Acute tryptophan depletion alters the effective connectivity of emotional arousal circuitry during visceral stimuli in healthy women.

OBJECTIVE: Alterations in serotonin signalling within the brain-gut axis have been implicated in the pathophysiology of irritable bowel syndrome (IBS) and is a treatment target. Acute tryptophan depletion (ATD) decreases brain serotonin (5-hydroxytryptamine; 5-HT) levels, and increases visceral perception and negative emotional bias in patients with IBS. The aim of the present study was to determine the effect of ATD on brain activity and connectivity during visceral stimuli in healthy women, and to compare the ATD-induced brain connectivity of an arousal circuit in female patients with IBS without ATD. METHODS: 12 healthy females (19-25 years) were studied under placebo (PLA) conditions and ATD. Functional MRI measurements were performed during a rectal barostat protocol, consisting of random non-painful and maximal tolerable distensions. Partial least squares analyses and structural equation modelling were used to evaluate the effect of ATD on functional and effective brain connectivity during distension. Results in healthy controls under ATD were compared with the effective connectivity of brain responses to 45 mm Hg rectal distension in 14 female patients with constipation-predominant IBS (IBS-C) (24-50 years). RESULTS: In healthy controls, ATD resulted in increased response of an extensive brain network to balloon distension, including the amygdala and nodes of emotional arousal and homeostatic afferent networks. The effect was greater during high inflation, suggesting greater engagement of the central serotonion system with more aversive visceral stimuli. Effective connectivity analysis revealed a profound effect of ATD on coupling between emotional arousal network nodes, resulting in loss of negative feedback inhibition of the amygdala. A near-identical pattern was identified in the patients with IBS-C. CONCLUSIONS: The findings are consistent with an ATD-induced disinhibition of and increased connectivity within an emotional arousal network during aversive stimulation. Together with the previous demonstration of ATD-induced visceral hyperalgesia in healthy controls, and the near-identical effective connectivity pattern observed in patients with IBS-C, these findings suggest that dysregulation of this brain network may play a role in central pain amplification and IBS pathophysiology.

Comparing probiotic and drug interventions in irritable bowel syndrome: a meta-analysis of randomised controlled trials.

Clinical decisions made by health professionals to recommend either drug or probiotic interventions for irritable bowel syndrome (IBS) should be supported by proper knowledge of the efficacy rates of both types of interventions. In this article, we performed a systematic review and meta-analysis to examine the efficacy of both probiotic- and drug interventions in IBS. Medline was searched between January 2015 - January 2021. Randomised controlled trials (RCT) recruiting participants > 18 years old with IBS and examining the effect of probiotics or drugs were eligible for inclusion. The data of the primary outcome, i.e. the persistence of IBS symptoms (dichotomous symptom data), were pooled to obtain a relative risk (RR), with a 95% confidence interval (CI). Secondary outcomes, abdominal pain- and bloating scores (continuous data), were pooled using a standardised mean difference with a 95% CI. The search identified 269 citations of which 32 RCTs were eligible. Our meta-analysis indicated that both probiotic and drug interventions are able to improve the persistence of IBS symptoms (RR 0.60 [0.51; 0.92] versus 0.87 [0.81; 0.92], respectively) and abdominal pain scores (standardised mean difference (SMD) -0.35 [-0.56; -0.14] versus -0.10 [-0.20; 0.00], respectively). However, determining the overall efficacy of both intervention types is inherently complex and such results should be interpreted with care, due to the large diversity of probiotic- and drug types and doses, which is also complicated by variety in IBS subtypes. Hence, as a first step, more large scale randomised double blind placebo-controlled trials focussing on a specific IBS subtype targeted with specific probiotic strains or specific pharmaceutical modalities should be executed, enabling a more proper comparison between trials.

Inadequate safety reporting in the publications of randomised clinical trials in irritable bowel syndrome: drug versus probiotic interventions.

Randomised controlled clinical trials (RCTs) offer a unique opportunity to obtain controlled efficacy and safety data to support clinical decisions. However, most RCT reporting has a stronger focus on efficacy rather than safety. This study aimed to identify the safety profile of both probiotic and drug interventions in irritable bowel syndrome (IBS). In connection to this paper, an accompanying paper was published in which a meta-analysis was conducted to evaluate the efficacy of probiotic interventions compared to that of drug interventions in IBS. Together, these two studies provide a first assessment regarding the feasibility to determine a burden to benefit ratio for both probiotic and drug interventions in IBS. RCTs including participants (>18 years old) with IBS and comparing probiotic or drugs interventions with control groups were identified by a systematic search of MEDLINE (January 2015 - Jan 2021). Reported safety profiles in drug studies were completer and more detailed as compared with studies on probiotics. Several inconsistencies in safety reporting were identified between and within drug and probiotic studies, such as: didn't report on safety; only reported adverse reactions (ARs) or adverse events (AEs) with a certain severity; didn't report the total number of AEs; didn't split in the control- or experimental arm; didn't specify AEs; and used different thresholds for 'common' AEs. Hence, it is difficult to compare safety data from drug and probiotic RCTs across and between different studies. On the current approaches to safety reporting, we could not establish an unambiguous safety profile for neither probiotic and drug interventions in IBS. These shortcomings hamper a critical comparison of the burden to benefit ratio for IBS intervention.

The effects of protein ingestion on GH concentrations in visceral obesity.

Growth hormone (GH), a hormone originating from the anterior pituitary gland, is an important regulator of metabolism and body composition. Low GH secretion is associated with features of the metabolic syndrome, in particular increased visceral body fat and decreased lean body mass. It has been shown that GH release can be promoted by ingestion of protein, in particular gelatin protein. The question remains; is the GH-promoting effect of gelatin protein also present in a population with blunted GH response, such as visceral obesity? 8 lean women (age: 23+/-3 years, BMI: 21.6+/-2.0 kg/m (2)) and 8 visceral obese women (age: 28+/-7 years, BMI: 33.8+/-5.5 kg/m (2)) were compared with regard to their 5-h GH response after oral ingestion of gelatin protein (0.6 g protein per kg bodyweight), placebo (water), or injection of growth hormone releasing hormone (GHRH) (1 mu/kg body weight), in a randomized crossover design. GH response after placebo, gelatin protein, or GHRH was higher in lean subjects than in visceral obese subjects (p<0.05). Ingestion of gelatin protein increased GH response compared with placebo in both visceral obese (182.1+/-81.6 microg/l.5 h vs. 28.4+/-29.8 microg/l.5 h) and lean (631.7+/-144.2 microg/l.5 h vs. 241.0+/-196.8 microg/l.5 h) subjects (p<0.05). GH response after ingestion of gelatin protein in visceral obese did not differ from that in lean, placebo-treated subjects (p=0.45). GH concentrations after GHRH injection correlated significantly with GH concentrations after gelatin ingestion (AUC; r=0.71, p<0.01, Peak; r=0.81, p<0.01). Further research is needed to investigate if gelatin protein is able to improve metabolic abnormalities in hyposomatotropism in the long term or to investigate the relevance of protein as diagnostic tool in hyposomatotropism.

The role of colonic metabolism in lactose intolerance.

Lactose maldigestion and intolerance affect a large part of the world population. The underlying factors of lactose intolerance are not fully understood. In this review, the role of colonic metabolism is discussed, i.e. fermentation of lactose by the colonic microbiota, colonic processing of the fermentation metabolites and how these processes would play a role in the pathophysiology of lactose intolerance. We suggest that the balance between the removal and production rate of osmotic-active components (lactose, and intermediate metabolites, e.g. lactate, succinate, etc.) in the colon is a key factor in the development of symptoms. The involvement of the colon may provide the basis for designing new targeted strategies for dietary and clinical management of lactose intolerance.

The effects of an acute serotonergic challenge on brain-gut responses in irritable bowel syndrome patients and controls.

BACKGROUND: Serotonin, a key denominator of the brain-gut axis is involved in the regulation of gastrointestinal function as well as cognition, mood and hypothalamic-pituitary-adrenal axis-mediated neuroendocrine responses. AIM: To assess the effects of an acutely increased serotonergic activity, using a 20 mg intravenous citalopram challenge test on visceral perception, affective memory performance, mood and neuroendocrine responses, respectively, in diarrhoea-predominant irritable bowel syndrome patients and controls. METHODS: In a randomized, double-blind crossover design, 14 diarrhoea-predominant irritable bowel syndrome patients and 14 matched controls were studied under citalopram and placebo conditions, respectively. Visceral perception was scored in response to rectal distensions. Affective memory performance, mood, levels of adrenocorticotropic hormone, cortisol, prolactin and biochemical parameters of serotonergic metabolism were simultaneously assessed. RESULTS: Visceral perception did not significantly differ between the citalopram and placebo condition. Citalopram administration enhanced affective memory performance because of a bias towards positive material but no significant changes in mood. Citalopram significantly increased plasma serotonin, adrenocorticotropic hormone and cortisol levels compared with placebo. Citalopram did not differentially affect the patient or control group. CONCLUSIONS: We have provided evidence that acutely increased serotonergic activity influences neuroendocrine responses and cognition in diarrhoea-predominant irritable bowel syndrome and controls without a significant effect on visceral perception.

Systematic review: serotonergic modulators in the treatment of irritable bowel syndrome--influence on psychiatric and gastrointestinal symptoms.

BACKGROUND: Both central and peripheral serotonergic modulators are used in the treatment of irritable bowel syndrome. The majority of patients with irritable bowel syndrome presenting to a gastroenterologist demonstrate affective dysregulation. Serotonin may play a regulatory role in both gastrointestinal motility and sensitivity, as well as in affective dysregulation, in irritable bowel syndrome. AIM: To analyse, systematically, randomized controlled trials studying the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome, in order to elucidate baseline irritable bowel syndrome symptomatology and possible differential effects of serotonergic modulation on this symptomatology. METHODS: A standardized qualitative analysis was performed of studies investigating the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome using a blind review approach. The studies were ranked according to their total quality score (maximum 100 points). RESULTS: Eleven studies fulfilled the entry criteria, six of which scored above 55 points. An association between gastroenterological and psychiatric changes was present in five of the six studies. CONCLUSIONS: The results strengthen the serotonergic association between gastroenterological and psychiatric symptoms. Adjusted guidelines for combined gastrointestinal and psychiatric assessments are recommended in order to further elucidate the serotonergic interaction between gastrointestinal and psychiatric symptoms.

Gastric myoelectrical activity in morbidly obese patients before and 3 months after gastric restrictive surgery.

BACKGROUND: Morbid obesity is often associated with gastrointestinal motor disorders. The aim of this study was to investigate gastric motility in morbid obesity, using electrogastrography (EGG) before and 3 months after gastric restrictive surgery. METHODS: 40 morbidly obese subjects (age 40.6+/-10.3 years, BMI 46.4+/-5.7 kg/m2) were studied. VBG and Lap-Band operations were performed in 19 and 21 patients respectively. The following EGG-parameters were determined, both during fasting (f) and postprandially (pp): dominant frequency (DF(f/pp)), dominant power (DP(f/pp)), dominant frequency and power instability coefficient (DFIC and DPIC respectively) and power ratio. RESULTS: In the Lap-Band group, DF(pp), DP(pp) and DFIC(pp) were significantly higher compared with the preprandial state, both preoperatively and 3 months postoperatively. After VBG, DF(f) and DFIC(pp) were significantly lower and DPIC(f) significantly higher compared with the preoperative state. Furthermore, DF(pp) and DP(pp) were significantly higher than the preprandial values. However, in both types of operations, power ratio did not differ significantly between the preoperative and postoperative situation. Furthermore, no clear difference in EGG-parameters between both operations could be observed. CONCLUSION: After gastric restrictive surgery, no major changes in gastric myoelectrical activity occurred, suggesting that if clinical motility problems occur after bariatric surgery, they are not due to gastric myoelectrical dysfunction.

Recombinant human lactoferrin ingestion attenuates indomethacin-induced enteropathy in vivo in healthy volunteers.

OBJECTIVE: To determine whether recombinant human lactoferrin ingestion inhibits nonsteroidal antiinflammatory drugs (NSAID)-induced gastroenteropathy in vivo in healthy volunteers as a model for disorders associated with a rise in permeability of the stomach and the small intestine. DESIGN: A randomized crossover dietary intervention. SUBJECTS AND INTERVENTIONS: In all, 15 healthy volunteers (age 23+/-1.4 y) were tested. A sucrose and a lactulose/rhamnose (L/R) permeability test was performed to assess gastroduodenal and small intestine permeability as indicator of NSAID-induced gastroenteropathy. All subjects consumed standardized meals for 2 days. On the second day at time=-24 h each subject ingested a drink containing 5 g recombinant human lactoferrin or placebo during breakfast. At t=-9 h, subjects ingested the same drink with 75 mg of the NSAID indomethacin and after an overnight fast at t=-1 h subjects consumed the drink and 50 mg indomethacin. After 1 h, at t=0, a permeability test was performed. RESULTS: Small intestine permeability after indomethacin and placebo was significantly higher (L/R ratio=0.036; 0.014-0.092, P<0.05) compared to the permeability observed after ingestion of indomethacin and lactoferrin (0.028; 0.015-0.056), whereas gastroduodenal permeability did not differ between the two interventions (P=0.3). CONCLUSION: Oral recombinant human lactoferrin supplementation during a short-term indomethacin challenge reduced the NSAID-mediated increase in small intestinal permeability and hence may provide a nutritional tool in the treatment of hyperpermeability-associated disorders. SPONSORSHIP: Grant and human recombinant lactoferrin donated from Agennix Inc., Houston, TX.

Irritable bowel syndrome in general practice: an overview.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is frequently seen in gastroenterological practice. Population-based studies have shown that at any point in time IBS symptoms are present in about 3%-22% of the general Western population. In general practice, half of all new patients have functional disorders and IBS is responsible for about five consultations per week. General practitioners (GPs) manage the majority of IBS patients, but most knowledge (and research) is based on the smaller percentage of patients managed in secondary care. There is a paucity of literature on differences or similarities between these two groups with regard to clinical characteristics or diagnostic approach. METHODS: The literature published in English about IBS in general practice was reviewed. CONCLUSIONS: Irritable bowel syndrome is frequently encountered in primary care. Primary care IBS patients, compared to secondary care patients, are likely to be young, female and to have less severe symptoms. But this is only true for some symptoms; for example, non-abdominal complaints are equally reported in both groups. The disorder can be diagnosed safely using internationally agreed symptom-based criteria, such as the Rome II criteria. Additional diagnostic measures will be necessary to support the diagnosis in only a minority of situations. Many primary care IBS patients can be managed given adequate reassurance and education, frequently without additional pharmacological treatment.

Alternative procedure to shorten rectal barostat procedure for the assessment of rectal compliance and visceral perception: a feasibility study.

BACKGROUND: Barostat methodology is widely used for assessing visceral perception. Different barostat protocols are described with respect to the measurement of rectal compliance and visceral perception. The choice of protocols affects the duration, which is normally 60-90 min, and accuracy of the procedure. This study aimed to shorten the procedure by using the semi-random distension protocol for both compliance and visceral perception measurement and a correction based on rectal capacity (RC) instead of minimal distension pressure (MDP). METHODS: Twelve irritable bowel syndrome (IBS) patients (7 females) and 11 healthy controls (8 females) underwent a barostat procedure. Compliance was determined during both a staircase distension and a semi-random protocol. Visceral perception data were compared as a function of pressure or relative volume, corrected for MDP or RC, respectively. RESULTS: Compliance measurement using the semi-random protocol instead of the staircase distension protocol resulted in an overestimation in healthy volunteers, but not in IBS patients. The overall conclusion that IBS patients had a lower compliance compared to controls was not different between protocols. Data presentation of the visceral perception scores as a function of corrected volume instead of pressures corrected for MDP did not alter the conclusion that sensation scores in IBS patients were higher as compared to healthy controls. CONCLUSIONS: This study showed that barostat procedures may be shortened by approximately 20 min, without losing the ability to discriminate between healthy controls and IBS patients. A correction for RC instead of MDP may improve the accuracy of the procedure.

Plasma very long-chain n-3 polyunsaturated fatty acids and age-related hearing loss in older adults.

OBJECTIVES: Age-related hearing loss is a common social and health problem in the older adult population. Up until now, very little scientific attention has been given to the potential role of fatty acids in age-related hearing loss. In this study we investigated whether plasma very long-chain n-3 polyunsaturated fatty acids (PUFAs) are associated with age-related hearing loss over three years. DESIGN: Cross-sectional and 3-year longitudinal analyses. SETTING: Wageningen, the Netherlands. PARTICIPANTS: 720 men and postmenopausal women (50-70 years of age) without middle ear dysfunction or unilateral hearing loss. MEASUREMENTS: Fatty acid proportions were measured in plasma cholesteryl esters. Hearing thresholds (in decibels, dB) at baseline and after three years were measured with pure-tone audiometry. Hearing loss was calculated as the increase in mean hearing thresholds in the low (0.5-kHz, 1-kHz, and 2-kHz) and high (4-kHz, 6-kHz, and 8-kHz) frequencies over three years. RESULTS: Subjects in the highest quartile of plasma very long-chain n-3 PUFA had less hearing loss in the low frequencies over three years than subjects in the lowest quartile (p < 0.01, ANCOVA, difference in mean adjusted hearing thresholds= -1.2 dB). There were no significant differences between the quartiles of plasma very long-chain n-3 PUFA in hearing loss in the high frequencies (p=0.49, ANCOVA). These associations are adjusted for baseline mean hearing thresholds, age, sex, level of education and alcohol consumption. CONCLUSION: This study is the first to show an inverse association between plasma very long-chain n-3 PUFAs and age-related hearing loss. These results are encouraging, but require confirmation from future studies.

The effects of butyrate enemas on visceral perception in healthy volunteers.

Fermentation of dietary fibres by colonic microbes leads to the production of short chain fatty acids (mainly propionate, butyrate and acetate), which are utilized by the colonic mucosa. Previous studies showed positive effects of butyrate on parameters of oxidative stress, inflammation and apoptosis. Recent studies in rats, however, showed that butyrate increased visceral sensitivity. The aim of this study was to determine the effects of physiologically relevant concentrations of butyrate on visceral perception in healthy human subjects. Eleven healthy volunteers participated in this randomized double-blind, placebo controlled cross-over study. The study consisted of three periods of 1 week each, in which the volunteers daily self-administered rectal enemas containing 100, 50 mmol L(-1) butyrate, or placebo (saline) prior to sleeping. A rectal barostat measurement was performed at the start and the end of each test period for the measurement of pain, urge and discomfort. Butyrate treatment resulted in a dose-dependent reduction of pain, urge and discomfort throughout the entire pressure range of the protocol. At a pressure of 4 mmHg, 50 and 100 mmol L(-1) butyrate concentrations resulted in a 23.9% and 42.1% reduction of pain scores, respectively, and the discomfort scores decreased by 44.2% and 69.0% respectively. At a pressure of 67 mmHg, 50 and 100 mmol L(-1) of butyrate decreased the pain scores by 23.8% and 42%, respectively, and discomfort scores 1.9% and 5.2% respectively. Colonic administration of butyrate, at physiologically relevant concentrations, dose-dependently decreases visceral sensitivity in healthy volunteers.

Altered omega-3 polyunsaturated fatty acid status in depressed post-myocardial infarction patients.

OBJECTIVE: Lower levels of long-chain omega-3 polyunsaturated fatty acids (n-3 LCPUFAs) and increased inflammation have been associated with both depressive disorder and myocardial infarction (MI). The present study investigated whether patients who develop depression post-MI, have higher arachidonic acid/eicosapentanoic acid (AA/EPA) ratios than non-depressed post-MI patients and whether depressed post-MI patients have signs of increased inflammation as measured by C-reactive protein (CRP). METHOD: Serum AA/EPA ratio and plasma CRP levels were quantified in 50 post-MI patients, of which 29 were depressed and 21 non-depressed. RESULTS: Compared with the non-depressed group, depressed post-MI patients had significantly higher AA/EPA ratios. No significant difference was observed in CRP levels. CONCLUSION: Depressed post-MI patients had lower levels of n-3 LCPUFAs as measured by mean AA/EPA ratio and no signs of increased inflammation as determined by CRP levels.

Acute tryptophan depletion affects brain-gut responses in irritable bowel syndrome patients and controls.

BACKGROUND: Serotonin, a key denominator of the brain-gut axis, is involved in the regulation of gastrointestinal motility, secretion, and perception as well as cognition and mood. AIM: To assess the effects of an acutely lowered serotonin synthesis, using the acute tryptophan depletion (ATD) method, on visceral perception, affective memory performance, and mood in diarrhoea predominant irritable bowel syndrome patients (d-IBS) and controls. METHODS: In a randomised, double blind, crossover design, 14 d-IBS patients and fourteen matched controls were studied under ATD and placebo conditions, respectively. Perception of urge and pain was scored during rectal distensions. Affective memory performance, mood, and biochemical parameters of serotonergic metabolism were simultaneously assessed. RESULTS: ATD significantly decreased plasma tryptophan (67.0 (2.0) v 24.9 (2.0) mumol/l) and 5-hydroxyindole acetic acid concentrations (29.9 (1.0) v 15.8 (0.6) nmol/l). ATD was associated with significantly increased urge scores specifically in the lower pressure range and overall increased pain scores. ATD significantly lowered the perceptual threshold for first perception compared with placebo (patients 10.6 (1.2) v 13.6 (0.8) mm Hg, controls 12.6 (1.3) v 15.7 (1.2) mm Hg) but not for maximal tolerable discomfort (patients 50.5 (3.6) v 51.6 (3.3) mm Hg, controls 50.9 (3.3) v 48.8 (2.9) mm Hg). ATD induced a significant shift in affective memory bias towards preferential loss of positive material but no significant changes in mood. ATD did not differentially affect the patient or control group. CONCLUSIONS: We have provided evidence that serotonergic modulation by ATD affects both visceral perception as well as cognition in d-IBS and controls. Simultaneous measurement of brain and gut function and the application of ATD contribute to the elucidation of the complex pathophysiology of IBS.