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Protective Role of Flavonoids Against Colonic Motor Dysfunctions Associated with High Fat Diet-Induced Obesity
stimulation (ES, 10 Hz, 0.5 msec, 30 mA). Nω-nitro-L-arginine methylester, alone or in combination with guanethidine, atropine, NK2 and NK3 receptor antagonists were used to record nitrergic and NK1 receptor-mediated tachykininergic motor responses. Results. When compared with SD mice, HFD animals displayed an increase in body and epididymal fat weight with alterations of blood metabolic indexes (Table 1). Colonic tissues from HFD mice showed also an increase in MDA, IL-1β and IL-6 levels versus SD mice (Table 1). Colonic LMS obtained from obese mice displayed an enhancement of electrically evoked nitrergic and tachykininergic responses (+48% and +126% vs SD mice, respectively). Dietary supplementation with luteolin, apigenin, and naringenin counteracted the increase of body and epididymal fat weight, as well as the alterations of metabolic indexes in HFD-fed mice (Table 1). In addition, flavonoids administration reduced MDA, IL-1β, IL-6 tissue levels in obese animals (Table 1). Luteolin, apigenin and naringenin treatment normalized the enhancement of colonic nitrergic and tachykininergic contractions. Of note, treatment with flavonoids did not induce significant changes in metabolic, inflammatory and functional parameters in SD-fed animals, in comparison with untreated mice. Conclusion. Diet-supplementation with luteolin, apigenin and naringenin prevented metabolic alterations associated with obesity. Moreover, flavonoids administration resulted in a reduction of intestinal inflammation and in counteract the colonic contractile dysfunctions associated with obesity. Table of the results
AGA Abstracts
Mo1942 TYPE 2 DIABETES RESOLUTION FOLLOWING ROUX-EN-Y GASTRIC BYPASS IS MORE STRONGLY ASSOCIATED WITH DUODENAL EXCLUSION THAN THE AMOUNT OF WEIGHT LOSS Pichamol Jirapinyo, Andrew C. Thompson, Paul T. Kroner, Walter W. Chan, Christopher C. Thompson Background: Roux-en-Y gastric bypass (RYGB) causes remission of type 2 DM (T2DM) in approximately 80% of patients. It is hypothesized that the exclusion of the duodenum and proximal jejunum from being exposed to nutrients may play an important role in improvement of T2DM after RYGB. Gastrogastric (GG) fistula is a unique complication after RYGB that allows nutrients to be reintroduced into the excluded duodenum and proximal jejunum. Aim: To determine if GG fistula, with loss of duodenal exclusion, is associated with failure to achieve long-term T2DM resolution after RYGB. Methods: Part I: A matched cohort study. 50 consecutive RYGB patients who developed GG fistula were matched to 50 RYGB patients without GG fistula. Inclusion criteria were presence of T2DM prior to RYGB defined as hemoglobin A1c (HbA1c) of ≥6.5 and being on at least 1 antihyperglycemic agent. Groups were matched based on age, sex, BMI, amount of weight regain at time of follow-up, and duration from RYGB at time of follow-up. Resolution of T2DM was defined as HbA1c <6.5 without any antihyperglycemic agent. Presence of GG fistula was confirmed on upper endoscopy or upper GI series. Primary outcome was failure to achieve long-term T2DM resolution defined as persistence of T2DM or recurrence of T2DM after initial resolution. Part II: Multivariate logistic regression was used to identify predictors of failure to achieve long-term T2DM resolution after RYGB. Proportions were compared using McNemar's test. Power analysis was conducted using an alpha of 0.05, a power of 0.85, which resulted in the desired sample size of 50 for each arm. Results: Part I: Clinical characteristics of the 2 matched groups are shown in Table 1. All patients had T2DM prior to RYGB. Out of 100 patients, 47% failed to achieve long-term T2DM resolution. Patients who developed GG fistula had a significantly higher rate of failed long-term T2DM resolution (58%) compared to those who did not have a GG fistula (36%, OR of 2.6, p=0.028), who had similar age, sex, BMI, amount of weight regain and time duration from RYGB. Part II: On a multivariate logistic regression, presence of GG fistula and history of insulin use prior to RYGB were significant predictors of failure to achieve long-term T2DM resolution (OR of 3.36, p=0.04 and OR of 16.61, p=0.0007, respectively). BMI, amount of weight regain and time duration from RYGB were not associated with failure to achieve T2DM resolution. Conclusion: RYGB patients who develop GG fistula are more likely to fail to achieve long-term T2DM resolution compared to those without GG fistula who have similar BMI and weight regain. This suggests that the metabolic effect of duodenal exclusion is more important than weight loss alone in achieving glycemic control following RYGB and substantiates mechanisms of action for endoscopic devices focusing on duodenal exclusion. Table 1. Clinical characteristics
aP < 0.05, cP < 0.001 versus SD *P < 0.05, $P < 0.01, #P < 0.001 versus HFD
Mo1944 ROLE OF GUT-ADIPOSE-MUSCLE AXIS IN BENEFICIAL EFFECT OF VOLUNTARY EXERCISE ON EXPERIMENTAL COLITIS IN MICE FED A DIET-INDUCED OBESITY. INVOLVEMENT OF PROTECTIVE IRISIN AND PROINFLAMMATORY BIOMARKERS RELEASED FROM MESENTERIC FAT AND COLONIC MUCOSA Jan Bilski, Agnieszka Mazur-Bialy, Magdalena Hubalewska-Mazgaj, Bartosz Brzozowski, Marcin Surmiak, Dagmara Wojcik, Marcin Magierowski, Anna Chmura, Katarzyna Magierowska, Tomasz Brzozowski
Table 2. Multivariable logistic regression of predictors of failure to achieve T2DM resolution following RYGB
Inflammatory bowel diseases (IBDs) are a heterogeneous group of disorders exhibited by two major phenotypic forms, Crohn's disease and ulcerative colitis. Although etiology of IBD is unknown, several factors from adipose tissue and skeletal muscles such as adipokines, cytokines, and myokines were implicated in the pathogenesis of these disorders. Among therapeutic options, exercise was proposed as one of the most important lifestyle practices to adopt as treatment options for IBD but mechanism of voluntary endurance training in amelioration of IBD has not been extensively studied. We determined whether diet-induced obesity (DIO) augments the severity of experimental colitis in C57 mice and whether moderate exercise can affect the disease activity index (DAI), the colonic blood flow (CBF) and the plasma irisin, adiponectin and expression of proinflammatory cytokines HIF-1α, TNF-α, leptin, IL-6, MCP-1, IL-13, IL-17, IL-1α, IL-12, keratinocyte chemoattractant (KC) in DIO mice with colitis. Mice were randomized into two series A and B and fed with 70% fat diet (cholesterol up to 70%, Altromin, Lage, Germany) and with normal standard diet (SD), respectively, and subjected to the voluntary wheel running to assess the effect of moderate physical activity on the healing of TNBS colitis. The macroscopic and microscopic colitis in sedentary SD mice was accompanied by the significant fall in the CBF, an increase in colonic tissue weight and WAT levels of TNF-α, IL-6, MCP-1 and IL-13 (p<0.05). In sedentary DIO mice, the colonic lesions, the colonic tissue weight, the white adipose tissue (WAT) and mesenteric fat weights were aggravated and the plasma TNF-α, IL-6, MCP-1, IL-17, IL-1α, KC, IL-12, IL-1β and leptin levels were significantly increased (p<0.05) but a significant decrease in plasma irisin and adiponectin levels (p<0.05) were observed comparing to sedentary SD ones. Exercise of DIO mice significantly decreased the macro- and microscopic severity of TNBS-induced colonic damage, significantly increased the CBF and attenuated the rise in plasma TNF-α, IL-6, MCP-1 and IL-1β levels (p<0.05). The WAT and plasma concentration of adiponectin was significantly decreased but leptin concentration was increased being reduced in DIO mice subjected to exercise. We conclude that 1) the experimental colitis is exacerbated in obese mice possibly due to fall in colonic microcirculation and an increase in proinflammatory biomarkers such as TNF-α, IL-6, MCP-1 and HIF1α in WAT and circulation; 2) voluntary physical activity can diminish of the severity of colonic damage in DIO mice mediated skeletal release of myokines such as protective irisin; 3) regular voluntary exercise may exert a beneficial effect in IBD by affecting abdominal adiposity due to restoration of protective adiponectin and anti-inflammatory activity involving the activation of gut-adipose-muscle axis.
Mo1943 PROTECTIVE ROLE OF FLAVONOIDS AGAINST COLONIC MOTOR DYSFUNCTIONS ASSOCIATED WITH HIGH FAT DIET-INDUCED OBESITY Daniela Gentile, Matteo Fornai, Rocchina Colucci, Carolina Pellegrini, Erika Tirotta, Laura Benvenuti, Cristina Segnani, Chiara Ippolito, Emiliano Duranti, Sara Carpi, Paola Nieri, Agostino Virdis, Laura Pistelli, Nunzia Bernardini, Corrado Blandizzi, Luca Antonioli Introduction. Obesity is a chronic disease characterized by low-grade systemic inflammation and by alteration in gastrointestinal motility. Recently, the beneficial effects of flavonoids in the prevention of some comorbidities associated with obesity have been reported. However, their putative effects in counteracting the enteric functional disorders related to obesity have not been investigated. This study examines the effect of dietary supplementation with luteolin, apigenin and naringenin on colonic motor and inflammatory abnormalities in a mouse model of diet-induced obesity. Methods. C57BL/6 mice (n=5/group) were fed with standard diet (SD, 18% calories from fat) or a high-fat diet (HFD, 60% calories from fat) for 8 weeks. Subgroups of mice on SD or HFD were treated for 8 weeks with luteolin (10 mg/Kg/die), apigenin (10 mg/Kg/die) and naringenin (10 mg/Kg/die). At the end of the treatments, body and epididymal fat weight, as well as blood cholesterol, triglycerides and glucose levels were evaluated. Malondialdehyde (MDA), IL-1β and IL-6 levels in colonic tissue were also examined. Colonic longitudinal muscle strips (LMS) were set up in organ baths with Krebs solution and connected to isometric transducers to record contractions elicited by electrical
AGA Abstracts
S-828
AGA Abstracts
Mo1942 TYPE 2 DIABETES RESOLUTION FOLLOWING ROUX-EN-Y GASTRIC BYPASS IS MORE STRONGLY ASSOCIATED WITH DUODENAL EXCLUSION THAN THE AMOUNT OF WEIGHT LOSS Pichamol Jirapinyo, Andrew C. Thompson, Paul T. Kroner, Walter W. Chan, Christopher C. Thompson Background: Roux-en-Y gastric bypass (RYGB) causes remission of type 2 DM (T2DM) in approximately 80% of patients. It is hypothesized that the exclusion of the duodenum and proximal jejunum from being exposed to nutrients may play an important role in improvement of T2DM after RYGB. Gastrogastric (GG) fistula is a unique complication after RYGB that allows nutrients to be reintroduced into the excluded duodenum and proximal jejunum. Aim: To determine if GG fistula, with loss of duodenal exclusion, is associated with failure to achieve long-term T2DM resolution after RYGB. Methods: Part I: A matched cohort study. 50 consecutive RYGB patients who developed GG fistula were matched to 50 RYGB patients without GG fistula. Inclusion criteria were presence of T2DM prior to RYGB defined as hemoglobin A1c (HbA1c) of ≥6.5 and being on at least 1 antihyperglycemic agent. Groups were matched based on age, sex, BMI, amount of weight regain at time of follow-up, and duration from RYGB at time of follow-up. Resolution of T2DM was defined as HbA1c <6.5 without any antihyperglycemic agent. Presence of GG fistula was confirmed on upper endoscopy or upper GI series. Primary outcome was failure to achieve long-term T2DM resolution defined as persistence of T2DM or recurrence of T2DM after initial resolution. Part II: Multivariate logistic regression was used to identify predictors of failure to achieve long-term T2DM resolution after RYGB. Proportions were compared using McNemar's test. Power analysis was conducted using an alpha of 0.05, a power of 0.85, which resulted in the desired sample size of 50 for each arm. Results: Part I: Clinical characteristics of the 2 matched groups are shown in Table 1. All patients had T2DM prior to RYGB. Out of 100 patients, 47% failed to achieve long-term T2DM resolution. Patients who developed GG fistula had a significantly higher rate of failed long-term T2DM resolution (58%) compared to those who did not have a GG fistula (36%, OR of 2.6, p=0.028), who had similar age, sex, BMI, amount of weight regain and time duration from RYGB. Part II: On a multivariate logistic regression, presence of GG fistula and history of insulin use prior to RYGB were significant predictors of failure to achieve long-term T2DM resolution (OR of 3.36, p=0.04 and OR of 16.61, p=0.0007, respectively). BMI, amount of weight regain and time duration from RYGB were not associated with failure to achieve T2DM resolution. Conclusion: RYGB patients who develop GG fistula are more likely to fail to achieve long-term T2DM resolution compared to those without GG fistula who have similar BMI and weight regain. This suggests that the metabolic effect of duodenal exclusion is more important than weight loss alone in achieving glycemic control following RYGB and substantiates mechanisms of action for endoscopic devices focusing on duodenal exclusion. Table 1. Clinical characteristics
aP < 0.05, cP < 0.001 versus SD *P < 0.05, $P < 0.01, #P < 0.001 versus HFD
Mo1944 ROLE OF GUT-ADIPOSE-MUSCLE AXIS IN BENEFICIAL EFFECT OF VOLUNTARY EXERCISE ON EXPERIMENTAL COLITIS IN MICE FED A DIET-INDUCED OBESITY. INVOLVEMENT OF PROTECTIVE IRISIN AND PROINFLAMMATORY BIOMARKERS RELEASED FROM MESENTERIC FAT AND COLONIC MUCOSA Jan Bilski, Agnieszka Mazur-Bialy, Magdalena Hubalewska-Mazgaj, Bartosz Brzozowski, Marcin Surmiak, Dagmara Wojcik, Marcin Magierowski, Anna Chmura, Katarzyna Magierowska, Tomasz Brzozowski
Table 2. Multivariable logistic regression of predictors of failure to achieve T2DM resolution following RYGB
Inflammatory bowel diseases (IBDs) are a heterogeneous group of disorders exhibited by two major phenotypic forms, Crohn's disease and ulcerative colitis. Although etiology of IBD is unknown, several factors from adipose tissue and skeletal muscles such as adipokines, cytokines, and myokines were implicated in the pathogenesis of these disorders. Among therapeutic options, exercise was proposed as one of the most important lifestyle practices to adopt as treatment options for IBD but mechanism of voluntary endurance training in amelioration of IBD has not been extensively studied. We determined whether diet-induced obesity (DIO) augments the severity of experimental colitis in C57 mice and whether moderate exercise can affect the disease activity index (DAI), the colonic blood flow (CBF) and the plasma irisin, adiponectin and expression of proinflammatory cytokines HIF-1α, TNF-α, leptin, IL-6, MCP-1, IL-13, IL-17, IL-1α, IL-12, keratinocyte chemoattractant (KC) in DIO mice with colitis. Mice were randomized into two series A and B and fed with 70% fat diet (cholesterol up to 70%, Altromin, Lage, Germany) and with normal standard diet (SD), respectively, and subjected to the voluntary wheel running to assess the effect of moderate physical activity on the healing of TNBS colitis. The macroscopic and microscopic colitis in sedentary SD mice was accompanied by the significant fall in the CBF, an increase in colonic tissue weight and WAT levels of TNF-α, IL-6, MCP-1 and IL-13 (p<0.05). In sedentary DIO mice, the colonic lesions, the colonic tissue weight, the white adipose tissue (WAT) and mesenteric fat weights were aggravated and the plasma TNF-α, IL-6, MCP-1, IL-17, IL-1α, KC, IL-12, IL-1β and leptin levels were significantly increased (p<0.05) but a significant decrease in plasma irisin and adiponectin levels (p<0.05) were observed comparing to sedentary SD ones. Exercise of DIO mice significantly decreased the macro- and microscopic severity of TNBS-induced colonic damage, significantly increased the CBF and attenuated the rise in plasma TNF-α, IL-6, MCP-1 and IL-1β levels (p<0.05). The WAT and plasma concentration of adiponectin was significantly decreased but leptin concentration was increased being reduced in DIO mice subjected to exercise. We conclude that 1) the experimental colitis is exacerbated in obese mice possibly due to fall in colonic microcirculation and an increase in proinflammatory biomarkers such as TNF-α, IL-6, MCP-1 and HIF1α in WAT and circulation; 2) voluntary physical activity can diminish of the severity of colonic damage in DIO mice mediated skeletal release of myokines such as protective irisin; 3) regular voluntary exercise may exert a beneficial effect in IBD by affecting abdominal adiposity due to restoration of protective adiponectin and anti-inflammatory activity involving the activation of gut-adipose-muscle axis.
Mo1943 PROTECTIVE ROLE OF FLAVONOIDS AGAINST COLONIC MOTOR DYSFUNCTIONS ASSOCIATED WITH HIGH FAT DIET-INDUCED OBESITY Daniela Gentile, Matteo Fornai, Rocchina Colucci, Carolina Pellegrini, Erika Tirotta, Laura Benvenuti, Cristina Segnani, Chiara Ippolito, Emiliano Duranti, Sara Carpi, Paola Nieri, Agostino Virdis, Laura Pistelli, Nunzia Bernardini, Corrado Blandizzi, Luca Antonioli Introduction. Obesity is a chronic disease characterized by low-grade systemic inflammation and by alteration in gastrointestinal motility. Recently, the beneficial effects of flavonoids in the prevention of some comorbidities associated with obesity have been reported. However, their putative effects in counteracting the enteric functional disorders related to obesity have not been investigated. This study examines the effect of dietary supplementation with luteolin, apigenin and naringenin on colonic motor and inflammatory abnormalities in a mouse model of diet-induced obesity. Methods. C57BL/6 mice (n=5/group) were fed with standard diet (SD, 18% calories from fat) or a high-fat diet (HFD, 60% calories from fat) for 8 weeks. Subgroups of mice on SD or HFD were treated for 8 weeks with luteolin (10 mg/Kg/die), apigenin (10 mg/Kg/die) and naringenin (10 mg/Kg/die). At the end of the treatments, body and epididymal fat weight, as well as blood cholesterol, triglycerides and glucose levels were evaluated. Malondialdehyde (MDA), IL-1β and IL-6 levels in colonic tissue were also examined. Colonic longitudinal muscle strips (LMS) were set up in organ baths with Krebs solution and connected to isometric transducers to record contractions elicited by electrical
AGA Abstracts
S-828