The interaction between the gut microbiota and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut-brain axis. The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites, which activates the vagus nerve and modulates the immune and neuroendocrine systems. Conversely, alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota, creating a dynamic network of microbial-host interactions. This reciprocal regulation affects neurodevelopment, neurotransmitter control, and behavioral traits, thus playing a role in the modulation of neurological diseases. The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation, mitochondrial dysfunction, abnormal energy metabolism, microglial activation, oxidative stress, and neurotransmitter release, which collectively influence the onset and progression of neurological diseases. This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway, along with its implications for potential therapeutic interventions in neurological diseases. Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders. This can be achieved through various methods such as dietary modifications, probiotic supplements, Chinese herbal extracts, combinations of Chinese herbs, and innovative dosage forms. These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.

Objective: Available data comparing the efficacy of liraglutide and semaglutide in managing weight loss is limited. The objective of this study was to compare efficacy of both drugs on weight loss. Methods: A retrospective observational cohort study conducted at our quaternary care hospital from June 2018 to July 2022. The study included adults who received either liraglutide or semaglutide during the study period. The primary outcome was weight loss, while secondary outcomes included effects on HbA1c levels and lipid profile. Results: A total of 366 patients were analyzed (122 on liraglutide, 244 on semaglutide). The groups were comparable in mean age (51.00 ± 11.55 vs 51.16 ± 12.35 years, P = 0.521) and baseline mean weight (94.7 ± 19.5 vs 94.6 ± 19.9 kg, P = 0.989). After a median follow-up of 10 (6-17) months for the liraglutide group and 7.5 (6-11) months for the semaglutide group (P < 0.001), the resultant weights were 90.8 ± 19.6 kg for the liraglutide group and 91.1 ± 19.8 kg for the semaglutide group (P < 0.001) when comparing each group to its baseline separately. When comparing the weight loss achieved in each group, liraglutide achieved a median weight loss of -4 (-7 to 0) kg versus -3 (-6 to 0) kg for semaglutide (P = 0.867). The reduction in HbA1c levels with liraglutide was significantly less than with semaglutide: -0.2 (-0.5 to 0.3) versus -0.5 (-1.1 to 0.1), respectively, (P = 0.003). Both drugs significantly lowered LDL and triglycerides. Multivariable linear regression analysis confirmed no significant difference between the drugs [B -0.577, 95% CI -1.87 to 0.7; P = 0.38], while baseline weight, diabetes, and SGLT2 inhibitors were significant factors affecting weight. Conclusion: Both liraglutide and semaglutide were effective in reducing weight, with no significant difference between the two drugs. However, semaglutide was more effective in reducing HbA1c levels.

Metabolic abnormalities and gut microbiota imbalance are intricately linked to the onset and progression of Alzheimer's disease (AD). Kai-Xin-San (KXS) is a traditional herbal formula known for its therapeutic effects on AD. Our previous research indicated that Kai-Xin-San polysaccharide (KXS-P) exhibits a significant therapeutic impact on AD, but the precise mechanisms remain incompletely understood. In this study, untargeted fecal metabolomics and 16S rRNA gene sequencing were used to investigate the potential mechanisms by which KXS-P acts against AD. Key metabolites and gut microbial species were identified using multivariate analysis and a comprehensive examination of intestinal microecology. Our findings revealed that KXS-P improves lipid metabolism in AD rats by modulating a series of lipid molecules and bile acid levels. Additionally, KXS-P regulated gut microbiota composition and restored the symbiotic relationships within the gut microbiome. Notably, the anti-inflammatory effect of KXS-P may be related to its regulation of specific lipotypes levels and the abundance of Romboutsia, Bifidobacterium and Alloprevotella. KXS-P demonstrates the ability to alleviate symptoms of AD rats through multiple mechanisms: ① Improving lipid metabolism and maintaining lipid homeostasis; ② Reducing neuronal and inflammatory damage; ③ Regulating the composition and symbiotic relationships of gut microbiota to preserve intestinal microecological balance.

GLP-1 analogues are a relatively new class of medications that form the cornerstone of diabetes treatment. They possess invaluable glucose-lowering properties without hypoglycemic effects as well as strong cardioprotective effects. The gut microbiome has become the focus of numerous studies, demonstrating its influence not only on the gut but also on the overall well-being of the entire body. However, the effects of GLP-1 analogs on gut microbiota remain uncertain.

Our systematic review (based on PRISMA guidelines) aimed to gather knowledge on the effects of GLP-1 analogue medications on the composition, richness, and abundance of gut microbiota in both animal and human models.

Thirty-eight studies were included in this systematic review. GLP-1 analogues have demonstrated a notable impact on the composition, richness, and diversity of gut microbiota. We can conclude, following the obtained research results of our study, that liraglutide promotes the growth of beneficial genera relevant for beneficial metabolic functions. Exenatide and exendin-4 administration showed various effects on the microbiome composition in animal and human studies. In animal models, it increased genera associated with improved metabolism; however, in human models, genera linked to better metabolic functions and escalated inflammation increased. Following dulaglutide administration, increases in Bacteroides, Akkermansia, and Ruminococcus, genera connected to an improved metabolic model, were significant. Finally, varied results were obtained after semaglutide treatment, in which A. muciniphila, known for its positive metabolic functions, increased; however, microbial diversity decreased. Semaglutide treatment provided various results indicating many confounding factors in semaglutide's impact on the gut microbiota. Results varied due to dissimilarities in the studied populations and the duration of the studies. Further research is essential to confirm these findings and to better recognize their implications for the clinical outcomes of patients.

Glucagon-like peptide 1 receptor agonists (GLP-1 RA) have transformed obesity management, but their safety and efficacy in patients with inflammatory bowel disease (IBD) warrants further evaluation.

This retrospective cohort study included adults with obesity and a diagnosis of IBD who were treated with GLP-1 RA within a large healthcare network. Primary outcomes were ≥ 5% total weight loss (TWL) at 12-months post initiation, and IBD flares, comparing 12-months pre- and post-GLP-1 RA initiation. Secondary outcomes included ≥ 10% TWL, adverse events (AE), and discontinuation of GLP-1 RA. Secondary analysis assessed anti-TNF exposure and primary outcomes. Statistical analysis used paired t-test for continuous outcomes, and McNemar's χ2 test for dichotomous outcomes. Logistic regression was performed for multivariable analysis of the primary efficacy outcome.

Of 272 patients included, 175 completed at least 12 months of GLP-1 RA. Among these individuals, 61% achieved ≥ 5% TWL and 42% achieved ≥ 10% TWL. AEs occurred in 40%, and were primarily gastrointestinal (93%). GLP-1 RA were stopped in 24% of patients (48% for AE/tolerability and 18% for access/cost issues). There was no difference in the proportion of patients with IBD flares within 12 months pre vs. post GLP-1 RA (17% vs. 13%, P = 0.40). Anti-TNF exposure did not affect the likelihood of achieving ≥ 5% TWL in comparison with other IBD therapies (66% vs. 58%, P = 0.33).

This study supports the safety, tolerability, and effectiveness of GLP-1 RA for treatment of obesity in patients with IBD.

Obesity is a chronic and complex disease associated with increased morbidity, mortality, and financial burden. It is expected that by 2030 one of two people in the United States will have obesity. The backbone for obesity management continues to be lifestyle interventions, consisting of calorie deficit diets and increased physical activity levels, however, these interventions are often insufficient to achieve sufficient and maintained weight loss. As a result, multiple patients require additional interventions such as antiobesity medications or bariatric interventions in order to achieve clinically significant weight loss and improvement or resolution of obesity-associated comorbidities. Despite the recent advances in the field of obesity pharmacotherapy that have resulted in never-before-seen weight loss outcomes, comorbidity improvement, and even reduction in cardiovascular mortality, there is still a significant interindividual variability in terms of response to antiobesity medications, with a subset of patients not achieving a clinically significant weight loss. Currently, the trial-and-error paradigm for the selection of antiobesity medications results in increased costs and risks for developing side effects, while also reduces engagement in weight management programs for patients with obesity. The implementation of a precision medicine framework to the selection of antiobesity medications might help reduce heterogeneity and optimize weight loss outcomes by identifying unique subsets of patients, or phenotypes, that have a better response to a specific intervention. The detailed study of energy balance regulation holds promise, as actionable behavioral and physiologic traits could help guide antiobesity medication selection based on previous mechanistic studies. Moreover, the rapid advances in genotyping, multi-omics, and big data analysis might hold the key to discover additional signatures or phenotypes that might respond better to a certain intervention and might permit the widespread adoption of a precision medicine approach for obesity management.

Myotonic Dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the 3' untranslated region of the DMPK gene. This expansion leads to the production of toxic RNA transcripts, which accumulate in the nucleus and interfere with normal RNA processing. DM1 affects a broad range of tissues and systems such as the skeletal muscle, the central nervous system, cardiac, visual, reproductive, and gastrointestinal (GI) system. GI dysfunction is a significant but poorly understood aspect of DM1. Particularly, it is unknown if there are alterations in the intestinal microbiome in DM1. Here, we used a transgenic humanized mouse model (DMSXL) to explore how the gut microbiome may be linked to GI issues in DM1. For this purpose, 68 stool samples from Homozygous, Heterozygous, and Wild-Type (WT) mice were collected. These samples were sequenced by MiSeq and analyzed with DADA2 to generate taxonomic profiles. Our analysis indicated that the overexpression of CTG repeats significantly influences the bacterial structure of the gut microbiome in Homozygous mice samples, especially in terms of the relative abundance of the Patescibacteria and Defferibacterota Phyla. These results provide valuable information about the gut microbiota structure thus improving the understanding of the role of these changes in the pathogenicity as well as GI problems of DM1 patients.

Our study focused on a mouse model of obesity induced by a high-fat diet (HFD). We administered Semaglutide intraperitoneally (Ozempic ®-0.05 mg/Kg-translational dose) every seven days for six weeks. HFD-fed mice had higher blood glucose, lipid profile, and insulin resistance. Moreover, mice fed HFD showed high gut levels of TLR4, NF-kB, TNF-α, IL-1β, and nitrotyrosine and low levels of occludin, indicating intestinal inflammation and permeability, culminating in higher serum levels of IL-1β and LPS. Treatment with semaglutide counteracted the dyslipidemia and insulin resistance, reducing gut and serum inflammatory markers. Structural changes in gut microbiome were determined by 16S rRNA sequencing. Semaglutide reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes. Meanwhile, semaglutide dramatically changed the overall composition and promoted the growth of acetate-producing bacteria (Bacteroides acidifaciens and Blautia coccoides), increasing hypothalamic acetate levels. Semaglutide intervention increased the number of hypothalamic GLP-1R+ neurons that mediate endogenous action on feeding and energy. In addition, semaglutide treatment reversed the hypothalamic neuroinflammation HDF-induced decreasing TLR4/MyD88/NF-κB signaling and JNK and AMPK levels, improving the hypothalamic insulin resistance. Also, semaglutide modulated the intestinal microbiota, promoting the growth of acetate-producing bacteria, inducing high levels of hypothalamic acetate, and increasing GPR43+ /POMC+ neurons. In the ARC, acetate activated the GPR43 and its downstream PI3K-Akt pathway, which activates POMC neurons by repressing the FoxO-1. Thus, among the multifactorial effectors of hypothalamic energy homeostasis, possibly higher levels of acetate derived from the intestinal microbiota contribute to reducing food intake.

As an incretin hormone, Glucagon-like peptide-1 (GLP-1) has obvious effects on blood glucose regulation and weight loss. GLP-1 receptor (GLP-1R) agonists are synthetic products that have similar effects to GLP-1 but are less prone to degradation, and they are widely used in the treatment of type 2 diabetes and obesity. In recent years, different beneficial effects of GLP-1R agonists were discovered, such as reducing ischemia-reperfusion injury, improving the function of various organs, alleviating substance use disorder, affecting tumorigenesis, regulating bone metabolism, changing gut microbiota composition, and prolonging graft survival. Therefore, GLP-1R agonists have great potential for clinical application in various diseases. Here, we briefly summarized the beneficial effects of GLP-1R agonists other than the anti-diabetic and anti-obesity effects.

The gut-liver axis plays a crucial role in the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Key metabolites, including lipopolysaccharides, short-chain fatty acids (SCFAs), bile acids, and beneficial gut bacteria such as Bifidobacterium and Lactobacillus, are pivotal in this process. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show promise in managing MASLD by promoting weight loss, enhancing insulin secretion, and improving liver health. They restore gut-liver axis functionality, and their effects are amplified through dietary modifications and gut microbiome-targeted therapies. Emerging research highlights the interplay between GLP-1 RAs and gut microbiota, indicating that the gut microbiome significantly influences therapeutic outcomes. Metabolites produced by gut bacteria, can stimulate glucagon-like peptide-1 (GLP-1) secretion, further improving metabolic health. Integrating dietary interventions with GLP-1 RA treatment may enhance liver health by modulating the gut microbiota-SCFAs-GLP-1 pathway. Future research is needed to understand personalized effects, with prebiotics and probiotics offering treatment avenues for MASLD.

Liver regeneration (LR) is a unique biological process with the ability to restore up to 70% of the organ. This allows for the preservation of liver resections for various liver tumors and for living donor liver transplantation (LDLT). However, in some cases, LR is insufficient and interventions that can improve LR are urgently needed. Gut microbiota (GM) is one of the factors influencing LR, as the liver and intestine are intimately connected through the gut-liver axis. Thus, healthy GM facilitates normal LR, whereas dysbiosis leads to impaired LR due to imbalance of bile acids, inflammatory cytokines, microbial metabolites, signaling pathways, etc. Therefore, GM can be considered as a new possible therapeutic target to improve LR. In this review, we critically observe the current knowledge about the influence of gut microbiota (GM) on liver regeneration (LR) and the possibility to improve this process, which may reduce complication and mortality rates after liver surgery. Although much research has been done on this topic, more clinical trials and systemic reviews are urgently needed to move this type of intervention from the experimental phase to the clinical field.

Type 2 diabetes (T2D) is the predominant metabolic epidemic posing a major threat to global health. Growing evidence indicates that gut microbiota (GM) may critically influence the progression from normal glucose tolerance, to pre-diabetes, to T2D. On the other hand, regular exercise contributes to the prevention and/or treatment of the disease, and evidence suggests that a possible way regular exercise favorably affects T2D is by altering GM composition toward health-promoting bacteria. However, research regarding this potential effect of exercise-induced changes of GM on T2D and the associated mechanisms through which these effects are accomplished is limited. This review presents current data regarding the association of GM composition and T2D and the possible critical GM differentiation in the progression from normal glucose, to pre-diabetes, to T2D. Additionally, potential mechanisms through which GM may affect T2D are presented. The effect of exercise on GM composition and function on T2D progression is also discussed.

This study aims to investigate the effects of semaglutide on gut microbiota, cognitive function, and inflammation in obese mice.

Twenty-four C57BL/6J male mice were randomly assigned to three groups: a normal-chow diet group (NCD, n = 8), high-fat diet group (HFD, n = 8), and HFD+semaglutide group (Sema, n = 8). The mice were fed a HFD to establish an animal model of obesity and then administered with semaglutide or saline for 12 weeks. Cognitive function was assessed using the Morris water maze test. Serum pro-inflammatory cytokines were measured. 16S rRNA gene sequencing technology was used to explore gut microbiota characteristics in obese mice.

Obese mice showed significant cognitive impairment and inflammation. Semaglutide improved cognitive function and attenuated inflammation induced by a HFD diet. The abundance of gut microbiota was significantly changed in the HFD group, including decreased Akkermansia, Muribaculaceae, Coriobacteriaceae_UCG_002, Clostridia_UCG_014 and increased Romboutsia, Dubosiella, Enterorhabdus. Whereas semaglutide could dramatically reverse the relative abundance of these gut microbiota. Correlation analysis suggested that cognitive function was positively correlated with Muribaculaceae and Clostridia_UCG_014, and negatively associated with Romboutsia and Dubosiella. Romboutsia was positively correlated with TNFα, IL-6 and IL-1β. While Clostridia_UCG_014 was negatively related to TNFα, IL-6 and IL-1β.

For the first time semaglutide displayed different regulatory effects on HFD-induced gut microbiota dysbiosis. Semaglutide could regulate the structure and composition of gut microbiota associated with cognitive function and inflammation. Thus, affecting gut microbiota might be a potential mechanism of semaglutide in attenuating cognitive function and inflammation.

Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.

Obesity significantly impacts gut microbial composition, exacerbating metabolic dysfunction and weight gain. Traditional treatment methods often fall short, underscoring the need for innovative approaches. Glucagon-like peptide-1 (GLP-1) agonists have emerged as promising agents in obesity management, demonstrating significant potential in modulating gut microbiota. These agents promote beneficial bacterial populations, such as Bacteroides, Lactobacillus, and Bifidobacterium, while reducing harmful species like Enterobacteriaceae. By influencing gut microbiota composition, GLP-1 agonists enhance gut barrier integrity, reducing permeability and systemic inflammation, which are hallmarks of metabolic dysfunction in obesity. Additionally, GLP-1 agonists improve metabolic functions by increasing the production of short-chain fatty acids like butyrate, propionate, and acetate, which serve as energy sources for colonocytes, modulate immune responses, and enhance the production of gut hormones that regulate appetite and glucose homeostasis. By increasing microbial diversity, GLP-1 agonists create a more resilient gut microbiome capable of resisting pathogenic invasions and maintaining metabolic balance. Thus, by shifting the gut microbiota toward a healthier profile, GLP-1 agonists help disrupt the vicious cycle of obesity-induced gut dysbiosis and inflammation. This review highlights the intricate relationship between obesity, gut microbiota, and GLP-1 agonists, providing valuable insights into their combined role in effective obesity treatment and metabolic health enhancement.

GLP-1 receptor agonists (GLP-1 RA) are presently used as the first-line drugs for the clinical treatment of type 2 diabetes mellitus (T2DM). It can regulate blood glucose by stimulating insulin secretion and lowering glucagon levels. We used 16S rRNA amplicon sequencing to detect structural changes in the composition of the intestinal flora of newly diagnosed T2DM after 1 and 48 weeks of dulaglutide administration. Our research found no significant changes in the intestinal flora after the administration of dulaglutide for 1 week to subjects with newly diagnosed T2DM. Nevertheless, after 48 weeks of dulaglutide administration, the composition of the intestinal flora changed significantly, with a significant reduction in the abundance of intestinal flora. Furthermore, we found that fasting glucose levels, fasting c-peptide levels, HbA1c levels, and BMI are also closely associated with intestinal flora. This reveals that intestinal flora may be one of the mechanisms by which dulaglutide treats T2DM.

Obesity is considered the leading public health problem in the medical sector. The phenotype includes overweight conditions that lead to several other comorbidities that drastically decrease health. Glucagon-like receptor agonists (GLP-1RAs) initially designed for treating type 2 diabetes mellitus (T2DM) had demonstrated weight loss benefits in several clinical trials. In vivo studies showed that GLP-1RA encourages reduced food consumption and consequent weight reduction by stimulating brown fat and enhancing energy outlay through the action of the sympathetic nervous system (SNS) pathways. Additionally, GLP-1RAs were found to regulate food intake through stimulation of sensory neurons in the vagus, interaction with the hypothalamus and hindbrain, and through inflammation and intestinal microbiota. However, the main concern with the use of GLP-1RA treatment was weight gain after withdrawal or discontinuation. We could identify three different ways that could lead to weight gain. Potential factors might include temporary hormonal adjustment in response to weight reduction, the central nervous system's (CNS) incompetence in regulating weight augmentation owing to the lack of GLP-1RA, and β-cell malfunction due to sustained exposure to GLP-1RA. Here, we also review the data from clinical studies that reported withdrawal symptoms. Although the use of GLP-1RA could be beneficial in multiple ways, withdrawal after years has the symptoms reversed. Clinical studies should emphasize the downside of these views we highlighted, and mechanistic studies must be carried out for a better outcome with GLP-1RA from the laboratory to the bedside.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is becoming a significant contributor to chronic liver disease globally, surpassing other etiologies, such as viral hepatitis. Prevention and early treatment strategies to curb its growing prevalence are urgently required. Recent evidence suggests that targeting the gut microbiota may help treat and alleviate disease progression in patients with MAFLD. This review aims to explore the complex relationship between MAFLD and the gut microbiota in relation to disease pathogenesis. Additionally, it delves into the therapeutic strategies targeting the gut microbiota, such as diet, exercise, antibiotics, probiotics, synbiotics, glucagon-like peptide-1 receptor agonists, and fecal microbiota transplantation, and discusses novel biomarkers, such as microbiota-derived testing and liquid biopsy, for their diagnostic and staging potential. Overall, the review emphasizes the urgent need for preventive and therapeutic strategies to address the devastating consequences of MAFLD at both individual and societal levels and recognizes that further exploration of the gut microbiota may open avenues for managing MAFLD effectively in the future.

There has been a major increase in Type 2 diabetes and obesity in many countries, and this will lead to a global public health crisis, which not only impacts on the quality of life of individuals well but also places a substantial burden on healthcare systems and economies. Obesity is linked to not only to type 2 diabetes but also cardiovascular diseases, musculoskeletal disorders, and certain cancers, also resulting in increased medical costs and diminished quality of life. A number of studies have linked changes in gut in obesity development. Dysbiosis, a deleterious change in gut microbiota composition, leads to altered intestinal permeability, associated with obesity and Type 2 diabetes. Many factors affect the homeostasis of gut microbiota, including diet, genetics, circadian rhythms, medication, probiotics, and antibiotics. In addition, bariatric surgery induces changes in gut microbiota that contributes to the metabolic benefits observed post-surgery. Current obesity management strategies encompass dietary interventions, exercise, pharmacotherapy, and bariatric surgery, with emerging treatments including microbiota-altering approaches showing promising efficacy. While pharmacotherapy has demonstrated significant advancements in recent years, bariatric surgery remains one of the most effective treatments for sustainable weight loss. However, access to this is generally limited to those living with severe obesity. This underscores the need for non-surgical interventions, particularly for adolescents and mildly obese patients. In this comprehensive review, we assess longitudinal alterations in gut microbiota composition and functionality resulting from the two currently most effective anti-obesity treatments: pharmacotherapy and bariatric surgery. Additionally, we highlight the functions of gut microbiota, focusing on specific bacteria, their metabolites, and strategies for modulating gut microbiota to prevent and treat obesity. This review aims to provide insights into the evolving landscape of obesity management and the potential of microbiota-based approaches in addressing this pressing global health challenge.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known for its pivotal role in enhancing insulin secretion and reducing glucagon release from the pancreas. Diabetic nephropathy, which is characterized by albuminuria, represents a significant microvascular complication of diabetes. Most of the previous studies mainly focused on the therapeutic renal protective effect in clinical trials after the administration of GLP-1 receptor agonists (GLP-1 RAs), rather than before administration. Hence, this study aimed to investigate the association between fasting plasma GLP-1 levels and albuminuria before GLP-1 RA administration. A cross-sectional study was designed to evaluate the association between fasting plasma GLP-1 levels and albuminuria in patients with type 2 diabetes mellitus (T2DM). A cohort of 68 participants with T2DM was analyzed using data collected at Wonkwang University Hospital in Iksan, Korea. Logistic regression analysis was employed to determine the odds ratio (OR) and 95% confidence interval (CI) of the incidence of albuminuria between two groups categorized by fasting GLP-1 levels, low (Group L) and high GLP-1 (Group H). The OR (95% CI) for the incidence of albuminuria comparing Group L with Group H of fasting plasma GLP-1 levels was 3.41 (1.16-10.02), p = 0.03 after adjustment for relevant variables including age, gender, fasting plasma glucose, HbA1c, C-peptide, creatinine, and medication use [angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors]. When analyzed as a continuous variable, each 1 pmol/L reduction in fasting plasma GLP-1 levels was associated with an OR (95% CI) of 1.67 (1.17-1.87), p = 0.02, following full adjustment. These results highlight a negative association between fasting plasma GLP-1 levels and the incidence of albuminuria in Korean patients with T2DM, before GLP-1 RA administration. These findings suggest that endogenous GLP-1 may have a beneficial impact in mitigating albuminuria.

Polycystic ovary syndrome (PCOS) is a frequent cause of infertility in reproductive-age women. Our work aims to evaluate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on gut microbiota, with metabolic parameters including body weight and the hormone profile in PCOS.

Dehydroepiandrosterone (DHEA)-induced PCOS mice were established and then treated with two GLP-1RAs: liraglutide and novel form semaglutide for four weeks. Changes in body weight and metabolic parameters were measured. Fecal samples were collected and analyzed using metagenomic sequencing.

Liraglutide and semaglutide modulated both alpha and beta diversity of the gut microbiota in PCOS. Liraglutide increased the Bacillota-to-Bacteroidota ratio through up-regulating the abundance of butyrate-producing members of Bacillota like Lachnospiraceae. Moreover, liraglutide showed the ability to reverse the altered microbial composition and the disrupted microbiota functions caused by PCOS. Semaglutide increased the abundance of Helicobacter in PCOS mice (p < 0.01) which was the only bacteria found negatively correlated with body weight. Moreover, pathways involving porphyrin and flavonoids were increased after semaglutide intervention.

Liraglutide and semaglutide improved reproductive and metabolic disorders by modulating the whole structure of gut microbiota in PCOS. The greater efficacy in weight loss compared with liraglutide observed after semaglutide intervention was positively related with Helicobacter. The study may provide new ideas in the treatment and the underlying mechanisms of GLP-1RAs to improve PCOS.

Obesity impairs homeostatic control of energy and is associated with chronic low-grade inflammation. Effects of glucagon-like peptide-1, the target in the gastrointestinal tract for anti-obesity drugs such as Liraglutide, were not properly associated with inflammation markers. This study investigated the effects of Liraglutide on metabolic and gastrointestinal parameters in a rat model of obesity.

Twenty-six Wistar rats with obesity were randomly distributed to receive saline (n = 10), 400 μg (n = 8), or 1200 μg of Liraglutide/kg/day (n = 8), subcutaneously for 30 consecutive days, once a day. Weight gain, feeding efficiency, caloric consumption, gastric motility, adiposity, histomorphometric, murinometric, biochemical parameters and cytokines TNF-α and TGF-β1 in duodenal tissue were measured. Data were analysed by ANOVA, followed by Bonferroni post hoc or Kruskal-Wallis test, followed by Dunn's multiple comparison test.

Liraglutide-treated animals had better feeding efficiency and higher caloric intake in a dose-dependent manner. Higher doses slowed gastric emptying and diminished the amplitude of gastric contractions. These effects were accompanied by decreases in intestinal muscle layer thickness and crypt depth. Liraglutide significantly reduced retroperitoneal and visceral white adipose tissue depots. High-dose treatment decreased levels of TNF-α and enhanced levels of TGF-β1 in duodenal tissue. Liraglutide treatment provided significant reductions in total cholesterol, triglyceride and hepatic transaminases.

Liraglutide reduced fat accumulation, improved metabolic parameters and downregulated levels of inflammatory signalling in duodenal tissue. Liraglutide at high doses controlled obesity-related outcomes, and such effects seemed to be driven by its action on glucagon-like peptide-1 receptors in the gastrointestinal tract slowing gastric motility.

Metformin (MET) is a first-line therapy for type-2 diabetes mellitus (T2DM). Liraglutide (LRG) is a glucagon-like peptide-1 receptor agonist used as a second-line therapy in combination with MET.

We performed a longitudinal analysis comparing the gut microbiota of overweight and/or pre-diabetic participants (NCP group) with that of each following their progression to T2DM diagnosis (UNT group) using 16S ribosomal RNA gene sequencing of fecal bacteria samples. We also examined the effects of MET (MET group) and MET plus LRG (MET+LRG group) on the gut microbiota of these participants following 60 days of anti-diabetic drug therapy in two parallel treatment arms.

In the UNT group, the relative abundances of Paraprevotella (P = 0.002) and Megamonas (P = 0.029) were greater, and that of Lachnospira (P = 0.003) was lower, compared with the NCP group. In the MET group, the relative abundance of Bacteroides (P = 0.039) was greater, and those of Paraprevotella (P = 0.018), Blautia (P = 0.001), and Faecalibacterium (P = 0.005) were lower, compared with the UNT group. In the MET+LRG group, the relative abundances of Blautia (P = 0.005) and Dialister (P = 0.045) were significantly lower than in the UNT group. The relative abundance of Megasphaera in the MET group was significantly greater than in the MET+LRG group (P = 0.041).

Treatment with MET and MET+LRG results in significant alterations in gut microbiota, compared with the profiles of patients at the time of T2DM diagnosis. These alterations differed significantly between the MET and MET+LRG groups, which suggests that LRG exerted an additive effect on the composition of gut microbiota.

The gut microbiota plays a pivotal role in metabolic disorders, notably type 2 diabetes mellitus (T2DM). In this study, we investigated the synergistic potential of combining the effects of Bifidobacterium longum NBM7-1 (CKD1) with anti-diabetic medicines, LobeglitazoneⓇ (LO), SitagliptinⓇ (SI), and MetforminⓇ (Met), to alleviate hyperglycemia in a diabetic mouse model. CKD1 effectively mitigated insulin resistance, hepatic steatosis, and enhanced pancreatic β-cell function, as well as fortifying gut-tight junction integrity. In the same way, SI-CKD1 and Met- CKD1 synergistically improved insulin sensitivity and prevented hepatic steatosis, as evidenced by the modulation of key genes associated with insulin signaling, β-oxidation, gluconeogenesis, adipogenesis, and inflammation by qRT-PCR. The comprehensive impact on modulating gut microbiota composition was observed, particularly when combined with MetforminⓇ. This combination induced an increase in the abundance of Rikenellaceae and Alistipes related negatively to the T2DM incidence while reducing the causative species of Cryptosporangium, Staphylococcaceae, and Muribaculaceae. These alterations intervene in gut microbiota metabolites to modulate the level of butyrate, indole-3-acetic acid, propionate, and inflammatory cytokines and to activate the IL-22 pathway. However, it is meaningful that the combination of B. longum NBM7-1(CKD1) reduced the medicines' dose to the level of the maximal inhibitory concentrations (IC50). This study advances our understanding of the intricate relationship between gut microbiota and metabolic disorders. We expect this study to contribute to developing a prospective therapeutic strategy modulating the gut microbiota.

Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a global public health concern. Currently, the cornerstone of NAFLD treatment is lifestyle modification and, if necessary, weight loss. However, compliance is a challenge, and this approach alone may not be sufficient to halt and treat the more serious disease development, so medication is urgently needed. Nevertheless, no medicines are approved to treat NAFLD. Glucagon-like peptide-1 (GLP-1) is an enteropeptide hormone that inhibits glucagon synthesis, promotes insulin secretion, and delays gastric emptying. GLP-1 has been found in recent studies to be beneficial for the management of NAFLD, and the marketed GLP-1 agonist drugs have different degrees of effectiveness for NAFLD while lowering blood glucose. In this article, we review GLP-1 and its physiological roles, the pathogenesis of NAFLD, the correlation between NAFLD and GLP-1 signaling, and potential strategies for GLP-1 treatment of NAFLD.

To investigate the effect of exenatide treatment on the composition of intestinal flora and metabolic pathways in patients with obesity with polycystic ovary syndrome.

Patients with obesity with polycystic ovary syndrome (PCOS) were distributed to two groups: one received exenatide combined with metformin (COM group, n = 14) and the other used metformin alone (MF group, n = 15). Fresh fecal specimens from the participants, including 29 patients with obesity with PCOS and 6 healthy controls, were collected for metagenomic sequencing. The effect of exenatide combination with metformin or metformin alone on the composition and function of intestinal flora in patients with obesity with PCOS were compared by bioinformatics analysis.

The level of BMI, TT, HbA1c, and HDL-c was significantly improved in both groups. The MF and COM groups were abundant in Firmicutes, Bacteroidetes, Uroviricota, Actinobacteria, and Proteobacteria. Abundance of Bacteroidetes, Proteobacteria, Hungatella, and certain probiotics like Phocaeicola and Anaerobutyricum significantly increased in both groups after treatment. Enriched microbial species in the MF and COM group were different. Clostridium, Fusobacterium, and Oxalobacter were the main bacteria in the post-MF group, while Lactococcus_garvieae, Clostridium_perfringens, and Coprococcus_sp_AF16_5 were the main bacteria in the post-COM group. The post-COM group had more probiotic species including Bifidobacterium, Prevotella, and Anaerobutyricum after treatment.

Both exenatide combined with metformin and metformin monotherapy can improve metabolic and endocrine markers, and the diversity and abundance of gut microbiota in patients with obesity with PCOS. The effects of the combination and monotherapy agents on intestinal flora were consistent to some extent but also unique respectively.

In this study, the impact of sn-2 palmitic triacyclglycerols (TAGs) in combination with their ratio of two major TAGs (1-oleoyl-2-palmitoyl-3-linoleoylglycerol (OPL) to 1,3-dioleoyl-2-palmitoylglycerol (OPO)) in human milk fat substitute (HMFS) on bile acid (BA) metabolism and intestinal microbiota composition was investigated in newly-weaned Sprague-Dawley rats after four weeks of high-fat feeding. Compared to those of control group rats, HMFS-fed rats had significantly increased contents of six hepatic primary BAs (CDCA, αMCA, βMCA, TCDCA, TαMCA and TβMCA), four ileal primary BAs (UDCA, TCA, TCDCA and TUDCA) and three secondary BAs (DCA, LCA and ωMCA), especially for the HMFS with the highest sn-2 palmitic acid TAGs of 57.9% and OPL to OPO ratio of 1.4. Meanwhile, the inhibition of ileal FXR-FGF15 and activation of TGR5-GLP-1 signaling pathways in HMFS-fed rats were accompanied by the increased levels of enzymes involved in BA synthesis (CYP7A1, CYP27A1 and CYP7B1) in the liver and two key thermogenic proteins (PGC1α and UCP1) in perirenal adipose tissue, respectively. Moreover, increasing sn-2 palmitic TAGs and OPL to OPO ratio in HMFS also altered the microbiota composition both on the phylum and genus level in rats, predominantly microbes associated with bile-salt hydrolase activity, short-chain fatty acid production and reduced obesity risk, which suggested a beneficial effect on host microbial ecosystem. These observations provided important nutritional evidence for developing new HMFS products for infants.

The gut-liver axis plays a prominent role in the pathogenesis and therapy of metabolic diseases such as diabetes. The intestinal specific origin of several hormones that guide both inter- and post-prandial metabolism of carbohydrates and lipids, drives the attention of scientists and clinicians on the gut as a major site to intervene with novel diagnostic or prognostic markers. The role of intestinal ecology in the metabolic syndrome was postulated when gut microbiota was directly connected with inflammation, hyperinsulinemia, and diabetes. There have been several discoveries with the role of gut microbiota and gut-liver axis in diabetes. Also, there are several trials ongoing on the therapeutic efficacy of probiotic administration in diabetes and its complications. Here we point to the metabolic action of microbiota and discuss the actual state of the art on gut microbiota as a novel prognostic biomarker with a putative therapeutic role in diabetes.

To describe the rationale and design of the SIB trial, an interventional clinical trial testing the hypothesis that subcutaneous (s.c.) once-weekly semaglutide can improve intestinal permeability and reduce systemic inflammation in participants with type 2 diabetes (T2D) and obesity.

SIB (NCT04979130) is an investigator-initiated, single-center randomized, double-blinded, placebo-controlled clinical study being conducted at the University of Colorado Anschutz Medical Campus. The primary objective of this novel trial is to test the hypothesis that subcutaneous (s.c.) once-weekly semaglutide could improve intestinal permeability and reduce systemic inflammation in participants with T2D and obesity. Eligible participants had a diagnosis of type 2 diabetes, elevated body mass index, and evidence of systemic inflammation. Participants were randomized 1:1 to s.c. semaglutide or placebo. Participants were assessed for intestinal permeability and markers of inflammation at baseline, mid-study, and at the end of the study. Efficacy assessments were based on the analysis of the following: lactulose:mannitol ratio test, serum lipopolysaccharide-binding protein (LBP), fecal calprotectin, inflammatory biomarkers (IL-6, TNF, IL-1, IL-8, hs-CRP), and HbA1c. All participants who enrolled in the trial provided written informed consent after having received written and oral information on the trial. The risks of semaglutide use were minimized by administration according to FDA-labeled use and close monitoring for adverse events.

SIB is the first study to examine the effects of GLP-1 receptor agonists on intestinal permeability in humans and will provide important data on their impact on systemic inflammation and intestinal permeability in the setting of T2D and obesity.

Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and economic burden. Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics (PK) and pharmacodynamics (PD), genetic diversity explains only a limited proportion of IVDR. The role of gut microbiota, also known as the second genome, and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies. Consequently, the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs. This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases, including cancer, cardiovascular diseases (CVDs), endocrine diseases, and others. We summarise how microbiota, directly and indirectly, modify the absorption, distribution, metabolism, and excretion (ADME) of drugs. Conversely, drugs can also modulate the composition and function of gut microbiota, leading to changes in microbial metabolism and immune response. We also discuss the practical challenges, strategies, and opportunities in this field, emphasizing the critical need to develop an innovative approach to multi-omics, integrate various data types, including human and microbiota genomic data, as well as translate lab data into clinical practice. To sum up, pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes, and further research in this field is imperative to unlock its full potential for precision medicine.

The circadian timing system enables organisms to adapt their physiology and behavior to the cyclic environmental changes including light-dark cycle or food availability. Misalignment between the endogenous circadian rhythms and external cues is known as chronodisruption and is closely associated with the development of metabolic and gastrointestinal disorders, cardiovascular diseases, and cancer. Time-restricted eating (TRE, in human) is an emerging dietary approach for weight management. Recent studies have shown that TRE or time-restricted feeding (TRF, when referring to animals) has several beneficial health effects, which, however, are not limited to weight management. This review summarizes the effects of TRE/TRF on regulating energy metabolism, gut microbiota and homeostasis, development of cardiovascular diseases and cancer. Furthermore, we will address the role of circadian clocks in TRE/TRF and propose ways to optimize TRE as a dietary strategy to obtain maximal health benefits.

Non-alcoholic fatty acid liver disease (NAFLD) is a reputed global health concern, affecting children and young adults. Accumulating evidence suggests that edible fungi polysaccharides have the potential to relieve NAFLD. Our previous study found that Auricularia cornea var. Li. polysaccharides (ACP) could improve immune by regulating gut microbiota. However, its NAFLD-alleviating potentials have been scarcely reported. This study analyzed the protective effects of Auricularia cornea var. Li. polysaccharides on high-fat diet (HFD)-induced NAFLD and mechanistic actions. We first analyzed the histology and hepatic lipid profile of animals to evaluate this variant's ameliorating effects on NAFLD. Then, antioxidant and anti-inflammatory potentials of ACP were studied. Finally, we explored changes in the gut microbiome diversity for mechanistic insights from the gut-liver region. Results showed that supplementation with ACP substantially reduced homeostasis model assessment-insulin resistance (HOMA-IR), body fat, liver index rates and weight gain (p < 0.05). This variant also improved HDL-C levels while decreasing triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels which were initially triggered by HFD. ACP mediation also decreased the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels considerably with H&E technique indicating that it can reduce liver lipid accumulation, thus lowering liver damages risks (p < 0.05). The antioxidant potentials of ACP were also demonstrated as it decreased the hepatic levels of malondialdehyde (MDA) and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). Proinflammatory markers like IL-6, IL-1β and TNF-α concentrations were decreased by ACP supplementation, accompanied with increased IL-4 levels. Finally, ACP supplementation regulated the intestinal microbiota to near normal patterns. In all, ACP protects HFD-induced NAFLD by improving liver characteristics and regulating colonic flora composition, our findings assert that ACP can be a promising strategy in NAFLD therapy.

Diabetic retinopathy is one of the major causes of blindness today, despite important achievements in diagnosis and therapy. The involvement of a gut-retina axis is thought to be a possible risk factor for several chronic eye disease, such as glaucoma, age-related macular degeneration, uveitis, and, recently, diabetic retinopathy. Dysbiosis may cause endothelial disfunction and alter retinal metabolism. This review analyzes the evidence regarding changes in gut microbiota in patients with DR compared with diabetics and healthy controls (HCs). A systematic review was performed on PubMed, Web of Science, and Google Scholar for the following terms: "gut microbiota" OR "gut microbiome" AND "diabetic retinopathy". Ultimately, 9 articles published between 2020 and 2022 presenting comparative data on a total of 228 T2DM patients with DR, 220 patients with T2DM, and 118 HCs were analyzed. All of the studies found a distinctive microbial beta diversity in DR vs. T2DM and HC, characterized by an altered Firmicutes/Bacteroidetes ratio, a decrease in butyrate producers, and an increase in LPS-expressing and pro-inflammatory species in the Bacteroidetes and Proteobacteria phyla. The probiotic species Bifidobacterium and Lactobacillus were decreased when compared with T2DM. Gut microbiota influence retinal health in multiple ways and may represent a future therapeutic target in DR.

Gut microbiota is known as unique collection of microorganisms (including bacteria, archaea, eukaryotes and viruses) that exist in a complex environment of the gut. Recently, this has become one of the most popular areas of research in medicine because this plays not only an important role in disease development, but gut microbiota also influences drug pharmacokinetics. These alterations in drug pharmacokinetic pathways and drug concentration in plasma and blood often lead to an increase in the incidence of toxicological events in patients. This review aims to present current knowledge of the most commonly used drugs in clinical practice and their dynamic interplay with the host's gut microbiota as well as the mechanisms underlying these metabolic processes and the consequent effect on their therapeutic efficacy and safety. These new findings set a foundation for the development of personalized treatments specific to each metabolism, maximizing drugs' therapeutic effects and minimizing the side effects because they are one of the major limiting factors in treating patients.

Excessive copper pollutes the environment and endangers human health, attracting plenty of global attention. In this study, a novel strain named Bacillus coagulans XY2 was discovered to have a great copper tolerance and adsorption capacity. B. coagulans XY2 might maintain copper homeostasis through multisystem synergies of copper resistance, sulfur metabolism, Fe-S cluster assembly, and siderophore transport. In mice, by promoting the expression of SREBF-1 and SREBF-2 and their downstream genes, B. coagulans XY2 significantly inhibited the copper-induced decrease in weight growth rate, ameliorated dyslipidemia, restored total cholesterol and triglyceride contents both in serum and liver. Furthermore, B. coagulans XY2 recovered the diversity of gut microbiota and suppressed the copper-induced reduction in the ratio of Firmicutes to Bacteroidota. Serum metabolomics analysis showed that the alleviating effect of B. coagulans XY2 on copper toxicity was mainly related to lipid metabolism. For the first time, we demonstrated mechanisms of copper toxicity mitigation by B. coagulans XY2, which was related to self-adsorption, host copper excretion promotion, and lipid metabolism regulation. Moreover, working model of B. coagulans XY2 on copper homeostasis was predicted by whole-genome analysis. Our study provides a new solution for harmfulness caused by copper both in human health and the environment.

The role of extracellular vesicles (EVs) from faeces (fEVs) and small circulating EVs (cEVs) in liver diseases such as non-alcoholic fatty diseases (NAFLD) and non-alcoholic steatohepatitis (NASH) has not been demonstrated. fEVs and cEVs of healthy donors, NAFLD and NASH patients were isolated and characterized. The effects of EVs were evaluated in intestinal, endothelial, Kupffer and stellate cells. Non-muscular myosin light chain kinase (nmMLCK) deficient mice were used in vivo. Bacterial origins of fEVs were analysed by 16s rDNA gene sequencing. fEVs and small cEVs were composed of prokaryotic and eukaryotic origins. Only NASH-fEVs exerted deleterious effects. NASH-fEVs increased intestinal permeability and reduced expression of tight junction proteins that were prevented by nmMLCK inhibition, increased endothelial cell permeability and inflammatory cytokines and chemokines requiring TLR4/lipopolysaccharide pathway. NASH-fEVs and NASH-cEVs activated profibrotic and proinflammatory proteins of hepatic stellate cells. Treatment with NASH-fEVs evoked an increase in intestinal permeability in wild type but not in nmMLCK deficient mice. Bacterial origins of fEVs were different between NAFLD and NASH patients and 16 amplicon sequence variants were differentially abundant. We demonstrate that fEVs actively participate in barrier dysfunctions leading to liver injuries underscoring the role of nmMLCK and lipopolysaccharide carried by fEVs.

Except for improving glycemic control, liraglutide, one of the glucagon-like peptide-1 receptor agonists, has exerted promising therapeutic effects for dyslipidemia. It has been proved that gut microbiota plays a dramatic role in regulating lipid metabolism. This study aims to explore whether liraglutide could improve dyslipidemia by modulating the gut microbiota in mice fed a high-fat diet (HFD). The C57BL/6 mice were fed a HFD to establish an animal model of dyslipidemia, and then administered with liraglutide or normal saline (NS) for 12 weeks. Indices of glucolipid metabolism were evaluated. Gut microbiota of the mice was analyzed by 16S rRNA gene sequencing. Compared with HFD group, liraglutide significantly alleviated weight, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels, meanwhile elevating high-density lipoprotein cholesterol (HDL) levels (all p < 0.05). The gut microbiota analysis revealed that liraglutide greatly reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes, with a concomitant drop in the Firmicutes/Bacteroidetes ratio. Meanwhile, liraglutide dramatically changed the overall composition, promoted the growth of beneficial microbes (Akkermansia, Lactobacillus, Parabacteroides, Oscillospira, etc.), and inhibited the growth of harmful microbes (AF12, Shigella, Proteobacteria, Xenorhabdus, etc.). Especially, the relative abundance of Akkermansia increased the most after liraglutide treatment. Correlation analysis suggested that TC and LDL were positively correlated with some harmful bacteria, and negatively associated with beneficial bacteria. This study confirmed that liraglutide had a certain therapeutic effect on dyslipidemia in HFD-fed mice and could regulate the composition of the gut microbiota associated with lipid metabolism, especially Akkermansia. Thus, affecting gut microbiota might be a potential mechanism of liraglutide in attenuating dyslipidemia.

Diabetes represents one of the most significant, and rapidly escalating, global healthcare crises we face today. Diabetes already affects one-tenth of the world's adults-more than 537 million people, numbers that have tripled since 2000 and are estimated to reach 643 million by 2030. Type 2 diabetes (T2D), the most prevalent form, is a complex disease with numerous contributing factors, including genetics, epigenetics, diet, lifestyle, medication use, and socioeconomic factors. In addition, the gut microbiome has emerged as a significant potential contributing factor in T2D development and progression. Gut microbes and their metabolites strongly influence host metabolism and immune function, and are now known to contribute to vitamin biosynthesis, gut hormone production, satiety, maintenance of gut barrier integrity, and protection against pathogens, as well as digestion and nutrient absorption. In turn, gut microbes are influenced by diet and lifestyle factors such as alcohol and medication use, including antibiotic use and the consumption of probiotics and prebiotics. Here we review current evidence regarding changes in microbial populations in T2D and the mechanisms by which gut microbes influence glucose metabolism and insulin resistance, including inflammation, gut permeability, and bile acid production. We also explore the interrelationships between gut microbes and different T2D medications and other interventions, including prebiotics, probiotics, and bariatric surgery. Lastly, we explore the particular role of the small bowel in digestion and metabolism and the importance of studying small bowel microbes directly in our search to find metabolically relevant biomarkers and therapeutic targets for T2D.

The intestine represents the body's largest interface between internal organs and external environments except for its nutrient and fluid absorption functions. It has the ability to sense numerous endogenous and exogenous signals from both apical and basolateral surfaces and respond through endocrine and neuronal signaling to maintain metabolic homeostasis and energy expenditure. The intestine also harbours the largest population of microbes that interact with the host to maintain human health and diseases. Furthermore, the gut is known as the largest endocrine gland, secreting over 100 peptides and other molecules that act as signaling molecules to regulate human nutrition and physiology. Among these gut-derived hormones, glucagon-like peptide 1 (GLP-1) and -2 have received the most attention due to their critical role in intestinal function and food absorption as well as their application as key drug targets. In this review, we highlight the current state of the literature that has brought into light the importance of GLP-1 and GLP-2 in orchestrating intestine-microbiota-immune system crosstalk to maintain intestinal barrier integrity, inflammation, and metabolic homeostasis.

Gut intraepithelial lymphocytes (IELs) are thought to calibrate glucagon-like peptide 1 (GLP-1) bioavailability, thereby regulating systemic glucose and lipid metabolism. Here, we show that the gut IEL GLP-1 receptor (GLP-1R) is not required for enteroendocrine L cell GLP-1 secretion and glucose homeostasis nor for the metabolic benefits of GLP-1R agonists (GLP-1RAs). Instead, the gut IEL GLP-1R is essential for the full effects of GLP-1RAs on gut microbiota. Moreover, independent of glucose control or weight loss, the anti-inflammatory actions of GLP-1RAs require the gut IEL GLP-1R to selectively restrain local and systemic T cell-induced, but not lipopolysaccharide-induced, inflammation. Such effects are mediated by the suppression of gut IEL effector functions linked to the dampening of proximal T cell receptor signaling in a protein-kinase-A-dependent manner. These data reposition key roles of the L cell-gut IEL GLP-1R axis, revealing mechanisms linking GLP-1R activation in gut IELs to modulation of microbiota composition and control of intestinal and systemic inflammation.