Recent advances in measuring the effects of diet on gastrointestinal physiology: Probing the "leaky gut" and application of real-time ultrasound.

There is a large pool of ideas in both mainstream and non-mainstream medicine on how diet can be manipulated in order to treat or prevent illnesses. Despite this, our understanding of how specific changes in diet influence the structure and function of the gastrointestinal tract is limited. This review aims to describe two areas that might provide key information on the integrity and function of the gastrointestinal tract. First, demystifying the "leaky gut syndrome" requires rational application and interpretation of tests of intestinal barrier function. Multiple ways of measuring barrier function have been described, but the inherent difficulties in translation from animal studies to humans have created misinterpretations and misconceptions. The intrinsic nature of intestinal barrier function is dynamic. This is seldom considered in studies of intestinal barrier assessment. To adequately understand the effects of dietary interventions on intestinal barrier function, background barrier function in different regions of the gut and the dynamic responses to stressors (such as psychological stress) should be assessed as a minimum. Second, intestinal ultrasound, which is now established in the assessment and monitoring of inflammatory bowel disease, has hitherto been poorly evaluated in assessing real-time intestinal function and novel aspects of structure in patients with disorders of gut-brain interaction. In conclusion, a more complete functional and structural profile that these investigations enable should permit a greater understanding of the effects of dietary manipulation on the gastrointestinal tract and provide clinically relevant information that, amongst other advantages, might permit opportunities for personalized health care delivery.

Comparison of Gas-sensing Capsule With Wireless Motility Capsule in Motility Disorder Patients.

Background/Aims: Motility disorders are prevalent, often leading to disrupted regional or whole gut transit times. In this study, we conducted a comparative analysis between the wireless motility capsule and an innovative gas-sensing capsule to evaluate regional and whole gut transit times in individuals with diagnosed motility disorders. Methods: We prospectively enrolled 48 patients (34 women) diagnosed with functional dyspepsia and/or functional constipation according to Rome IV criteria. Patients ingested the capsules in tandem. We assessed the agreement between transit times recorded by both devices using Spearman correlation and Bland-Altman analysis. Additionally, diagnostic concordance between the capsules were evaluated using confusion matrices. Results: We observed a significant correlation between the wireless motility capsule and the gas-sensing capsule for gastric emptying time (r = 0.79, P < 0.001) and colonic transit time (r = 0.66, P < 0.001). The gas-sensing capsule exhibited a sensitivity of 0.83, specificity of 0.96, and accuracy of 0.94 when using the standard cutoff for delayed gastric emptying (5 hours). Similarly, when applying the cutoff value for delayed colonic transit (> 59 hours), the gas-sensing capsule demonstrated a sensitivity of 0.79, specificity of 0.84, and accuracy of 0.82. Importantly, the gas-sensing capsule was well-tolerated, and no serious adverse events were reported during the study. Conclusions: Our findings underscore the gas-sensing capsule's suitability as a dependable tool for assessing regional and whole gut transit times. It represents a promising alternative to the wireless motility capsule for evaluating patients with suspected motility disorders.

Development of Novel High and Low Emulsifier Diets Based upon Emulsifier Distribution in the Australian Food Supply for Intervention Studies in Crohn's Disease.

BACKGROUND: The aims of this study were to develop and evaluate a high/low-emulsifier diet and compare emulsifier content with preclinical studies that have associated Crohn's disease with emulsifiers. METHODS: Supermarkets were audited with a seven-day high- (HED) and low-emulsifier diet (LED) meal plan developed. The emulsifier content of food was sought from food manufacturers, compared to acceptable daily intake (ADI), and doses were provided in trials. Nutritional composition analysis was completed. Healthy adults ate these diets for seven days in a randomized single-blinded cross-over feeding study to assess palatability, tolerability, satiety, food variety, dietary adherence, blinding and the ease of following the meal plan via visual analogue scale. RESULTS: A database of 1680 foods was created. There was no difference in nutritional content between the HED and LED, except HED had a higher ultra-processed food content (p < 0.001). The HED contained 41 emulsifiers, with 53% of the products able to be quantified for emulsifiers (2.8 g/d), which did not exceed the ADI, was similar to that in observational studies, and was exceeded by doses used in experimental studies. In ten participants, diets were rated similarly in palatability-HED mean 62 (5% CI 37-86) mm vs. LED 68 (54-82) mm-in tolerability-HED 41 (20-61) mm vs. LED 55 (37-73) mm-and in satiety HED 57 (32-81) mm vs. LED 49 (24-73) mm. The combined diets were easy to follow (82 (67-97) mm) with good variety (65 (47-81)) and excellent adherence. CONCLUSION: Nutritionally well-matched HED and LED were successfully developed, palatable and well tolerated.

Comparison of digitally-delivered gut-directed hypnotherapy program to an active control for irritable bowel syndrome.

OBJECTIVES: Gut-directed hypnotherapy (GDH) treats irritable bowel syndrome (IBS) but its accessibility is limited. This problem may be overcome by digital delivery. This study aimed to perform a randomised control trial comparing the efficacy of a digitally-delivered program with and without GDH in IBS. METHODS: Adults with IBS were randomized to a 42-session daily digital program with the GDH Program (Nerva) or without (Active Control). Questionnaires were completed to assess gastrointestinal symptoms via IBS-SSS, quality of life (IBS-QOL) and psychological symptoms (DASS-21) at regular intervals during the program and 6 months following conclusion on the intervention. The primary endpoint was the proportion of participants with ≥50-point decrease in IBS-SSS between the interventions at the end of the program. RESULTS: Of 240/244 randomized participants, 121 received GDH Program - median age 38 (range 20-65) years, 90% female, IBS-SSS 321 (IQR 273-367) - and 119 Active Control - 36 (21-65), 91% female, IBS-SSS 303 (255-360). At program completion, 81% met the primary endpoint with GDH Program versus 63% Active Control (p=0.002). IBS-SSS was median 208 (IQR 154-265) with GDH and 244 (190-308) with Control (p=0.004), 30% reduction in pain was reported by 71% compared with 35% (p<0.001), and IBS-QOL improved by 14 (6-25) compared with 7 (1-15), respectively (p<0.001). Psychological status improved similarly in both groups. CONCLUSIONS: A digitally-delivered GDH Program provided to patients with IBS was superior to the active control, with greater improvement in both gastrointestinal symptoms and quality of life and provides an equitable alternative to face-to-face behavioural strategies.

People with Inflammatory Bowel Disease Prefer Cognitive Behavioral Therapy for Fatigue Management: A Conjoint Analysis.

BACKGROUND: Psychological interventions are a promising area for fatigue management in patients with inflammatory bowel disease (IBD). However, most interventions trialled to date have been pilots with limited direct input from patients about the type of intervention they want. Thus, this study aimed to explore patient preferences for a psychological IBD fatigue intervention. METHODS: An international online cross-sectional survey was conducted with adults with self-reported IBD. A conjoint analysis was employed to elicit, through a series of forced-choice scenarios, patient preferences for a fatigue intervention. For this study, the attributes manipulated across these forced-choice scenarios were type of intervention, modality of delivery, and duration of intervention. RESULTS: Overall, 834 people with IBD were included in analysis. Respondents ranked the type of psychological intervention as most important for overall preference (with cognitive-behavioral therapy (CBT) preferred over the other approaches), followed by modality of delivery, but placed very little importance on how long the intervention runs for. Patients with IBD appear to most strongly preference a short online CBT intervention for managing their IBD-related fatigue. CONCLUSION: This study helps provide therapists and program developers clear direction on patient preferences when it comes to developing new psychological programs that address fatigue in IBD.

Probiotics: are they beneficial?

There are wide-ranging probiotic choices in Australasia. We reviewed the efficacy of probiotics for the management of gastrointestinal (GI) conditions in adults and assessed relevance to clinical practice. The benefits of probiotics were inconsistent, with a strong consensus reached for only a few of the indications. As different species/strains and combinations differ in efficacy, results cannot be extrapolated from one to another. This review endorses specific probiotics for limited indications. Efficacy of most marketed probiotic formulations remains unstudied and unproven, warranting further research.

Clinical utility of C-reactive protein-to-albumin ratio in the management of patients with inflammatory bowel disease.

Background and Aim: C-reactive protein (CRP)-to-albumin ratio (CAR) is a novel score with prognostic value in inflammatory conditions. This study assessed the performance of CAR as an objective marker of disease activity and prediction of subtherapeutic infliximab trough levels in patients with inflammatory bowel disease (IBD). Methods: A retrospective study was conducted on three different patient cohorts with IBD: patients who had (i) fecal calprotectin (FC) measurements; (ii) Mayo Endoscopic Scores; and (iii) infliximab trough levels available. The relative performances of CAR, albumin, and CRP were compared in predicting disease activity (based on FC or Mayo Endoscopic Score) and infliximab trough levels. Results: In both the FC (n = 289) and endoscopy (n = 65) cohorts, albumin and CAR correlated with objective disease activity. CAR (area under the curve [AUC] 0.70) was only marginally better at detecting active disease, measured by FC, compared to CRP (AUC 0.68). A CAR >0.15 was able to detect Mayo 3 disease (AUC 0.83, sensitivity 81%, specificity 89%). Albumin (r = 0.38) and CAR (r = -0.42) correlated with infliximab trough levels (n = 204). The optimal CAR for detecting subtherapeutic infliximab trough levels was >0.08 (AUC 0.70, sensitivity 66%, specificity 64%). Both albumin and CAR were independent predictors of subtherapeutic infliximab trough levels but correlated poorly with infliximab trough levels longitudinally in the same patient. Conclusion: CAR was only a modest discriminator of subtherapeutic infliximab levels and offers little more than CRP in detecting active disease. CAR has potential to detect severe Mayo 3 disease and could be calculated in patients admitted with suspected acute severe ulcerative colitis.

Nutrition Assessment and Management in Celiac Disease.

Celiac disease (CeD) is the most common immune condition affecting the gastrointestinal tract; it is triggered by gluten and the only available treatment is a strict gluten-free diet (GFD). Therefore, for patients with CeD, adopting a GFD is not a lifestyle choice. The major problem is that a GFD is restrictive and, like all restrictive diets, it has the potential for adverse nutritional outcomes, especially if adopted for a long term. It is well known that GFD can be nutritionally inadequate and is frequently associated with vitamin and mineral deficiencies; it is also associated with excessive sugar and fat intake, particularly when gluten-free substitutes are consumed. Consequently, people with CeD are affected by higher rates of overweight and obesity and metabolic complications, such as fatty liver and cardiovascular disease. Therefore, assessment of nutritional status and diet quality at diagnosis and while on a long-term GFD is key in the management of CeD. This narrative review addresses nutritional considerations in CeD and management of common challenges associated with a GFD.

Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero.

BACKGROUND & AIMS: Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable. METHODS: This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age. RESULTS: A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported. CONCLUSIONS: Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.

Intestinal barrier biomarkers in clinical evaluation of patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with chronic intestinal barrier dysfunction, though its non-invasive assessment remains challenging. This study aimed to determine how four putative circulating markers vary across differing states of intestinal inflammation and with therapy in patients with IBD. METHODS: Plasma samples from one prospective cross-sectional and four longitudinal studies, including healthy controls, were analysed for markers of lipopolysaccharide translocation, lipopolysaccharide-binding protein (LBP) and soluble-CD14 (sCD14), and markers of epithelial injury, syndecan-1 and intestinal-type fatty acid-binding protein (IFABP). Inflammatory activity was determined using objective measures. RESULTS: Compared with healthy subjects, concentrations of LBP and sCD14 were higher in patients with active (P < 0.001) and severe ulcerative colitis (UC) (P < 0.0001) and active Crohn's disease (CD) (P < 0.001). In UC in remission, LBP was less than in active disease (P = 0.011) LBP levels decreased longitudinally before and after induction of medical therapy in patients with IBD (P = 0.030) and as severe UC was brought into remission at weeks 2 and 12 (P ≤ 0.022). Response to treatment was associated with higher baseline levels of LBP (P = 0.019) and soluble-CD14 (P = 0.014). Concentrations of syndecan-1 and IFABP were or tended to be lower in UC and CD in active disease and did not change with successful therapy. CONCLUSION: While markers of epithelial injury were subnormal with active disease and did not change with therapy, markers of lipopolysaccharide translocation directly reflected intestinal inflammation, reduced with successful therapy and predicted treatment response.

Characterisation of biomarkers of intestinal barrier function in response to a high fat/high carbohydrate meal and corticotropin releasing hormone.

BACKGROUND: Variation of circulating concentrations of putative biomarkers of intestinal barrier function over the day and after acute physiological interventions are poorly documented on humans. This study aimed to examine the stability and pharmacokinetics of changes in plasma concentrations of intestinal Fatty-acid -binding -protein (IFABP), Lipopolysaccharide-binging-protein (LBP), soluble CD14, and Syndecan-1 after acute stress and high fat-high-carbohydrate meal. METHODS: In a single-blinded, cross-over, randomised study, healthy volunteers received on separate days corticotropin-releasing hormone (CRH, 100 µg) or normal saline (as placebo) intravenously in random order, then a HFHC meal. Participants were allowed low caloric food. Markers of intestinal barrier function were measured at set timed intervals from 30 minutes before to 24 hours after interventions. RESULTS: 10 participants (50% female) completed all three arms of the study. IFABP decreased by median 3.6 (IQR 1.4-10)% from -30 minutes to zero time (p = 0.001) and further reduced by 25 (20-52)% at 24 hours (p = 0.01) on the low caloric diet, but did not change in response to the meal. Syndecan-1, LBP and sCD14 were stable over a 24-hour period and not affected acutely by food intake. LBP levels 2 hours after CRH reduced by 0.61 (-0.95 to 0.05) µg/ml compared with 0.16 (-0.3 to 0.5) µg/ml post placebo injection (p = 0.05), but other markers did not change. CONCLUSION: Concentrations of IFABP, but not other markers, are unstable over 24 hours and should be measured fasting. A HFHC meal does not change intestinal permeability. Transient reduction of LPB after CRH confirms acute barrier dysfunction during stress.

Review article: Current status and future directions of ingestible electronic devices in gastroenterology.

BACKGROUND: Advances in microelectronics have greatly expanded the capabilities and clinical potential of ingestible electronic devices. AIM: To provide an overview of the structure and potential impact of ingestible devices in development that are relevant to the gastrointestinal tract. METHODS: We performed a detailed literature search to inform this narrative review. RESULTS: Technical success of ingestible electronic devices relies on the ability to miniaturise the microelectronic circuits, sensors and components for interventional functions while being sufficiently powered to fulfil the intended function. These devices offer the advantages of being convenient and minimally invasive, with real-time assessment often possible and with minimal interference to normal physiology. Safety has not been a limitation, but defining and controlling device location in the gastrointestinal tract remains challenging. The success of capsule endoscopy has buoyed enthusiasm for the concepts, but few ingestible devices have reached clinical practice to date, partly due to the novelty of the information they provide and also due to the challenges of adding this novel technology to established clinical paradigms. Nonetheless, with ongoing technological advancement and as understanding of their potential impact emerges, acceptance of such technology will grow. These devices have the capacity to provide unique insight into gastrointestinal physiology and pathophysiology. Interventional functions, such as sampling of tissue or luminal contents and delivery of therapies, may further enhance their ability to sharpen gastroenterological diagnoses, monitoring and treatment. CONCLUSIONS: The development of miniaturised ingestible microelectronic-based devices offers exciting prospects for enhancing gastroenterological research and the delivery of personalised, point-of-care medicine.

Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study).

BACKGROUND: Thiopurines are established treatments for inflammatory bowel disease (IBD), yet concerns remain regarding their safety. AIM: To evaluate the use of thiopurine-allopurinol combination therapy compared to standard thiopurine therapy in IBD. METHODS: We performed a multicentre, randomised, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD. Patients had active disease at baseline; dosing of therapy was based on a pre-specified regimen and subsequent metabolites. The primary outcome was the proportion of patients achieving a composite of symptomatic disease activity remission (Harvey Bradshaw Index <5 for Crohn's disease, Simple Clinical Colitis Activity Index <4 for ulcerative colitis) and a faecal calprotectin <150 µg/g after 26 weeks of treatment. RESULTS: The trial was terminated early due to slow recruitment. We randomised 102 participants (54 thiopurine-allopurinol, 48 thiopurine with placebo) with similar age (median 42 vs 48 years) and sex distribution (46% women per group). A higher proportion achieved the primary outcome in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02). Also, within the thiopurine-allopurinol group, thiopurine dose adjustments were less frequent (69% vs 92%, p = 0.03), a higher proportion achieved an early therapeutic 6-TGN level at week 6 (71% vs 53%, p = 0.19), and adverse events attributed to therapy were less frequent (15% vs 44%, p = 0.002). CONCLUSION: Thiopurine-allopurinol therapy is safe and mitigates thiopurine adverse effects, thus enhancing tolerability without compromising efficacy (ACTRN12613001347752).

Application of a Precision-Dosing Model to a Real-World Cohort of Patients on Infliximab Maintenance Therapy: Drug Usage and Cost Analysis.

Precision-dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses determined by iDOSE precision dosing with standard dosing, and the associated drug costs, in patients with IBD. In this retrospective study, patients with IBD treated with infliximab every 8 weeks at 5 mg/kg were included. An infliximab dose was named dose X if 3 previous infliximab doses, laboratory values including trough infliximab concentrations, and the patient's weight were recorded. The actual dose X was compared to an iDOSE-predicted dose X. Net drug use and costs were evaluated. A total of 174 patients-56% men; median age, 36 (interquartile range, 29-47) years; 135 with Crohn disease; and 31 with ulcerative colitis-were included, with 417 dose X recordings. Median prior infliximab therapy was 2 (0-4) years. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough concentrations of 5-10 and 3-7 µg/mL, respectively. Treatment costs increased by 102% and 29% for the 2 trough ranges, respectively. On multivariate regression analysis, subtherapeutic infliximab concentrations were associated with ulcerative colitis compared with Crohn disease (odds ratio, 9.81; 95% confidence interval, 1.28-75.40; P = .028) and predose X infliximab trough concentration [odds ratio, 0.07; 95% confidence interval, 0.03-0.15; P < .001]. Over half of maintenance infliximab drug doses were too low to achieve infliximab blood concentrations of 5 µg/mL or greater. While applying precision dosing may improve patient outcomes, drug costs could be considerably greater.

The value of whole-body dual-energy x-ray absorptiometry in assessing body composition in patients with inflammatory bowel disease: a prospective study.

OBJECTIVES: Low skeletal muscle index (SMI) is common in inflammatory bowel disease (IBD) but has an uncertain relationship with active intestinal inflammation. This study evaluated body composition by whole-body dual-energy X-ray absorptiometry (DXA) in patients with IBD and healthy controls to enable the value of formal body composition analysis to be judged. METHODS: Patients with IBD and sex/age-matched controls prospectively underwent full body composition assessment by DXA, assessment by BMI, eating questionnaires and handgrip strength. Disease activity was assessed by faecal calprotectin (active ≥150 µg/g). A cohort undergoing biologic induction therapy were assessed at baseline and after ≥13 weeks. RESULTS: Total fat mass was higher in 54 patients with IBD (56% Crohn's disease, 61% male) than in 30 controls (median 25.1 vs. 18.7 kg, P  = 0.042). DXA offered little more than BMI. Low SMI was more common than in controls (15% vs. 0%, P  = 0.027). A normal BMI was seen in many patients with low SMI and handgrip strength was a poor marker of change in SMI. Body composition was similar in 28 patients with active vs. 22 with inactive disease. However, SMI increased specifically by 9.7% ( P  = 0.004) and BMI by 6.4% ( P  = 0.012) in 9 responders to therapy. CONCLUSION: DXA identifies many patients with reduced SMI who are not detected by standard methodologies. While disease activity is not associated with low SMI, resolution of inflammation leads to improved SMI. The potential for recognition of such patients to influence therapeutic decisions underlines the need for DXA assessment in clinical practice.

Perceived dietary intolerances, habitual intake and diet quality of patients with an ileoanal pouch: Associations with pouch phenotype (and behaviour).

BACKGROUND AND AIMS: Ileoanal pouch patients frequently attribute pouch-related symptoms and pouchitis with diet. We aimed to assess perceived food intolerance and habitual dietary intake and their relationship with pouch indication, symptoms and current or history of pouchitis. METHODS: In this cross-sectional study, patients with an ileoanal pouch completed a dietary intolerance and a food frequency questionnaire, that specifically quantifies habitual intake of FODMAPs. Perceived dietary intolerance rates, nutrient intake and diet quality, and their differences based on pouch indication, symptom, and current or history of pouchitis were assessed. Associations between intolerances and intake, and between dietary intake with pouchitis risk were analysed using univariable and multivariable regression analysis. RESULTS: Of the 58 (10 FAP and 48 UC) patients with complete data, 81% of UC and 80% of FAP patients reported dietary intolerances. Overall diet quality was good. Differences in dietary intake were limited to a few food groups. Patients with a history of pouchitis had a lower intake of fruits (p = 0.03) and nuts (p = 0.004). Patients with current pouchitis had a lower intake of nuts (p = 0.02). On multivariable logistic regression, intake of dietary fibre was associated negatively [OR 0.68(95%CI:0.51-0.92)] and of non-digestible oligosaccharides positively with pouchitis history [OR 5.5(95% CI:1.04-29.1)]. CONCLUSIONS: In patients with an ileoanal pouch, perceived dietary intolerances are common but had minimal impact on nutritional adequacy and diet quality. Negative associations of the intakes of fruits, nuts and dietary fibre and positive association with non-digestible oligosaccharides with a history of pouchitis require further study to inform dietary recommendations.