-Lowering Agents and Gut Microbiota in Type 2 Diabetes Mellitus

Journal of Diabetes Research ◽

10.1155/2018/1890978 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

You Lv ◽

Xue Zhao ◽

Weiying Guo ◽

Ying Gao ◽

Shuo Yang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gut Microbiota ◽

Metabolic Diseases ◽

Short Chain Fatty Acids ◽

Current Evidence ◽

Diabetic Patients ◽

Glucose Lowering ◽

Patients With Diabetes ◽

Gastrointestinal Side Effects ◽

Underlying Mechanisms

Metabolic diseases, especially diabetes mellitus, have become global health issues. The etiology of diabetes mellitus can be attributed to genetic and/or environmental factors. Current evidence suggests the association of gut microbiota with metabolic diseases. However, the effects of glucose-lowering agents on gut microbiota are poorly understood. Several studies revealed that these agents affect the composition and diversity of gut microbiota and consequently improve glucose metabolism and energy balance. Possible underlying mechanisms include affecting gene expression, lowering levels of inflammatory cytokines, and regulating the production of short-chain fatty acids. In addition, gut microbiota may alleviate adverse effects caused by glucose-lowering agents, and this can be especially beneficial in diabetic patients who experience severe gastrointestinal side effects and have to discontinue these agents. In conclusion, gut microbiota may provide a novel viewpoint for the treatment of patients with diabetes mellitus.

Download Full-text

Effects of gut microbiota on leptin expression and body weight are lessened by high-fat diet in mice

British Journal Of Nutrition ◽

10.1017/s0007114520001117 ◽

2020 ◽

Vol 124 (4) ◽

pp. 396-406 ◽

Cited By ~ 1

Author(s):

Hongyang Yao ◽

Chaonan Fan ◽

Xiuqin Fan ◽

Yuanyuan Lu ◽

Yuanyuan Wang ◽

...

Keyword(s):

Body Weight ◽

Gut Microbiota ◽

High Fat Diet ◽

Body Weight Gain ◽

High Fat ◽

Hepatic Expression ◽

Reduced Body ◽

Expression Of Genes ◽

Underlying Mechanisms ◽

Leptin Expression

AbstractAberration in leptin expression is one of the most frequent features in the onset and progression of obesity, but the underlying mechanisms are still unclear and need to be clarified. This study investigated the effects of the absence of gut microbiota on body weight and the expression and promoter methylation of the leptin. Male C57 BL/6 J germ-free (GF) and conventional (CV) mice (aged 4–5 weeks) were fed either a normal-fat diet (NFD) or a high-fat diet (HFD) for 16 weeks. Six to eight mice from each group, at 15 weeks, were administered exogenous leptin for 7 d. Leptin expression and body weight gain in GF mice were increased by NFD with more CpG sites hypermethylated at the leptin promoter, whereas there was no change with HFD, compared with CV mice. Adipose or hepatic expression of genes associated with fat synthesis (Acc1, Fas and Srebp-1c), hydrolysis and oxidation (Atgl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was lower, and hypothalamus expression of Pomc and Socs3 was higher in GF mice than levels in CV mice, particularly with NFD feeding. Exogenous leptin reduced body weight in both types of mice, with a greater effect on CV mice with NFD. Adipose Lep-R expression was up-regulated, and hepatic Fas and hypothalamic Socs3 were down-regulated in both types of mice. Expression of fat hydrolysis and oxidative genes (Atgl, Hsl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was up-regulated in CV mice. Therefore, the effects of gut microbiota on the leptin expression and body weight were affected by dietary fat intake.

Download Full-text

A Novel Combination of Fruits and Vegetables Prevents Diet-Induced Hepatic Steatosis and Metabolic Dysfunction in Mice

Journal of Nutrition ◽

10.1093/jn/nxaa259 ◽

2020 ◽

Vol 150 (11) ◽

pp. 2950-2960

Author(s):

Weimin Guo ◽

Dayong Wu ◽

Maria C Dao ◽

Lijun Li ◽

Erin D Lewis ◽

...

Keyword(s):

Adipose Tissue ◽

Weight Gain ◽

Gut Microbiota ◽

Hepatic Steatosis ◽

Fruits And Vegetables ◽

Causal Relation ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Freeze Dried ◽

Underlying Mechanisms

ABSTRACT Background Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption correlates with reduced risk of hepatic steatosis, yet evidence for causality and the underlying mechanisms is lacking. Objectives We aimed to determine the causal relation between F&V consumption and improved metabolic disorders in mice fed high-fat (HF) (Experiment-1) or normal-fat (Experiment-2) diets and its underlying mechanisms. Methods Six-week-old male C57BL/6J mice were randomly grouped and fed diets supplemented at 0%–15% (wt:wt) with a freeze-dried powder composed of 24 commonly consumed F&V (human equivalent of 0–9 servings/d) for 20 wk. In Experiment-1, mice were fed an HF (45% kcal fat) diet with 0% (HF0), 5%, 10%, or 15% (HF15) F&V or a matched low-fat control diet (10% kcal fat). In Experiment-2, mice were fed an AIN-93 diet (basal) (B, 16% kcal fat) with 0% (B0), 5%, 10%, or 15% (B15) F&V supplementation. Body weight and composition, food intake, hepatic steatosis, inflammation, ceramide levels, sphingomyelinase activity, and gut microbiota were assessed. Results In Experiment-1, mice fed the HF15 diet had lower weight gain (17.9%), hepatic steatosis (48.4%), adipose tissue inflammation, blood (24.6%) and liver (33.9%) ceramide concentrations, and sphingomyelinase activity (38.8%) than HF0 mice (P < 0.05 for all). In Experiment-2, mice fed the B15 diet had no significant changes in weight gain but showed less hepatic steatosis (28.5%), blood and adipose tissue inflammation, and lower blood (30.0%) ceramide concentrations than B0 mice (P < 0.05 for all). These F&V effects were associated with favorable microbiota changes. Conclusions These findings represent the first evidence for a causal role of high F&V intake in mitigating hepatic steatosis in mice. These beneficial effects may be mediated through changes in ceramide and/or gut microbiota, and suggest that higher than currently recommended servings of F&V may be needed to achieve maximum health benefits.

Download Full-text

Icariin enhances intestinal barrier function by inhibiting NF-κB signaling pathways and modulating gut microbiota in a piglet model

RSC Advances ◽

10.1039/c9ra07176h ◽

2019 ◽

Vol 9 (65) ◽

pp. 37947-37956

Author(s):

Wen Xiong ◽

Haoyue Ma ◽

Zhu Zhang ◽

Meilan Jin ◽

Jian Wang ◽

...

Keyword(s):

Gut Microbiota ◽

Signaling Pathways ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Underlying Mechanisms

This study investigated the effects of icariin on intestinal barrier function and its underlying mechanisms.

Download Full-text

SAT-657 The Gut Microbiome Regulates Host Glucose Homeostasis via Peripheral Serotonin

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.775 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Damien Keating

Keyword(s):

Gut Microbiota ◽

Glucose Homeostasis ◽

Gut Microbiome ◽

Microbiota Composition ◽

Serotonin Synthesis ◽

Pharmacological Inhibition ◽

Genetic Deletion ◽

Underlying Mechanisms ◽

Induced Changes ◽

Host Metabolism

Abstract The gut microbiome is an established regulator of aspects of host metabolism, such as glucose handling. Despite the known impacts of the gut microbiota on host glucose homeostasis, the underlying mechanisms are unknown. The gut microbiome is also a potent mediator of gut-derived serotonin synthesis, and this peripheral source of serotonin is itself a regulator of glucose homeostasis. Here, we determined whether the gut microbiome influences glucose homeostasis through effects on gut-derived serotonin. Using both pharmacological inhibition and genetic deletion of gut-derived serotonin synthesis, we find [1] that the improvements in host glucose handling caused by antibiotic-induced changes in microbiota composition are dependent on the synthesis of peripheral serotonin. [1] The gut microbiome regulates host glucose homeostasis via peripheral serotonin. Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):19802-19804. Martin AM, Yabut JM, Choo JM, Page AJ, Sun EW, Jessup CF, Wesselingh SL, Khan WI, Rogers GB, Steinberg GR, Keating DJ.

Download Full-text

MECHANISMS IN ENDOCRINOLOGY: Gut microbiota in patients with type 2 diabetes mellitus

Acta Endocrinologica ◽

10.1530/eje-14-0874 ◽

2015 ◽

Vol 172 (4) ◽

pp. R167-R177 ◽

Cited By ~ 77

Author(s):

Kristine H Allin ◽

Trine Nielsen ◽

Oluf Pedersen

Keyword(s):

Type 2 Diabetes ◽

Gut Microbiota ◽

Metabolic Diseases ◽

Short Chain Fatty Acids ◽

Intestinal Content ◽

Low Grade ◽

Bacterial Fermentation ◽

Underlying Mechanisms

Perturbations of the composition and function of the gut microbiota have been associated with metabolic disorders including obesity, insulin resistance and type 2 diabetes. Studies on mice have demonstrated several underlying mechanisms including host signalling through bacterial lipopolysaccharides derived from the outer membranes of Gram-negative bacteria, bacterial fermentation of dietary fibres to short-chain fatty acids and bacterial modulation of bile acids. On top of this, an increased permeability of the intestinal epithelium may lead to increased absorption of macromolecules from the intestinal content resulting in systemic immune responses, low-grade inflammation and altered signalling pathways influencing lipid and glucose metabolism. While mechanistic studies on mice collectively support a causal role of the gut microbiota in metabolic diseases, the majority of studies in humans are correlative of nature and thus hinder causal inferences. Importantly, several factors known to influence the risk of type 2 diabetes, e.g. diet and age, have also been linked to alterations in the gut microbiota complicating the interpretation of correlative studies. However, based upon the available evidence, it is hypothesised that the gut microbiota may mediate or modulate the influence of lifestyle factors triggering development of type 2 diabetes. Thus, the aim of this review is to critically discuss the potential role of the gut microbiota in the pathophysiology and pathogenesis of type 2 diabetes.

Download Full-text

Neuroprotective Effects ofClostridium butyricumagainst Vascular Dementia in Mice via Metabolic Butyrate

BioMed Research International ◽

10.1155/2015/412946 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 51

Author(s):

Jiaming Liu ◽

Jing Sun ◽

Fangyan Wang ◽

Xichong Yu ◽

Zongxin Ling ◽

...

Keyword(s):

Gut Microbiota ◽

Vascular Dementia ◽

Morphological Examination ◽

Neuroprotective Effects ◽

Akt Phosphorylation ◽

Underlying Mechanisms ◽

Related Proteins ◽

Common Carotid Arteries ◽

Hematoxylin Eosin

Probiotics actively participate in neuropsychiatric disorders. However, the role of gut microbiota in brain disorders and vascular dementia (VaD) remains unclear. We used a mouse model of VaD induced by a permanent right unilateral common carotid arteries occlusion (rUCCAO) to investigate the neuroprotective effects and possible underlying mechanisms ofClostridium butyricum. Following rUCCAO,C. butyricumwas intragastrically administered for 6 successive weeks. Cognitive function was estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The BDNF-PI3K/Akt pathway-related proteins were assessed by western blot and immunohistochemistry. The diversity of gut microbiota and the levels of butyrate in the feces and the brains were determined. The results showed thatC. butyricumsignificantly attenuated the cognitive dysfunction and histopathological changes in VaD mice.C. butyricumnot only increased the levels of BDNF and Bcl-2 and decreased level of Bax but also induced Akt phosphorylation (p-Akt) and ultimately reduced neuronal apoptosis. Moreover,C. butyricumcould regulate the gut microbiota and restore the butyrate content in the feces and the brains. These results suggest thatC. butyricummight be effective in the treatment of VaD by regulating the gut-brain axis and that it can be considered a new therapeutic strategy against VaD.

Download Full-text