Efeito do jejum agudo no período ativo sobre os peptídeos gastrointestinais em mulheres eutróficas e com obesidade / Effect of acute fasting in the active period on gastrointestinal peptides in women eutrophic and with obesity

A prática do jejum tem mostrado resultados benéficos no que diz respeito aos parâmetros metabólicos e perda de peso. Essa prática tem sido frequentemente realizada ao longo do dia, durante as atividades de vida diária dos indivíduos. Dentre os efeitos do jejum sobre o metabolismo intermediário, destaca-se seu potencial em modular a secreção de peptídeos gastrointestinais relacionados ao controle da fome e regulação metabólica. Por outro lado, é desconhecido os efeitos do jejum agudo durante as atividades de vida diária, diferentemente do realizado durante a noite, e ainda se indivíduos eutróficos e com obesidade respondem da mesma forma. Objetivo: Investigar o efeito do jejum agudo realizado durante o período ativo sobre os peptídeos gastrointestinais em mulheres eutróficas e com obesidade. Métodos: Trata-se de ensaio clínico não randomizado, estratificado por estado nutricional em dois grupos de acordo com o Índice de Massa Corporal (IMC): (i) grupo eutrófico (IMC > 18,5 kg/m² e < 24,9 kg/m²) e (ii) grupo obesidade (IMC > 35 kg/m²). A amostra foi composta por mulheres adultas, com idade entre 18 a 60 anos. A avaliação inicial foi realizada no período da manhã, após 10h de jejum noturno, em que as seguintes medidas foram aferidas e os dados pessoais foram coletados: antropometria, calorimetria indireta e composição corporal. As participantes foram submetidas à coleta de 5 mL de sangue, para análise dos peptídeos gastrointestinais (GIP, GLP-1, PP, PYY e grelina), adiponectina, insulina (glicose e índices HOMA). Em seguida, foi ofertado desjejum padronizado com valor calórico correspondente a 20% da necessidade energética estimada calculada após a coleta dos dados iniciais. Após, as voluntárias foram dispensadas para realização das atividades diárias habituais e foi orientado a manutenção do jejum por 10h ao longo do dia. As voluntárias retornaram ao final do dia para repetição dos procedimentos realizados na primeira avaliação e coleta de sangue. As análises estatísticas foram efetuadas com o auxílio dos programas Statistical Package for the Social Sciences for Windows Student Version® (SPSS) versão 20.0 e os gráficos foram criados por meio do programa GraphPad Prism versão 8.0.1, adotando-se nível de significância de 5%. Resultados: 54 mulheres foram incluídas no estudo, sendo 29 no grupo eutrófico e 25 no grupo com obesidade. O jejum no período ativo promoveu redução nas concentrações de insulina e adiponectina e nos índices HOMA-IR e HOMA-BETA, além de aumento no polipeptídeo pancreático (PP) circulante, tanto nas mulheres eutróficas como nas mulheres com obesidade. Somente o grupo com obesidade teve redução na leptina e aumento no peptídeo-1 semelhante ao glucagon (GLP-1) após o jejum diurno. Entre os grupos, eutrofia versus obesidade, as concentrações de leptina e insulina foram maiores no grupo obesidade após o jejum no período ativo. Já os peptídeos GIP, grelina e peptídeo YY (PYY) não tiveram mudanças após o jejum no período ativo quando comparados ao jejum noturno. Conclusão: O jejum durante as atividades diárias diminui os hormônios anorexígenos insulina e leptina. No entanto, também aumenta o PP e o GLP-1, especialmente em mulheres com obesidade. O jejum durante as atividades diárias pode reorganizar uma intrincada rede de sinais endócrinos que de alguma forma podem modular o comportamento alimentar homeostático e hedônico.

Fasting practice has shown beneficial results concerning metabolic parameters and weight loss. This practice is often performed throughout the day during individuals daily life activities. Among the effects of fasting on intermediary metabolism, its potential to modulate the secretion of gastrointestinal peptides related to hunger control and metabolic regulation stands out. On the other hand, the effects of acute fasting during daily activities, unlike fasting during the night, and whether eutrophic and individuals with obesity respond in the same way are unknown. Objective: To investigate the effect of acute fasting during the active period on gastrointestinal peptides in eutrophic women and with obesity. Methods: This was a non-randomized clinical trial, stratified by nutritional status into two groups according to Body Mass Index (BMI): (i) eutrophic group (BMI > 18.5 kg/m² and < 24.9 kg/m²) and (ii) group with obesity (BMI > 35 kg/m²). The sample consisted of adult women aged 18 to 60 years. The initial evaluation was conducted in the morning after a 10-hour overnight fasting, during which the following measurements were taken, and personal data were collected: anthropometry, indirect calorimetry, and body composition. Participants had 5 mL of blood collected for the analysis of gastrointestinal peptides (GIP, GLP-1, PP, PYY, and ghrelin), adiponectin, insulin (glucose and HOMA indices). Then, a standardized breakfast with a caloric value corresponding to 20% of the estimated energy needs calculated after the initial data collection was provided. Afterward, the participants were released to perform their usual daily activities and were instructed to maintain fasting for 10 hours throughout the day. Participants returned at the end of the day for the repetition of the procedures performed in the initial assessment and blood collection. Statistical analyses were performed using the Statistical Package for the Social Sciences for Windows Student Version® (SPSS) version 20.0, and the graphs were created using the GraphPad Prism version 8.0.1 program, adopting a significance level of 5%. Results: 54 women were included in the study, with 29 in the eutrophic group and 25 in the group with obesity. Fasting during the active period led to a reduction in insulin and adiponectin concentrations and in HOMA-IR and HOMA-BETA indices, as well as an increase in circulating pancreatic polypeptide (PP), both in eutrophic women and with obesity. Only the group with obesity experienced a reduction in leptin and an increase in glucagon-like peptide-1 (GLP-1) after daytime fasting. Between the eutrophic group and with obesity, leptin and insulin concentrations were higher in the group with obesity after fasting during the active period. GIP, ghrelin, and peptide YY (PYY) did not show changes after fasting during the active period when compared to overnight fasting. Conclusion: Fasting during daily activities reduces anorexigenic hormones insulin and leptin. However, it also increases PP and GLP-1, especially in women with obesity. Fasting during daily activities may reorganize a complex network of endocrine signals that can somehow modulate homeostatic and hedonic eating behavior.

Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus

BACKGROUND: The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated. OBJECTIVE: To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome. MATERIALS/METHODS: Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the DDCT method, and b-actin was used as an endogenous control. RESULTS: The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02). CONCLUSION: The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical hyperplasia. New prospective studies will be able to clarify the exact role of the glucose-dependent insulinotropic peptide receptor in the molecular pathogenesis of MEN1 adrenocortical lesions.

Motilin receptor expression in the interstitial cells of Cajal / 中华儿科杂志

<p><b>OBJECTIVE</b>To look for the evidences of motilin receptor expression on interstitial cells of Cajal (ICC) of the rabbit.</p><p><b>METHOD</b>Smooth muscle segments with ICC were isolated from the small intestine of 10-day old rabbits. The tissue segments equilibrated in Ca(2+)-free Hanks' solution were dispersed with an enzyme solution containing collagenase type II and then Ficoll density centrifugation was used to dissociate ICC. The cells were suspended and cultured in the M199 medium. The c-kit antibody was applied to distinguish the cultured ICC. The motilin receptor was identified by immunocytochemical assay with GPR38 antibody, c-kit antibody and hoechst 33342 combined to label ICC. Cells cultured for a few days were sorted for ICC with c-kit stained green fluorescent through flow cytometry. The total RNA and proteins extracted from the sorted ICC were respectively used to verify motilin receptor on the ICC by reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blotting.</p><p><b>RESULT</b>We had successfully dissociated and cultured ICC of rabbit small intestine in vitro. Fluorescent staining with c-kit antibody confirmed that the culture ICC was successful. Triple-labeled immunofluorescent staining had detected the motilin receptor on membrane of ICC. Flow cytometry analysis showed that the ratio of c-kit positive cell in the cultured cells was 64.3%. The number of sorted ICC was 6.7 × 10(5) and 5.6 × 10(6). The results of RT-PCR and Western blot confirmed that the ICC had motilin receptor expression.</p><p><b>CONCLUSION</b>Our study demonstrated presence of motilin receptor on ICC of the rabbit. The present results may suggest that ICC play an important role in gastrointestinal movement induced by motilin.</p>

Effect of interstitial cells of Cajal on gastrointestinal motility induced by motilin receptor agonist ABT-229 / 中华儿科杂志

<p><b>OBJECTIVE</b>To investigate the effect of interstitial cells of Cajal (ICC) on contraction of intestinal tract smooth muscle induced by motilin receptor agonist.</p><p><b>METHODS</b>Two kinds of smooth muscle segments were isolated from the duodenum and colon of rabbit. Both kinds of smooth muscle were divided into two groups: group a (normal ICC group of duodenum); group c (impaired ICC group of duodenum); group b (normal ICC group of colon); group d (impaired ICC group of colon), each group contained 20 segments. The impairment of ICC was induced by selectively destroying ICC in the smooth muscle via treatment with methylene blue plus light. Then the frequency and amplitude of contraction of group a and c, group b and d was compared. Then motilin receptor agonist (ABT-229) was added into the Krebs solution, the frequency and amplitude of smooth muscle contraction before and after adding ABT-229 were recorded and compared.</p><p><b>RESULTS</b>The electron microscopy demonstrated that ICC in methylene blue plus light group were destroyed; the smooth muscle cells and neuron scattered close to ICC were normal. In group a, the contraction frequency, (17.89 +/- 1.88) times/min, was significantly lower as compared with that measured after ABT-229 was added [(18.76 +/- 1.18) times/min (P > 0.05)]; the amplitude of group a was (343 +/- 28) mg, which was lower as compared with that after adding ABT-229 [(597 +/- 68) mg (P < 0.001)]; in group b, the frequency was (5.89 +/- 1.03) times/min, the amplitude was (724 +/- 85) mg, after ABT-229 was added, the construction frequency increased to (8.45 +/- 0.69) times/min (P < 0.001), and the amplitude was (897 +/- 89) mg (P < 0.05), which was not affected by pretreatment with TTX, however it could be weakened by nifedipine significantly. In group c and d, the rhythmic contraction almost disappeared: in group c the contraction frequency was (1.06 +/- 0.24) times/min, and the amplitude were (50 +/- 10) mg. In group d, the amplitude and frequency significantly decreased as compared with the normal group (P < 0.001), in group c, and d, no significant difference in amplitude and frequency was found between the values measured before and after adding ABT-229 (P > 0.05). After Ach (100 micromol/L) was added, both group c and d could generate contraction.</p><p><b>CONCLUSION</b>ICC may play an important role in the rhythmic contraction of intestinal tract. The promoting effect of motilin receptor agonist on intestinal tract may be mediated by ICC. ICC deficiency may cause functional impairment of gastrointestinal tract motivation. The medication may become ineffective when the number of ICC is reduced to a certain extent or the network of ICC is incomplete.</p>

Analysis of glucose-dependent insulinotropic peptide receptor (GIPR) and luteinizing hormone receptor (LHCGR) expression in human adrenocortical hyperplasia / Análise da expressão dos receptores do peptídeo insulinotrópico dependente de glicose (GIPR) e do hormônio luteinizante (LHCGR) nas hiperplasias adrenocorticais humanas

OBJECTIVE: To analyze the aberrant expression of the GIPR and LHCGR in different forms of adrenocortical hyperplasia: ACTH-independent macronodular adrenal hyperplasia (AIMAH), primary pigmented nodular adrenocortical disease (PPNAD) and diffuse adrenal hyperplasia secondary to Cushing's disease (DAHCD). METHODS: We quantified GIPR and LHCGR expressions using real time PCR in 20 patients with adrenocortical hyperplasia (seven with AIMAH, five with PPNAD, and eight with DAHCD). Normal adrenals tissues were used as control and the relative expression was compared with β-actin. RESULTS: GIPR and LHCGR expressions were demonstrated in all tissues studied. Median GIPR and LHCGR mRNA levels were 1.6; 0.4; 0.5 and 1.3; 0.9; 1.0 in adrenocortical tissues from AIMAH, PPNAD and DAHCD respectively. There were no differences between GIPR and LHCGR expressions in all tissues studied. CONCLUSIONS: GIPR and LHCGR overexpression were not identified in the studied cases, thus suggesting that this molecular mechanism is not involved in adrenocortical hyperplasia in our patients.

OBJETIVO: Analisar a expressão aberrante do GIPR e do LHCGR em diferentes formas de hiperplasias adrenocorticais: hiperplasia adrenal macronodular independente de ACTH (AIMAH), doença adrenocortical nodular pigmentada primária (PPNAD) e hiperplasia adrenal difusa secundária à doença de Cushing (DAHCD). MÉTODOS: Quantificou-se por PCR em tempo real a expressão desses receptores em 20 pacientes: sete com AIMAH, cinco com PPNAD e oito com DAHCD. Adrenais normais foram utilizadas como controle e a expressão relativa desses receptores foi comparada à expressão da β-actina. RESULTADOS: A expressão desses receptores foi demonstrada em todos os tecidos estudados. A mediana da expressão do GIPR e do LHCGR foi de 1,6; 0,4; 0,5 e de 1,3; 0,9; 1,0 nos tecidos dos pacientes com AIMAH, PPNAD e DAHCD, respectivamente. Não houve diferença significativa na expressão desses receptores nos tecidos estudados. CONCLUSÕES: Hiperexpressão do GIPR e do LHCGR não foi observada, sugerindo que esse mecanismo não está envolvido na patogênese molecular da hiperplasia adrenal nesses pacientes.

Cushing's syndrome secondary to ACTH-Independent macronodular adrenal hyperplasia

ACTH-Independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's syndrome (CS), in which clinical features usually become apparent only after several decades of life. This form of adrenal hyperplasia typically produces excess cortisol with overt or subclinical CS, but concurrent secretion of mineralocorticoids or sexual steroids can also occur. The diagnosis is suspected by bilateral adrenal nodules larger than 1 cm on incidental imaging studies or following the demonstration of ACTH-independent hormonal hypersecretion. The pathophysiology of this entity is heterogeneous and has been intensely explored in recent years. Several G-protein coupled receptors aberrantly expressed in the adrenal cortex have been implicated in the regulation of steroidogenesis and in the initial cell proliferation in AIMAH. Several familial cases of AIMAH have been recently described with the same pattern of aberrant hormone receptors in all affected members of the family. It is probable that additional somatic genetic events related to cell cycle regulation, adhesion and transcription factors occur in addition over time in the various nodules; other mechanisms, as Gsp or ACTH receptor mutations and paracrine adrenal hormonal secretion have been rarely identified as the molecular mechanism in some cases. When systematically screened, most patients with AIMAH exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. The identification of these receptors creates the possibility of a specific pharmacological treatment isolated or associated with adrenalectomy.

A hiperplasia adrenal macronodular independente de ACTH (AIMAH) é uma causa rara de síndrome de Cushing (SC) endógena, na qual alguns aspectos clínicos só se tornam evidentes depois de várias décadas de vida. Esta forma de hiperplasia adrenal caracteristicamente produz excesso de cortisol resultando na síndrome de Cushing franca ou subclínica, embora a secreção concomitante de mineralocorticóide, estrógeno e andrógenos também possa ocorrer. A suspeita diagnóstica é feita pela presença de nódulos adrenais bilaterais maiores que 1 cm, como achado incidental em exames de imagem ou pela demonstração de hipersecreção hormonal independente de ACTH. A fisiopatologia desta doença é heterogênea e tem sido intensamente estudada nos últimos anos. Vários receptores acoplados à proteína G, com expressão aberrante no córtex adrenal, têm sido implicados na regulação da esteroidogênese e no início da proliferação celular que ocorre na AIMAH. Diversos casos familiais de AIMAH foram recentemente descritos, e um mesmo padrão de expressão anormal dos receptores aberrantes foi observado em todos os membros afetados das famílias investigadas. Ao longo do tempo, é provável que ocorram, nos nódulos, eventos genéticos adicionais relacionados à regulação do ciclo celular, adesão e fatores de transcrição. Outros mecanismos moleculares, como mutações nos genes da proteína Gsa e do receptor de ACTH, ou secreção hormonal parácrina na adrenal, têm sido raramente identificados em alguns casos. A maioria dos pacientes com AIMAH, quando sistematicamente investigados, desenvolve uma produção anormal de cortisol em resposta a vários ligantes, sugerindo a presença de receptores adrenais aberrantes. A identificação destes receptores cria a possibilidade para um tratamento farmacológico específico isolado ou associado à adrenalectomia.

Expression of motilin in the hypothalamus and the effect of central erythromycin on gastric motility in diabetic rats / 神经科学通报·英文版

<p><b>OBJECTIVE</b>To investigate the expression of motilin-immunoreactive neurons in the hypothalamus and the effect of central administration of erythromycin (EM) on the regulation of gastric motility in diabetic rats.</p><p><b>METHODS</b>The motilin immunoreactive neurons in the hypothalamus and the hippocampus were detected by immunohistochemistry with rabbit anti-motilin polyclonal antibody. To measure the gastric motility, force transducers were surgically affixed to the gastric serosa. A microinjection syringe was connected via a plastic tube to an injection cannula, which was connected with a stainless steel guide cannula. The syringe was inserted into the right lateral cerebral ventricle for microinjecting the chemicals.</p><p><b>RESULTS</b>Diabetic mellitus was successfully induced in cohorts of rats. Motilin-immunoreactive neurons significantly increased in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus in the diabetic rats. Intracerebroventricular (i.c.v.) administration of EM, a motilin receptor agonist, stimulated the gastric motility of diabetic rats. EM (91.56 nmol, i.c.v.) dose-dependently increased the amplitude by (174.82 +/- 48.62)% (P<0.05), and increased the frequency by (70.43 +/- 27.11)% (P < 0.05) in 5 min. The stimulatory effect lasted more than 15 min to the end of the measurement, and can be blocked partially by the prior treatment of motilin receptor antagonist GM-109.</p><p><b>CONCLUSION</b>Motilin-immunoreactive neurons are increased in the PVN and SON of the hypothalamus in diabetic rats. Centrally administered EM may regulate gastric motility by binding to the central motilin receptors, and central motilin might be involved in regulation of gastric motility in diabetic rats.</p>

Human obesity: its hormonal basis and the role of gastric inhibitory polypeptide

Obesity is an abnormal expansion of the adipose organ and is a pathophysiological response to an imbalance between energy intake and energy expenditure. It is the result of a large number of diverse factors involving heritable and environmental characteristics. A simple definition of obesity is difficult and unsatisfactory and its age dependency has largely been ignored. Differentiation between healthy, age-related plumpness and obesity is often blurred and responsible for overdiagnosis of obesity in the developed world. In the past, epidemiological studies have often ignored the different prognostic significance of the two major phenotypes of human obesity making their conclusions of limited value. The role of heritable factors in determining both the propensity to develop obesity under favourable environmental conditions, including inactivity and unlimited access to fat-rich foods, and the phenotype it assumes received an enormous fillip from experiments involving genetically modified animals. The most important of these have demonstrated the key role played by a number of newly discovered or recently resurrected polypeptide hormones that are released from the intestine in response to food. Molecular manipulation of these hormones, especially of glucose-dependent insulin-stimulatory polypeptide offers a new therapeutic approach

Effects of motilin agonists on intracellular calcium mobilization in cultured rat myenteric neurons / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the effects of motilin agonists on intracellular Ca(2+) mobilization in primary cultured rat myenteric neurons.</p><p><b>METHODS</b>Motilin-induced and erythromycin-induced intracellular Ca(2+) signaling was studied in primary cultures of rat myenteric neurons using the radiometric Ca(2+) indicator Furo3/AM with a laser confocal microscope.</p><p><b>RESULTS</b>In Hank's solution, 10(-8), 10(-7), and 10(-6) mol/L motilin could elevate intracellular Ca(2+) concentration ([Ca(2+)]i) to the peak levels of 10.6-/+2.1, 15.9-/+1.2, and 30.6-/+3.7 respectively with their relative percentage change in fluorescent intensity of (40.1-/+6.3)%, (63.0-/+11.2)%, and (100.8-/+18.4)% respectively, indicating the dose-dependent effect of motilin on [Ca(2+)]i. In Hank's solution, 10 microg/ml erythromycin could induce the elevation of [Ca(2+)]i to the average peak of 23.2-/+5.6 with the relative percentage change in fluorescent intensity of (82.8-/+13.0)%. When pretreated with the antibody against motilin receptor in Hank's solution, the effect of 10 microg/ml erythromycin was almost inhibited completely.</p><p><b>CONCLUSION</b>Motilin can increase [Ca(2+)]i, and erythromycin also has this effect by binding to motilin receptor.</p>

Effect of motilin receptor agonist-erythromycin on the glucose responsive neurons in hypothalamus of rats / 中国应用生理学杂志

<p><b>AIM</b>In order to explore the mechanism of central motilin-induced feeding behavior, the effects of erythromycin, a motilin receptor agonist, on glucose responsive neurons in hypothalamus were observed.</p><p><b>METHODS</b>Extracellular recordings were made from single neurons in region of lateral hypothalamic area (LHA) and ventromedial hypothalamic nucleus (VMH) in anesthetized rats. On the basis of their responsiveness to intracarotid injection of 0.58 mol/L glucose solution 0.2 ml, glucose-sensitive neurons (GSNs) in LHA and glucoreceptor neurons (GRNs) in VMH were recognized. Effects of intracerebroventricularly (i. c. v.) administration of 4 microg erythromycin on neural activities of glucose responsive neurons and non-glucose responsive neurons were examined. The mixture of EM and GM-109 1 microl were used to GSNs and GRNs which were sensitive to i. c. v. administration of EM.</p><p><b>RESULTS</b>In LHA, EM increased activity of GSNs significantly (P < 0.05 vs non-glucose-sensitive neurons group). Whereas in VMH, EM significantly decreased the activities of GRNs (P < 0.01 vs non-glucoreceptor neurons group). The mixture of EM and GM-109 had no effect on GSNs and GRNs.</p><p><b>CONCLUSION</b>EM, a motilin receptor agonist, can stimulate GSNs in LHA and suppress GRNs in VMH and this may contribute to central motilin's effect on feeding behavior.</p>

Endocrinología gastroenterológica: aspectos básicos / Gastrointestinal endocrinology: basic aspects

El presente artículo revisa los aspectos básicos y generales de la endocrinología del tracto gastrointestinal, conocimientos que facilitan la comprensión de sus aspectos fisiológicos y clínicos. Las células del tracto digestivo producen diversos mensajeros químicos que son liberados por mecanismos endocrinos, neurocrinos y paracrinos; la interrelación de estos eventos hormonales con eventos neuronales, van a regular los procesos de absorción, secreción, y de motilidad digestiva