Gastrointestinal Hormones Research Articles

Discovery of novel glucagon-like peptide 1/cholecystokinin 1 receptor dual agonists

The combined use of gastrointestinal hormones for treating metabolic diseases is gaining increasing attention. The potential of developing novel dual agonists targeting both cholecystokinin 1 (CCK-1) receptor and glucagon-like peptide 1 (GLP-1) receptor to improve the treatment of type 2 diabetes and obesity have not been fully explored. In this investigation, we reported a series of novel GLP-1/CCK-1 receptor co-agonists constructed by linking the C-terminus of a GLP-1 receptor agonist (bullfrog GLP-1) to the N-terminus of a CCK-1 receptor selective agonist NN9056. In comprehensive in vitro assays, these co-agonists exhibited complete agonistic potency on GLP-1 and CCK-1 receptor. Remarkably, 1f displayed superior hypoglycemic and insulinotropic effects when compared to NN9056 and semaglutide. Evaluation in Kunming and diet-induced obesity (DIO) mice unveiled significant acute and enduring hypoglycemic effects of 1f. Administration of 1f to DIO mice resulted in substantial weight loss, normalized lipid metabolism, and enhanced glucose regulation. These preclinical observations strongly advocate for the therapeutic potential CCK-1 and GLP-1 pathways could be harnessed in a single fusion peptide, yielding a promising combination therapy strategy for treating metabolic disorders.

Appetite, food intake, and gut hormone responses to glycomacropeptide protein ingestion in older adults: A feasibility, acceptability, and pilot study

Glycomacropeptide (GMP) has a unique amino acid profile which may make less satiating than other dietary proteins. This study assessed the feasibility and likely acceptability of a leucine-enriched GMP drink and determined appetite response in older adults (OA). Thirteen OA (11f; 70 ± 4 years) were recruited for sensory assessments of a leucine-enriched GMP drink when mixed with water and with fruit smoothie, compared with whey protein isolate (WHEY). Participants also partook in a single focus group exploring acceptability to protein and supplementation. Separately, a counterbalanced, double-blind study with twelve OA (8f; 69 ± 3 years) was conducted to determine appetite and gut hormone responses. Fasting subjective appetite was recorded using visual analogue scales and a fasted venous blood sample was collected (to measures acyl-ghrelin, PYY, GLP-1, and CCK) before participants consumed either: GMP protein (27g + 3g leucine, 350 mL water), WHEY (30g, 350 mL water), or water. Participants rested for 240 min, with appetite measures and blood sampling throughout. An ad libitum pasta-based meal was then consumed. Sensory testing revealed low pleasantness rating for GMP in water vs. WHEY (16 ± 14 vs 31 ± 24, p = 0.016). GMP addition to smoothie reduced pleasantness (26 ± 21 vs. 61 ± 29, p = 0.009) and worsened the aroma (46 ± 15 vs. 69 ± 28, p = 0.014). The focus group revealed uncertainty of protein needs and a scepticism of supplements, with preference for food. Gut hormone response did not differ between GMP and WHEY (nAUC for all gut hormones p > 0.05). There was no difference between conditions for lunch ad libitum intake (549 ± 171 kcal, 512 ± 238 kcal, 460 ± 199 kcal for GMP, WHEY, and water, p = 0.175), or for subjective appetite response. Leucine-enriched GMP was not less satiating than WHEY, and low palatability and scepticism of supplements question the likely acceptability of GMP supplementation. Providing trusted nutritional advice and food enrichment/fortification may be preferred strategies for increasing protein intake in OA.

Effects of Breaking Up Sitting on Gut Hormone Responses and Subsequent Compensatory Behaviors in Physically Inactive Adults.

The effects of breaking up sitting on gut hormone responses and free-living energy compensatory behaviors are still unclear in people of Asian ethnicity. Twenty-six Asians including 13 lean individuals (Lean) and 13 individuals with centrally overweight/obesity (OW), aged between 20 and 45 yr, completed a randomized crossover study with either 5.5-h uninterrupted sitting (SIT) or 5.5-h sitting with 2-min walking at 6.4 km·h -1 every 20 min (ACTIVE) in the laboratory. Blood samples were collected at regular time points to examine postprandial glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and glucose-dependent insulinotropic polypeptide (GIP) concentrations. Free-living physical activity and energy intake were recorded using wearable devices and weighed food diaries outside the laboratory until midnight. Paired t -tests were conducted to compare responses between trials. Postprandial GLP-1 and PYY incremental area under the curve values were higher in the ACTIVE trial versus SIT in both Lean and OW groups (all, P < 0.05), but there was no difference in GIP in either group (both, P > 0.05). There were no differences in free-living physical activity (volume and intensity) or energy intake (total and macronutrients) between trials in either group (all, P > 0.05), resulting in greater total physical activity over the 24-h monitoring period in ACTIVE trial versus SIT trial (both, P < 0.05). Breaking up sitting increases postprandial GLP-1 and PYY concentrations in Asians, but does not induce subsequent behavioral compensation, resulting in greater 24-h physical activity levels and lower relative energy intake, in inactive individuals irrespective of bodyweight status.

Augmented gut hormone response to feeding in older adults exhibiting low appetite.

Age-related changes in gut hormones may play a role in anorexia of ageing. The aim of this study was to determine concentrations of ghrelin, PYY, and GLP-1 in older adults exhibiting an anorexia of ageing phenotype. Thirteen older adults with healthy appetite (OA-HA; 8f, 75 ± 7 years, 26.0 ± 3.2 kg m−2), fifteen older adults with low appetite (OA-LA; 10f, 72 ± 7 years, 23.6 ± 3.1 kg m−2), and twelve young adults (YA; 6f, 22 ± 2 years, 24.4 ± 2.0 kg m−2) completed the study. Healthy appetite and low appetite were determined based on BMI, habitual energy intake, self-reported appetite, and laboratory-assessed ad libitum lunch intake. Participants provided a fasted measure of subjective appetite and blood sample (0 min) before consuming a standardised breakfast (450 kcal). Appetite was measured and blood samples were drawn throughout a 240-min rest period. At 240 min, an ad libitum lunch meal was consumed. Relative intake at lunch (expressed as percentage of estimated total energy requirement) was lower for OA-LA (19.8 ± 7.7%) than YA (41.5 ± 9.2%, p < 0.001) and OA-HA (37.3 ± 10.0%, p < 0.001). Ghrelin suppression was greater for OA-LA (net AUC, −78719 ± 74788 pg mL−1·240min−1) than both YA (−23899 ± 27733 pg mL−1·240min−1, p = 0.016) and OA-HA (−21144 ± 31161 pg mL−1·240min−1, p = 0.009). There were trends for higher GLP-1 concentrations in OA-LA compared with YA at 90 min (8.85 ± 10.4 pM vs. 1.88 ± 4.63 pM, p = 0.073) and 180 min (5.00 ± 4.71 pM vs. 1.07 ± 2.83 pM, p = 0.065). There was a trend for a greater PYY response for OA-LA compared with OA-HA (net AUC p = 0.062). “Anorexigenic response score” – a composite score of gut hormone responses to feeding – showed greater anorexigenic response in OA-LA, compared with YA and OA-HA. No differences were seen in subjective appetite. These observations suggest augmented anorexigenic responses of gut hormones to feeding may be causal mechanisms of anorexia of ageing.

Impact of Gut–Brain Axis on Hepatobiliary Diseases in Fetal Programming

The hepatobiliary system is vital for the biotransformation and disposition of endogenous molecules. Any impairment in the normal functioning of the hepatobiliary system leads to a spectrum of hepatobiliary diseases (HBDs), such as liver cirrhosis, fatty liver, biliary dyskinesia, gallbladder cancer, etc. Especially in pregnancy, HBD may result in increased maternal and fetal morbidity and mortality. Maternal HBD is a burden to the fetus’s growth, complicates fetal development, and risks the mother’s life. In fetal programming, the maternal mechanism is significantly disturbed by multiple factors (especially diet) that influence the development of the fetus and increase the frequency of metabolic diseases later in life. Additionally, maternal under-nutrition or over-nutrition (especially in high-fat, high-carbohydrate, or protein-rich diets) lead to dysregulation in gut hormones (CCK, GLP-1, etc.), microbiota metabolite production (SCFA, LPS, TMA, etc.), neurotransmitters (POMC, NPY, etc.), and hepatobiliary signaling (insulin resistance, TNF-a, SREBPs, etc.), which significantly impact fetal programming. Recently, biotherapeutics have provided a new horizon for treating HBD during fetal programming to save the lives of the mother and fetus. This review focuses on how maternal impaired hepatobiliary metabolic signaling leads to disease transmission to the fetus mediated through the gut–brain axis.

Exploring the Gut-Brain Axis: A Comprehensive Review of Interactions Between the Gut Microbiota and the Central Nervous System

The gut-brain axis represents a complex network of interactions among the gut microbiota, the enteric nervous system (ENS), the autonomic nervous system (ANS), and the central nervous system (CNS), exerting profound influences on both digestive and mental health. Dysfunction within this axis has been implicated in a spectrum of disorders ranging from irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) to depression, anxiety, and neurodegenerative conditions. While early observations of the relationship between emotions and gastrointestinal function date back to the early 20th century, recent decades have witnessed significant strides in understanding this intricate interplay, fueled by advancements in molecular biology, microbiology, and neuroscience. Key milestones include the discovery of the enteric nervous system, elucidation of gut hormone functions, and recognition of the pivotal role played by gut microbiota in shaping brain function and behavior. The gut microbiota, comprising trillions of microorganisms residing within the gastrointestinal tract, actively contribute to gut-brain communication by producing an array of metabolites, neurotransmitters, and immune modulators. This communication pathway underscores the critical importance of comprehending the intricate interplay between gut microbiota and the central nervous system for devising innovative therapeutic interventions targeting a broad spectrum of psychiatric and neurological disorders. Furthermore, lifestyle factors such as diet, stress, and antibiotic usage wield significant influence over the composition and functionality of gut microbiota, thereby emphasizing the pivotal role of lifestyle interventions in fostering and preserving gut-brain health. This abstract encapsulates the current understanding of the gut-brain axis, highlighting its multifaceted implications for health and disease management, and underscores the pressing need for continued research to unlock its therapeutic potential.

Impact of chickpea hummus on postprandial blood glucose, insulin and gut hormones in healthy humans combined with mechanistic studies of food structure, rheology and digestion kinetics

Slowing the rate of carbohydrate digestion leads to low postprandial glucose and insulin responses, which are associated with reduced risk of type 2 diabetes. There is increasing evidence that food structure plays a crucial role in influencing the bioaccessibility and digestion kinetics of macronutrients. The aims of this study were to compare the effects of two hummus meals, with different degrees of cell wall integrity, on postprandial metabolic responses in relation to the microstructural and rheological characteristics of the meals. A randomised crossover trial in 15 healthy participants was designed to compare the acute effect of 27 g of starch, provided as hummus made from either intact chickpea cells (ICC) or ruptured chickpea cells (RCC), on postprandial metabolic responses. In vitro starch digestibility, microstructural and rheological experiments were also conducted to evaluate differences between the two chickpea hummus meals. Blood insulin and GIP concentrations were significantly lower (P < 0.02, P < 0.03) after the consumption of the ICC meal than the meal containing RCC. In vitro starch digestion for 90 min was slower in ICC than in RCC. Microscopic examination of hummus samples digested in vitro for 90 min revealed more intact chickpea cells in ICC compared to the RCC sample. Rheological experiments showed that fracture for ICC hummus samples occurred at smaller strains compared to RCC samples. However, the storage modulus for ICC was higher than RCC, which may be explained by the presence of intact cells in ICC. Food structure can affect the rate and extent of starch bioaccessibility and digestion and may explain the difference in the time course of metabolic responses between meals. The rheological properties were measured on the two types of meals before ingestion, showing significant differences that may point to different breakdown mechanisms during subsequent digestion.This trial was registered at clinicaltrial.gov as NCT03424187.

Testis–Gut-Reproduction Axis: The Key to Reproductive Health

Reproductive health is an important issue for humanity. In the context of the increasing incidence rate of male infertility, it is essential to find the factors that affect male reproductive health. Gastrointestinal health is closely related to reproductive health. Gastrointestinal hormones (GIH) and gut microbiota (GM), as important material foundations for gastrointestinal function, can promote or inhibit testicular reproductive function, including spermatogenesis, sperm maturation, androgen synthesis, and even broader male diseases such as sexual function, prostate cancer, etc. On the contrary, the functional health of the testes is also of great significance for the stability of gastrointestinal function. This review mainly discusses the important regulatory effects of GIH and GM on male reproductive function.

Food temperature altered macronutrients induced changes in satiety hormones; glucagon - like peptide -1 and cholecystokinin and their correlation with subjective satiety.

The benefits of dietary macronutrients for weight management depend on the integrity of gut hormones. The role of food temperature in the release of satiety hormones and satiety needs elucidation. We aimed to determine the impact of different food temperatures with varying macronutrient compositions on satiety-related gut hormones glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) and find the correlation of satiety hormones with appetite scores and remainder-day food (energy) intake. Thirteen healthy participants (eight males and five females) aged 25-35 years with body mass index 18.5-24.9 kg/m2 with no medical illnesses or eating disorders consumed three compositions of meals (high carbohydrate, high fat, and high protein meals) each at three temperatures (cold, warm, and hot) in a randomized, double-blinded, controlled crossover design. Plasma concentrations of peptide hormones were determined at 0, 30, and 240 minutes by enzyme-linked immunosorbent assay, and 24-hours food recall was used for remainder-day food intake (remainder energy). Data were analyzed using SPSS version 27.0. The change in plasma levels of gut hormones with time was assessed using Friedman test; Kruskal-Wallis test was employed to compare GLP-1 and CCK hormonal levels across nine meals. A comparison of the three meals at the three temperatures (total of nine groups), showed that the GLP-1 and CCK plasma concentrations were significantly different (P < 0.001). GLP-1 and CCK responses increased more after hot meals than cold meals. Overall, high-fat meals had more effective gut hormone secretions. The area under the curve was increased for GLP-1 in high-fat meals and for CCK in hot meals. The peptide hormones (GLP-1 and CCK) were positively correlated with satiety scores and inversely with remainder food intake. The temperature of food was found to be an effective stimulus for the regulation of CCK and GLP-1 secretion. Hot food temperature increased satiety hormones (CCK and GLP-1), independent of food macronutrient composition.

Polycystic Ovarian Syndrome: Effect of Hormones, Associated Comorbidities and Recent Advances in Therapy

This study addresses the prevalent endocrine disorder, Polycystic Ovarian Syndrome (PCOS), affecting women of reproductive age. The research aims to explore the epidemiology, etiology, genetic factors, transmission patterns, environmental influences, hormonal imbalances, and comorbidities associated with PCOS. The methodology involves a comprehensive review of literature, including studies on PCOS prevalence, diagnostic criteria, phenotype classification, neuroendocrine links, genetic markers, environmental and lifestyle factors, heavy metal exposure, oxidative stress, follicular ER stress, hormonal imbalances, gut hormones, and adipose tissue dysfunction in PCOS. Results point to PCOS having a multigenetic basis, being transmitted across generations, and being influenced by environmental variables. Hormonal imbalances, including androgen excess, insulin resistance, and dysregulation of gonadotropin hormones, are significant in PCOS pathophysiology. The study also discusses the impact of PCOS on infertility, psychological stress, thyroid dysfunction, insulin resistance, dyslipidemia, diabetes,and obesity. The implications of this research highlight the need for a comprehensive strategy to managing PCOS, considering genetic predispositions, environmental exposures, lifestyle modifications, and hormonal imbalances. It also discussed alternative therapies. such as yoga, tai chi, qigong, acupuncture, and Chinese herbal medicine, and discusses the current treatment options for PCOS, including meditative stress reduction, melatonin, and cryptotanshinone.

Comprehensive visualization of bariatric surgery and gut microbiota research: a global analysis

BackgroundIn recent years, there has been a noteworthy increase in research exploring the relationship between gut microbiota and bariatric surgery. This increase can be attributed to the growing recognition of the importance of gut microbiota in diverse health issues, such as obesity, and its alterations following bariatric surgery. Consequently, this study seeks to employ bibliometric analysis to show the current research landscape and identify key areas of focus for future investigations on the link between bariatric surgery and gut microbiota.MethodsWe conducted a comprehensive search of the Scopus database to gather literature concerning bariatric surgery and its impact on the gut microbiota. The search encompassed documents published between 2009 and 2023. To analyze the bibliometric data, we employed diverse metrics, including publication count, citation count, and evaluation of the performance of countries, institutions, and journals. Additionally, we utilized VOSviewer to visually present the findings.ResultsA total of 555 articles focused on the correlation between bariatric surgery and the gut microbiota. Original research articles constituted 55.32% of all publications on this topic, followed by reviews at 37.30%. The leading countries in terms of publication volume were the USA (n = 156; 28.11%), China (n = 73; 13.15%), and the UK (n = 52; 9.37%). Co-occurrence analysis highlighted three main clusters of research topics: (1) the impact of bariatric surgery on the gut microbiota composition in relation to obesity remission, (2) the relationship between glucose metabolism, circulating bile acids, gut hormones, and gut microbiome remodeling, and (3) the connections between alterations in the gut microbiota and insulin resistance.ConclusionsOngoing research has investigated the connection between bariatric surgery and the gut microbiota, providing new perspectives on metabolic improvements after surgery. Further studies are necessary to comprehensively grasp how bariatric procedures influence the gut microbiota and to formulate precise interventions aimed at optimizing the health advantages of surgery.

Endoscopic transoral outlet reduction induces enterohormonal changes in patients with weight regain after Roux-en-Y gastric bypass

Abstract Background and study aims Transoral outlet reduction (TORe) has long been employed in treating weight regain after Roux-en-Y gastric bypass. However, its impact on gut hormones and their relationship with weight loss remains unknown. Patients and methods This was a substudy of a previous randomized clinical trial. Adults with significant weight regain and dilated gastrojejunostomy underwent TORe with argon plasma coagulation (APC) alone or APC plus endoscopic suturing (APC-suture). Serum levels of ghrelin, GLP-1, and PYY were assessed at fasting, 30, 60, 90, and 120 minutes after a standardized liquid meal. Results were compared according to allocation group, clinical success, and history of cholecystectomy. Results Thirty-six patients (19 APC vs. 17 APC-suture) were enrolled. There were no significant baseline differences between groups. In all analyses, the typical postprandial decrease in ghrelin levels was delayed by 30 minutes, but no other changes were noted. GLP-1 levels significantly decreased at 12 months in both allocation groups. Similar findings were noted after dividing groups according to the history of cholecystectomy and clinical success. The APC cohort presented an increase in PYY levels at 90 minutes, while the APC-suture group did not. Naïve patients had significantly lower PYY levels at baseline (P = 0.01) compared with cholecystectomized individuals. This latter group experienced a significant increase in area under the curve (AUC) for PYY levels, while naïve patients did not, leading to a higher AUC at 12 months (P = 0.0001). Conclusions TORe interferes with the dynamics of gut hormones. APC triggers a more pronounced enteroendocrine response than APC-suture, especially in cholecystectomized patients.

Novel regulation of kidney function by gastrointestinal hormones

The control of whole-body energy metabolism involves intricate crosstalk between multiple organ systems including the gut and the brain that play well-recognized roles in this process. However, the important contributions and mechanisms by other organs are poorly understood. Errors in metabolic regulation can lead to human metabolic diseases including diabetes and obesity that affect 75% of the population and can lead to significant comorbidities. Improving our mechanistic understanding of multi-organ metabolic crosstalk in health and disease is essential for developing highly effcient and new therapeutic approaches. Macula densa (MD) cells in the kidney are chief regulators of renal blood flow and tissue remodeling. We hypothesized that the kidney is a major player in body metabolism via a new mechanism of gut-kidney crosstalk that involves the gut hormones gastrin and cholecystokinine (CCK) activating intrarenal, MD-specific mechanisms to increase blood flow and filtration, progenitor cells and tissue growth factors. High-resolution MD bulk and single-cell transcriptome analysis was performed from freshly isolated, enriched MD cells using MD-GFP mouse kidneys. Single cell MD Ca2+ signaling was analyzed in vivo using intravital multiphoton microscopy (MPM) of Sox2-GT mice that express the ratiometric Ca2+ reporter GCaMP6f/tdTomato in all renal cells. The altered expression of MD specific markers in response to gastrin/CCK8 stimuli was studied using western blot and the novel MDgeo immortalized cell line cultured in vitro. RNA sequencing and transcriptome analysis identified the gastrin/CCK receptor Cckbr as one of the highest expressed genes in MD versus control kidney cells. Intravital multiphoton imaging of Sox2-GCaMP6 reporter mouse kidneys revealed robust and entirely MD cell-specific calcium signaling in response to systemic gastrin/CCK injection. Using the novel MDgeo immortalized cell line cultured in vitro, CCK8 treatment led to 3-fold increases in MD cell synthesis of Prostaglandin E2 (PGE2)-generating COX2 and CCN1 that are established mediators of MD-induced glomerular hyperfiltration and tissue remodeling, respectively. Chronic treatment of Ren1d-Confetti mice with Darunavir, an HIV protease inhibitor significantly increased plasma CCK levels, Ren+ mesenchymal progenitor cell number and clonality, renal cell proliferation and tissue hypertrophy. This study uncovered new regulatory mechanisms of systemic metabolism especially the role of MD cells in the kidney. Repurposing the commonly used HIV drug Darunavir for kidney and metabolic diseases may provide therapeutic benefit for millions of patients worldwide. DK064234, DK123564, DK135290. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Fucoidan alleviates high sucrose-induced metabolic disorders and enhances intestinal homeostasis through modulation of Notch signaling

IntroductionThe therapeutic potential of fucoidan (FUC), a natural polysaccharide, in metabolic disorders is recognized, yet its underlying mechanisms remain unclear. MethodsWe conducted investigations into the therapeutic mechanisms of FUC sourced from Sargassum fulvellum concerning metabolic disorders induced by a high-sucrose diet (HSD), employing Drosophila melanogaster and mice models. Drosophila larvae were subjected to HSD exposure to monitor growth inhibition, reduced pupation, and developmental delays. Additionally, we examined the impact of FUC on growth- and development-related hormones in Drosophila. Furthermore, we assessed the modulation of larval intestinal homeostasis by FUC, focusing on the regulation of Notch signaling. In mice, we evaluated the effects of FUC on HSD-induced impairments in intestinal epithelial barrier integrity and gut hormone secretion. ResultsFUC supplementation significantly enhanced pupal weight in Drosophila larvae and effectively countered HSD-induced elevation of glucose and triglyceride levels. It notably influenced the expression of growth- and development-related hormones, particularly augmenting insulin-like peptides production while mitigating larval growth retardation. FUC also modulated larval intestinal homeostasis by negatively regulating Notch signaling, thereby protecting against HSD-induced metabolic stress. In mice, FUC ameliorated HSD-induced impairments in ileum epithelial barrier integrity and gut hormone secretion. ConclusionsOur findings demonstrate the multifaceted therapeutic effects of FUC in mitigating metabolic disorders and maintaining intestinal health. FUC holds promise as a therapeutic agent, with its effects attributed partly to the sulfate group and its ability to regulate Notch signaling, emphasizing its potential for addressing metabolic disorders.

Vagal nerve and sympathetic nerve activity in response to glucagon-like peptide-1 (GLP-1) receptor stimulation in conscious rats

GLP-1 (Glucagon-Like Peptide-1) is a type of gastrointestinal hormone that plays an integral role in regulating glucose homeostasis and appetite control. GLP-1 receptors are expressed throughout the body, and it has been suggested that GLP-1 can be detected by vagal afferent nerve activity, leading to changes in sympathetic nerve activity. However, the details of the effects of GLP-1 receptor stimulation on autonomic nerve activity have not been reported. Therefore, this study investigated the effects of different sites of GLP-1 receptor stimulation on autonomic nerve activity by administering GLP-1 receptor agonists via three routes: intravenous (IV), intraportal vein (iport), and intraperitoneal (iperi). Male Wistar rats were chronically implanted with electrodes, catheters for measuring cervical vagal activity, renal and lumbar sympathetic nerve activity, electroencephalogram, electromyogram, electrocardiogram, arterial pressure, sensors for tissue fluid glucose concentration, and catheters for drug administration in the vein, portal vein, and abdominal cavity. Exendin-4, a GLP-1 receptor agonist, was administered to conscious rats via one of the following routes: intravenous, intra-portal vein, or intra-abdominal. Cervical vagal activity was increased in all routes of Exendin-4 administration. Renal sympathetic nerve activity was rapidly decreased by Exendin-4 administration and gradually recovered to pre-administration levels. There were no significant differences in renal sympathetic nerve activity among the different routes of Exendin-4 administration. On the other hand, lumbar sympathetic nerve activity increased slowly after Exendin-4 administration through the iperi and iport routes, while it decreased initially, then gradually increased following administration through the IV route. These results demonstrate that stimulation of GLP-1 receptors by Exendin-4 increases vagal nerve activity, decreases renal sympathetic nerve activity, and produces regionally different responses in lumbar sympathetic nerve activity depending on the site of stimulation. JST (JPMJMS2023). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Multi-omics integrated analyses indicated that non-polysaccharides of Sijunzi decoction ameliorated spleen deficiency syndrome via regulating microbiota-gut-metabolites axis and exerted synergistic compatibility

Ethnopharmacological relevanceAs a classical traditional Chinese medicine formula to invigorating spleen and replenishing qi, Sijunzi decoction (SJZD) is composed of four herbs, which is applied to cure spleen deficiency syndrome (SDS) clinically. The non-polysaccharides (NPSs) of SJZD (SJZD_NPS) are important pharmacodynamic material basis. However, the amelioration mechanism of SJZD_NPS on SDS has not been fully elaborated. Additionally, the contribution of herbs compatibility to efficacy of this formula remains unclear. Aim of the studyThe aim was to explore the underlying mechanisms of SJZD_NPS on improving SDS, and uncover the scientific connotation in SJZD compatibility. Materials and methodsA strategy integrating incomplete formulae (called “Chai-fang” in Chinese) comparison, pharmacodynamics, gut microbiome, and metabolome was employed to reveal the role of each herb to SJZD compatibility against SDS. Additionally, the underlying mechanism harbored by SJZD_NPS was further explored through targeted metabolomics, network pharmacology, molecular docking, pseudo-sterile model, and metagenomics. ResultsSJZD_NPS significantly alleviated diarrhea, disordered secretion of gastrointestinal hormones and neurotransmitters, damage of ileal morphology and intestinal barrier in SDS rats, which was superior to the NPSs of Chai-fang. 16S rRNA gene sequencing and metabolomics analyses revealed that SJZD_NPS effectively restored the disturbed gut microbiota community and abnormal metabolism caused by SDS, showing the most evident recovery. Moreover, SJZD_NPS recalled the levels of partial amino acids, short chain fatty acids and bile acids, which possessed strong binding affinity towards potential targets. The depletion of gut microbiota confirmed that the SDS-amelioration efficacy of SJZD_NPS is dependent on the intact gut microbiome, with the relative abundance of potential probiotics such as Lactobacillus_johnsonii and Lactobacillus_taiwanensis been enriched. ConclusionNPSs in SJZD can improve SDS-induced gastrointestinal-nervous system dysfunction through regulating microbiota-gut-metabolites axis, with four herbs exerting synergistic effects, which indicated the compatibility rationality of SJZD.

Treatment Effects of Bifidobacterium Quadruple Viable Tablets Combined With Quadruple Therapy on Helicobacter Pylori-Infected Peptic Ulcer in Children.

This study aimed to investigate the treatment effects of Bifidobacterium quadruple viable tablets combined with quadruple therapy on Helicobacter pylori (Hp)-infected peptic ulcer in children. A total of 124 children with Hp-infected peptic ulcers were allocated into 2 treatment groups: control group (quadruple therapy) and observation group (quadruple therapy plus Bifidobacterium quadruple viable tablets). After treatment, the 2 groups were compared in terms of ulcer healing, serum inflammatory cytokines, Hp elimination, gastrointestinal hormones, and intestinal flora. After treatment, the children in the observation group possessed lower serum interleukin-6, tumor necrosis factor α, procalcitonin, C-reactive protein, gastrin, and motilin levels, and higher ulcer healing rate, Hp clearance rate, somatostatin levels and bifidobacterium and lactobacillus versus those in the control group. Bifidobacterium quadruple viable tablets combined with quadruple therapy has good efficacy in Hp-associated peptic ulcer disease.

Developing insulin-like peptide 5-based antagonists for the G protein-coupled receptor, RXFP4

Human insulin-like peptide 5 (INSL5) is a gut hormone produced by colonic L-cells, and its biological functions are mediated by Relaxin Family Peptide Receptor 4 (RXFP4). Our preliminary data indicated that RXFP4 agonists are potential drug leads for the treatment of constipation. More recently, we designed and developed a novel RXFP4 antagonist, A13-nR that was shown to block agonist-induced activity in cells and animal models. We showed that A13-nR was able to block agonist-induced increases in colon motility in mice of both genders that express the receptor, RXFP4. Our data also showed that colorectal propulsion induced by intracolonic administration of short-chain fatty acids was antagonized by A13-nR. Therefore, A13-nR is an important research tool and potential drug lead for the treatment of colon motility disorders, such as bacterial diarrhea. However, A13-nR acted as a partial agonist at high concentrations in vitro and demonstrated modest antagonist potency (∼35 nM). Consequently, the primary objective of this study is to pinpoint novel modifications to A13-nR that eliminate partial agonist effects while preserving or augmenting antagonist potency. In this work, we detail the creation of a series of A13-nR-modified analogues, among which analogues 3, 4, and 6 demonstrated significantly improved RXFP4 affinity (∼3 nM) with reduced partial agonist activity, enhanced antagonist potency (∼10 nM) and maximum agonist inhibition (∼80 %) when compared with A13-nR. These compounds have potential as candidates for further preclinical evaluations, marking a significant stride toward innovative therapeutics for colon motility disorders.

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis.

Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.

Adaptive thermogenesis, at the level of resting energy expenditure, after diet alone or diet plus bariatric surgery.

The objective of this study was to compare the magnitude of adaptive thermogenesis (AT), at the level of resting energy expenditure (REE), after a very low-energy diet alone or combined with Roux-en-Y gastric bypass or sleeve gastrectomy, as well as to investigate the association between AT and changes in appetite. A total of 44 participants with severe obesity underwent 10 weeks of a very low-energy diet alone or combined with Roux-en-Y gastric bypass or sleeve gastrectomy. Body weight and composition, REE, subjective appetite feelings, and plasma concentrations of gastrointestinal hormones were measured at baseline and week 11. AT, at the level of REE, was defined as a significantly lower measured versus predicted (using a regression model with baseline data) REE. Participants lost 18.4 ± 3.9 kg of body weight and experienced AT, at the level of REE (-121 ± 188 kcal/day; p < 0.001), with no differences among groups. The larger the AT, at the level of REE, the greater the reduction in fasting ghrelin concentrations and the smaller the reduction in feelings of hunger and desire to eat in the postprandial state. Weight-loss modality does not seem to modulate the magnitude of AT, at the level of REE. The greater the AT, at the level of REE, the greater the drive to eat following weight loss.