Celiac disease: Hope for new treatments beyond a gluten-free diet.

BACKGROUND & AIMS: Celiac disease (CD) is a chronic inflammatory disease of the small intestine induced and maintained by gluten ingestion in susceptible individuals. Current treatment consists of strict adherence to a lifelong gluten-free diet (GFD) which is considered safe and effective in the large majority of patients. However, since adherence to a GFD is difficult and has a negative impact on quality of life, an increasing interest in other treatment options has emerged. Moreover, in some individuals a GFD is not sufficiently effective, necessitating alternative treatments. METHODS: By performing a systematic search, we constructed a detailed narrative review. Only treatment options considered relevant and conducted in a phase I, II or III clinical trial were included. RESULTS: Based on the pathophysiology of CD, four major therapeutic approaches can be distinguished: firstly, by focusing on intraluminal gluten detoxification before absorption occurs, secondly, by modulating intestinal permeability and preventing paracellular uptake, thirdly, by enhancing immunological tolerance to gluten and finally, by regulating gluten auto-immunity. CONCLUSIONS: Despite significant efforts, no treatment has yet completed a phase III clinical trial. Future studies will likely focus on the use of supplemental drugs in conjunction to a GFD, with ALV003 and ZED-1227 currently being the most promising therapeutic options.

Understanding the gastrointestinal tract in obesity: From gut motility patterns to enzyme secretion.

BACKGROUND AND PURPOSE: The pathophysiology of obesity has been the product of extensive research, revealing multiple interconnected mechanisms contributing to body weight regulation. The regulation of energy balance involves an intricate network, including the gut-neuroendocrine interplay. As a consequence, research on the gut-brain-microbiota axis in obesity has grown extensively. The physiology of the gastrointestinal tract, far from being underexplored, has significant implications for the development of specific complications in people living with obesity across the fields of gastroenterology, nutrition, and pharmacology. Clinical research indicates higher fasting bile acids serum levels, and blunted postprandial increases in bilious secretions in people living with obesity. Findings are less straightforward for the impact of obesity on gastric emptying with various studies reporting accelerated, normal, or delayed gastric emptying rates. Conversely, the effect of obesity on gastrointestinal pH, gastrointestinal transit, and gastric and pancreatic enzyme secretion is largely unknown. In this review, we explore the current evidence on the gastrointestinal physiology of obesity.

Physiological stress response to urbanisation differs between native and invasive squirrel species.

Novel pressures derived from urbanisation can alter native habitats and ultimately impact wildlife. Coping with such human-driven changes might induce shifts in species phenotypic traits, such as physiological responses to anthropogenic stressors. Preadaptation to face those challenges has been suggested to favour settlement and spread of invasive alien species in urbanised areas which, consequently, might respond differently than ecologically similar native species to stressors posed by urbanisation. The activation of the hypothalamic-pituitary-adrenal (HPA) axis and the subsequent release of glucocorticoids (GCs) has been suggested to mediate responses to anthropogenic disturbance in vertebrates. Furthermore, intraspecific competition, in conjunction with stressors related to urbanisation, might affect invasive and native species physiological stress responses differently. Using a parallel pseudo-experimental study system we measured faecal glucocorticoid metabolite (FGM) concentrations of the native Eurasian red squirrel and the invasive alien Eastern grey squirrel along a rural-urban gradient and in relation to conspecific density. The two species responded differently to challenges posed by the synergic effect of urbanisation and intraspecific competition. Association of FGMs and conspecific density in native red squirrels varied between rural and suburban sites, potentially depending on differential HPA axis responses. In urban sites, this relationship did not differ significantly from that in rural and suburban ones. Conversely, invasive grey squirrels' FGMs did not vary in relation to conspecific density, nor differed along the rural-urban gradient. Improving knowledge about native and competing invasive species' physiological responses to anthropogenic stressors can support conservation strategies in habitats altered by man. Our findings suggested that the invasive squirrels might be preadapted to cope with these challenges in urbanised areas, potentially increasing their success under the future global change scenario.

Use of infrared thermography to detect reactions to stressful events: does animal personality matter?

The study of the relationship between animal stress and personality for free-ranging animals is limited and provides contrasting results. The perception of stressors by an individual may vary due to its personality, and certain personality traits may help individuals to better cope with them. Using non-invasive infrared thermography (IRT), we investigated the link between physiological and behavioral components expressed during an acute stress event by free-ranging Fremont's squirrels (Tamiasciurus fremonti). We expected that, during the acute stress event of being approached by the researcher, individuals that showed a fast pace-of-life syndrome (bolder, more active, and less social/more aggressive) based on an arena test would exhibit stronger sympathetic-adrenal-medullary system reactivity showing a more intense stress-induced hyperthermia (high core body temperature and low peripheral temperature) than individuals with a slow pace of life (shy, less active, and more social). We successfully employed IRT technology to images of Fremont's squirrels with identification of the individuals' body parts (eye, nose, ear, hind foot). However, we found no support for our hypothesis. Squirrels' body surface temperatures told us more about a squirrel's external environment and less about the thermal state of the body in that environment following a stressful event. Further studies need to assess how to make IRT effective and efficient in the field and improve its performance in studying the relationships between physiology and personality in wildlife.

Shifts in immune responses of an invasive alien species: A test of the evolution of increased competitive ability hypothesis using American Eastern gray squirrels in Italy.

Based on the Evolution of Increased Competitive Ability (EICA) hypothesis, a reduced investment in immunity, consequent to parasite loss, could partly explain the success of invasive alien species. We investigated variation in parasite load and immune responses of alien Eastern gray squirrels (Sciurus carolinensis) along the invasion wave of an expanding population. We first verified by fecal analyses that 1) parasite abundance decreased moving from the core towards the invasion front. Next, we used multiple measures of immunity to investigate whether, in response to the lower parasite pressure, individuals at the invasion front 2) dampened their costly inflammatory response, and 3) increased their investment in less expensive acquired immunity. We first explored variation in hematological variables related either to the inflammatory or the acquired response. On a subset of individuals, we carried out ex vivo cell cultures to analyse the basal expression of MHC class II genes and the expression of TNF-α genes in response to an immune challenge. Platelet counts and TNF-α expression suggested higher inflammation in individuals living at the invasion core, whereas parameters associated with an acquired response (lymphocyte counts and MHC II expression by spleen cells), conversely, were higher in squirrels at the front. Overall, our results suggest a shift between different immune strategies along the invasion wave, supporting a reduced investment in costly inflammatory responses and an increased investment in acquired immunity in individuals at the expanding edge of the range, which are subjected to high selective pressures for dispersal and reproduction.

Treatment of short bowel syndrome: Breaking the therapeutic ceiling?

Short bowel syndrome (SBS) is the most common cause of chronic intestinal failure, requiring home parenteral support (intravenous fluid, parenteral nutrition, or parenteral nutrition with intravenous fluid) to compensate for severe malabsorption. The loss of mucosal absorptive area after extensive intestinal resection is accompanied by an accelerated transit and hypersecretion. Changes in physiology and clinical outcomes differ between patients with SBS with or without the distal ileum and/or colon-in-continuity. This narrative review summarizes the treatments used in SBS, with a focus on novel approaches with intestinotrophic agents. During the early postoperative years, spontaneous adaptation occurs and can be induced or accelerated with conventional therapies, which include dietary and fluid modifications and antidiarrheal and antisecretory drugs. Based on the proadaptive role of enterohormones (eg, glucagon-like peptide [GLP]-2), analogues have been developed to allow enhanced or hyperadaptation after a period of stabilization. Teduglutide is the first GLP-2 analogue developed and commercialized with proadaptive effects resulting in reduced parenteral support needs; however, the potential for weaning of parenteral support is variable. Whether early treatment with enterohormones or accelerated hyperadaptation would further improve absorption and outcomes remains to be shown. Longer-acting GLP-2 analogues are currently being investigated. Encouraging reports with GLP-1 agonists require confirmation in randomized trials, and dual GLP-1 and GLP-2 analogues have yet to be clinically investigated. Future studies will prove whether the timing and/or combinations of different enterohormones will be able to break the ceiling of intestinal rehabilitation in SBS.

Clinical outcomes in pediatric inflammatory bowel disease patients: a systematic review of prospective studies.

BACKGROUND AND AIM: We studied response and remission rates in children and adolescents with inflammatory bowel disease whose real-world data were collected prospectively. METHODS: A systematic literature search was performed in MEDLINE, Embase, and the Improve Care Now registry from inception until March 17, 2022. Inclusion criteria were prospective studies with patients < 18 years at diagnosis (M0) and minimum follow-up of 1 year (M12) mentioning disease phenotype and disease activity. Exclusion criteria were (i) reporting disease activity only at diagnosis, (ii) retrospective studies, and (iii) outcome limited to steroid-free remission. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines and the Newcastle-Ottawa scale were applied. Proportions between groups were compared using a chi-square test (α = 0.05). RESULTS: The search yielded 394 records and 7 inclusions with a sample size ranging from 33 to 390 patients (total population: 888) and a median follow-up of 1-5 years. Proportions of disease activity differed between M0 and M12 (P < 0.0001) with more inactive (χ2  = 5.5) and less moderate-to-severe disease (χ2  = 23) at M12. Interestingly, disease activity after 1 year did not differ globally (P = 0.53). Proportions of disease activity in Crohn's disease only and limited to Belgium significantly differed from baseline after 5 years (P < 0.0001 for evolution) but not between 1- and 5-year follow-up (P = 0.94). CONCLUSIONS: The few available prospective cohorts reported a significant decrease in disease activity after 1 year, with no global differences. Proportions of disease activity did not differ between 1- and 5-year follow-up in the Belgian Crohn's disease cohort, suggesting stable disease activity.

Targeting the altered duodenal microenvironment in functional dyspepsia.

Duodenal micro-inflammation and microbial dysregulation are increasingly recognized to play an important role in functional dyspepsia (FD) pathophysiology, previously regarded as a purely functional disorder. With current therapeutic options contested through insufficient efficacy or unfavorable adverse effects profiles, novel treatments directed to duodenal alterations could result in superior symptom control in at least a subset of patients. Indeed, recent advances in FD research provided evidence for anti-inflammatory therapies to relieve gastroduodenal symptoms by reducing duodenal eosinophils or mast cells. In addition, restoring microbial homeostasis by probiotics proved to be successful in FD. As the exact mechanisms by which these novel pharmacological approaches result in clinical benefit often remain to be elucidated, future research should focus on how immune activation and dysbiosis translate into typical FD symptomatology.

Effect of sleeve gastrectomy and Roux-en-Y gastric bypass on gastrointestinal physiology.

BACKGROUND: Knowledge regarding the gastrointestinal physiology after sleeve gastrectomy and Roux-en-Y gastric bypass is urgently needed to understand, prevent and treat the nutritional and pharmacological complications of bariatric surgery. AIM: To investigate the effect of sleeve gastrectomy and Roux-en-Y gastric bypass on gastrointestinal motility (e.g., transit and pressure), pH, and intestinal bile acid concentration. MATERIAL AND METHODS: An exploratory cross-sectional study was performed in six participants living with obesity, six participants who underwent sleeve gastrectomy, and six participants who underwent Roux-en-Y gastric bypass. During the first visit, a wireless motility capsule (SmartPill©) was ingested after an overnight fast to measure gastrointestinal transit, pH, and pressure. During the second visit, a gastric emptying scintigraphy test of a nutritional drink labeled with 99mTc-colloid by a dual-head SPECT gamma camera was performed to measure gastric emptying half-time (GET1/2). During the third visit, two customized multiple lumen aspiration catheters were positioned to collect fasting and postprandial intestinal fluids to measure bile acid concentration. RESULTS: Immediate pouch emptying (P = 0.0007) and a trend for faster GET1/2 (P = 0.09) were observed in both bariatric groups. There was a tendency for a shorter orocecal transit in participants with sleeve gastrectomy and Roux-en-Y gastric bypass (P = 0.08). The orocecal segment was characterized by a higher 25th percentile pH (P = 0.004) and a trend for a higher median pH in both bariatric groups (P = 0.07). Fasting total bile acid concentration was 7.5-fold higher in the common limb after Roux-en-Y gastric bypass (P < 0.0001) and 3.5-fold higher in the jejunum after sleeve gastrectomy (P = 0.009) compared to obesity. Postprandial bile acid concentration was 3-fold higher in the jejunum after sleeve gastrectomy (P = 0.0004) and 6.5-fold higher in the common limb after Roux-en-Y gastric bypass (P < 0.0001) compared to obesity. CONCLUSION: The anatomical alterations of sleeve gastrectomy and Roux-en-Y gastric bypass have an important impact on gastrointestinal physiology. This data confirms changes in transit and pH and provides the first evidence for altered intraluminal bile acid concentration.

Malnutrition with Low Muscle Mass Is Common after Weaning off Home Parenteral Nutrition for Chronic Intestinal Failure.

The differences in outcomes after weaning off intravenous support (IVS) for chronic intestinal failure (IF) are unclear. Adult IF patients who are weaned off IVS at a tertiary care center (June 2019−2022) were included in this study, and nutritional and functional markers were assessed before, during, and after weaning. Short bowel syndrome (SBS) was present in 77/98 of the IF patients, with different outcomes according to the final anatomy. The body weight and the BMI increased during IVS in those with a jejunocolonic (JC) anastomosis (p < 0.001), but weight loss was significant during follow-up (p < 0.001). Malnutrition was present in >60%, with a reduced muscle mass, which was found using bioelectrical impedance analysis (BIA), in >50% of SBS-JC patients. Although reduced hand-grip strength and sarcopenia were less common, the muscle quality, or phase angle (BIA), decreased during follow-up, also correlating with serum albumin and muscle mass (p ≤ 0.01). The muscle quality and albumin were low in the patients restarting IVS, which was only the case with ≤60 cm of small bowel. Closer follow-up and earlier treatment with teduglutide (TED) should be considered in these patients, as none of the TED-treated patients were malnourished or sarcopenic. Studies on the potential benefits of nutritional and physical interventions for low muscle mass and associations with outcomes are needed in chronic IF patients.

Living on the edge: morphological and behavioral adaptations to a marginal high-elevation habitat in an arboreal mammal.

Habitats are characterized by different local environmental conditions that influence both behavior and morphology of species, which can result in habitat-dependent phenotypic differences among animals living in heterogeneous environments. We studied 3 alpine populations of Eurasian red squirrels (Sciurus vulgaris), 1 living in a marginal high-elevation habitat at the edge of the species' altitudinal distribution, and 2 occurring in higher-quality habitats. Here, we investigated whether squirrels living in the marginal area differed in 2 morphological parameters (body size and body mass) and/or in the expression of 4 personality traits estimated with an open field test and a mirror image stimulation test (activity, exploration, activity-exploration, and social tendency). Furthermore, we tested whether within-individual variance of the traits (behavioral plasticity) was higher in the edge habitat. Male squirrels in the edge habitat were smaller and weighed less than in the other study areas, while among females, size-habitat relationships were less marked. These sex-specific patterns were explained by a strong association between body mass and reproductive success in female squirrels. Squirrels in the marginal habitat were more active, explorative, and had a more social personality than in the other habitats. However, in contrast to our predictions, behavioral plasticity was smaller in the marginal habitat, but only for the trait exploration. Our results suggest that animals choose the habitat that best fits their personality, and that habitat-related differences in selective pressures may shape animals' morphology.

Native species exhibit physiological habituation to invaders: a reason for hope.

Animals cope with environmental perturbations through the stress response, a set of behavioural and physiological responses aimed to maintain and/or return to homeostasis and enhance fitness. Vertebrate neuroendocrine axis activation in response to environmental stressors can result in the secretion of glucocorticoids (GCs), whose acute increases may be adaptive, while chronic elevation may be detrimental. Invasive grey squirrels (Sciurus carolinensis) act as a stressor eliciting elevation of GCs in native red squirrels (Sciurus vulgaris). Here we used 6-year data of variation in faecal glucocorticoid metabolite (FGM) concentrations following invasion by grey squirrels in three red squirrel populations, to identify if red squirrels showed physiological habituation to this stressor. The decrease in FGMs over time was more pronounced shortly after invasion and at high densities of grey squirrels while it decreased less strongly and was no longer influenced by the invader density as time since invasion elapsed. At the individual level, FGMs also decreased more markedly as each red squirrel experienced prolonged contact with the invader. Our study provides compelling new data suggesting that native species in the wild can habituate to prolonged contact with invasive species, showing that they may avoid the potentially harmful effects of chronic elevations in GCs.

Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect.

Disorders of gut-brain interaction (DGBI), formerly termed functional gastrointestinal disorders (FGID), are highly prevalent although exact pathophysiological mechanisms remain unclear. Intestinal immune activation has been recognized, but increasing evidence supports a pivotal role for an active inflammatory state in these disorders. In functional dyspepsia (FD), marked eosinophil and mast cell infiltration has been repeatedly demonstrated and associations with symptoms emphasize the relevance of an eosinophil-mast cell axis in FD pathophysiology. In this Review, we highlight the importance of immune activation in DGBI with a focus on FD. We summarize eosinophil biology in both homeostasis and inflammatory processes. The evidence for immune activation in FD is outlined with attention to alterations on both cellular and molecular level, and how these may contribute to FD symptomatology. As DGBI are complex and multifactorial conditions, we shed light on factors associated to, and potentially influencing immune activation, including bidirectional gut-brain interaction, allergy and the microbiota. Crucial studies reveal a therapeutic benefit of treatments targeting immune activation, suggesting that specific anti-inflammatory therapies could offer renewed hope for at least a subset of DGBI patients. Lastly, we explore the future directions for DGBI research that could advance the field. Taken together, emerging evidence supports the recognition of FD as an immune-mediated organic-based disorder, challenging the paradigm of a strictly functional nature.

Potential importance of early treatment of SARS-CoV-2 infection in intestinal transplant patient: A case report.

BACKGROUND: Predispositions for severe coronavirus disease 2019 (COVID-19) are age, immunosuppression, and co-morbidity. High levels of maintenance immunosuppression render intestinal transplant (ITx) patients vulnerable for severe COVID-19. COVID-19 also provokes several gastroenterological pathologies which have not been discussed in ITx, so far. CASE SUMMARY: During the second European COVID-19 wave in November 2020, an ITx recipient was admitted to the hospital because of electrolyte disturbances due to dehydration. Immunosuppression consisted of tacrolimus, azathioprine, and low-dose corticosteroids. During hospitalization, she tested positive on screening COVID-19 nasopharyngeal polymerase chain reaction swab, while her initial test was negative. She was initially asymptomatic and had normal inflammatory markers. Tacrolimus levels were slightly raised, as Azathioprine was temporarily halted. Due to elevated D-dimers at that time, prophylactic low-molecular weight heparin was started. Seven days after the positive test, dyspnea, anosmia, and C-reactive protein increase (25 mg/L) were noted. Remdesivir was administered during 5 d in total. High stomal output was noted in two consecutive days and several days thereafter. To exclude infection or rejection, an ileoscopy and biopsy were performed and excluded these. Four weeks later, she was discharged from the hospital and remains in good health since then. CONCLUSION: Early eradication of severe acute respiratory syndrome coronavirus 2 in ITx recipients may be warranted to prevent acute rejection provocation by it.

The Role of Leaky Gut in Functional Dyspepsia.

Patients with functional dyspepsia (FD) complain of epigastric symptoms with no identifiable cause. Increased intestinal permeability has been described in these patients, especially in the proximal small bowel or duodenum, and was associated with mucosal immune activation and symptoms. In this review, we discuss duodenal barrier function, including techniques currently applied in FD research. We summarize the available data on duodenal permeability in FD and factors associated to increased permeability, including mucosal eosinophils, mast cells, luminal and systemic factors. While the increased influx of antigens into the duodenal mucosa could result in local immune activation, clinical evidence for a causal role of permeability is lacking in the absence of specific barrier-protective treatments. As both existing and novel treatments, including proton pump inhibitors (PPI) and pre- or probiotics may impact duodenal barrier function, it is important to recognize and study these alterations to improve the knowledge and management of FD.

Estrogens Play a Critical Role in Stress-Related Gastrointestinal Dysfunction in a Spontaneous Model of Disorders of Gut-Brain Interaction.

BACKGROUND: Disorders of the gut-brain interaction (DGBI), such as irritable bowel syndrome and functional dyspepsia, are more prevalent in women than in men, with a ratio of 2:1. Furthermore, stressful life events have been reported as one of the triggers for symptoms in DGBI patients. METHODS: Here, we studied the effect of an early-life stressor (maternal separation (MS)) on jejunal and colonic alterations, including colonic sensitivity and immune cells infiltration and activation in a validated spontaneous model of DGBI (BBDP-N), and investigated the involvement of ß-estradiol on stress-worsened intestinal alterations. RESULTS: We found that maternal separation exacerbated colonic sensitivity and mast cell and eosinophil infiltration and activation in females only. Ovariectomy partially rescued the stress phenotype by decreasing colonic sensitivity, which was restored by ß-estradiol injections and did not impact immune cells infiltration and activation. Stressed males exposed to ß-estradiol demonstrated similar intestinal alterations as MS females. CONCLUSION: Estrogen plays a direct critical role in colonic hypersensitivity in a spontaneous animal model of DGBI, while for immune activation, estrogen seems to be involved in the first step of their recruitment and activation. Our data point towards a complex interaction between stress and ß-estradiol in DGBI.

Lactobacillus rhamnosus CNCM I-3690 decreases subjective academic stress in healthy adults: a randomized placebo-controlled trial.

Psychological stress negatively affects the intestinal barrier function in animals and humans. We aimed to study the effect of Lactobacillus rhamnosus CNCM I-3690 on intestinal permeability and stress-markers during public speech. Healthy students were randomized to L. rhamnosus-containing (test) or acidified (placebo) milk consumed twice daily for 4 weeks, with 46 subjects per treatment group. Small intestinal permeability was quantified by a 2 h urinary lactulose-mannitol ratio (LMR, primary outcome), fractional excretion of lactulose (FEL) and mannitol (FEM). Salivary cortisol, State-Trait Anxiety Inventory (STAI) and Perceived Stress scores (PSS) were collected. No between-treatment differences were found for LMR (p = .71), FEL or FEM. Within-treatment analyses showed similar LMR and FEL but a stress-induced increase of FEM with the placebo (p < .05) but not test product. Despite a similar increase in salivary cortisol, the stress-induced increase in STAI was significantly lower with the test product vs. placebo (p = .01). Moreover, a stress-preventative effect of the probiotic was found for PSS and more pronounced in subjects with high stress-induced cortisol (p = .01). While increased FEM was mediated by salivary cortisol levels, the effect of the test product on subjective stress was not mediated by changes in FEM. No serious adverse events occurred. In conclusion, we demonstrated that L. rhamnosus CNCM I-3690 prevented stress-induced hyperpermeability to mannitol. Subjective but not objective stress-markers were reduced with L. rhamnosus vs. placebo, suggesting anxiolytic effects, which were independent of barrier stabilization and attractive for the reduction of stress in both health and disease. Clinicaltrials.gov, number NCT03408691.