The "Biology-First" Hypothesis: Functional disorders may begin and end with biology-A scoping review.

While it is generally accepted that gastrointestinal infections can cause functional disturbances in the upper and lower gastrointestinal tract-known as postinfectious irritable bowel syndrome (PI-IBS) and functional dyspepsia (PI-FD)-it has still not been widely recognized that such an infection can also initiate functional non-intestinal diseases, and that non-intestinal infections can provoke both intestinal and non-intestinal functional disturbances. We conducted a scoping review of the respective literature and-on the basis of these data-hypothesize that medically unexplained functional symptoms and syndromes following an infection may have a biological (genetic, endocrine, microbiological) origin, and that psychological and social factors, which may contribute to the disease "phenotype," are secondary to this biological cause. If this holds true, then the search for psychological and social theories and factors to explain why one patient develops a chronic functional disorder while another does not is-at least for postinfectious states-misleading and detracts from exploring and identifying the true origins of these essentially biological disorders. The biopsychosocial model may, as the term implies, always begin with biology, also for functional (somatoform) disorders.

Stress reactivity in childhood functional abdominal pain or irritable bowel syndrome.

BACKGROUND: Frequent abdominal pain (AP) in childhood has been shown to be associated with elevated experience of stress and with deficits in stress coping, but psychophysiological stress reactivity has been studied rarely. METHODS: We examined whether children with frequent AP show altered reactions of the parasympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis during and following an afternoon laboratory social stress task in comparison to healthy children and children with anxiety disorders. Twenty-four children with frequent AP (18 with functional AP and six with irritable bowel syndrome; M = 9.9 years), and 24 healthy controls underwent stressful free speech and arithmetic tasks. Twelve children with anxiety disorders served as second comparison sample. Groups were compared regarding parasympathetic reaction and saliva cortisol concentration. RESULTS: We found no differences in parasympathetic withdrawal between the groups. Concerning the HPA axis, we detected an attenuated cortisol reactivity in children with AP compared to both other groups. CONCLUSIONS: This study provides preliminary evidence that childhood AP is not associated with altered parasympathetic withdrawal during stress. It seems to be related to a down-regulated reactivity of the HPA axis. This pattern was ascertained in comparison to healthy children and also in comparison to children with anxiety disorders. SIGNIFICANCE: Childhood abdominal pain could be related to down-regulated HPA axis reactivity to stress but not to altered parasympathetic reaction. Children with abdominal pain and children with anxiety disorders exhibit a divergent stress-related HPA axis reaction.

A fresh look at IBS-opportunities for systems medicine approaches.

NeuroGUT is a EU-funded initial training network (ITN) of 14 research projects in neurogastroenterology that have employed an equal number of early-stage researchers. Neurogut trainees have-among other activities-attended an international conference on irritable bowel syndrome (IBS) in Bologna in 2016 and were asked to critically review and evaluate the current knowledge on IBS for their respective research activities, and to state what they were missing. Most appreciated were the topics brain imaging of gut activity, the role of the gut microbiota, the pharmacology of gut functions, the IBS-IBD interrelation, the new Rome IV criteria, the role of gas, and the placebo response in functional disorders. Missed were more detailed coverage of high-resolution manometry, functional brain imaging, advanced "systems medicine" approaches and bioinformatics technology, better sub-classification of IBS patients, and the development of disease biomarkers, extended at the molecular (genetic/epigenetic, proteonomic) level. They summarize that despite excellent specialized research, there is a gap open that should be filled with systems medicine. For this, it would be necessary that medical research learns even more from the data sciences and other basic disciplines, for example, information technology and system biology, and also welcomes a change in paradigm that enhances open sharing of data, information, and resources.

[Psychobiological mechanisms in the pathophysiology of chronic visceral pain]. / Psychobiologische Mechanismen bei der Pathophysiologie chronischer viszeraler Schmerzen.

Although visceral pain is of high clinical relevance, it remains poorly understood especially when compared to somatic pain. Nevertheless, interdisciplinary research approaches bridging psychophysiology and neurogastroenterology have contributed to a more refined knowledge about the complex peripheral and central mechanisms of the bidirectional brain-gut axis in recent years. This review summarizes current knowledge regarding psychobiological mechanisms in the pathophysiology of chronic visceral pain in functional gastrointestinal disorders with a focus on irritable bowel syndrome (IBS). Special attention is paid to the role of affective disturbances and emotions, particularly psychological stress as well as to influences of cognition and learning on gastrointestinal motor and sensory functions in healthy individuals and patients with IBS. In this emerging field of research, new evidence from the fields of placebo research and pain-related fear conditioning provide new insights into the psychological and neurobiological mechanisms involved in the transition from acute to chronic pain and the maintenance of pain. This opens up new perspectives for innovative treatment approaches for IBS and other functional gastrointestinal disorders.

Functional neuroimaging studies in functional dyspepsia patients: a systematic review.

BACKGROUND: There is increasing evidence in support of the presence of abnormal central changes (compared to healthy controls) in functional dyspepsia (FD) in addition to the peripheral changes in gastrointestinal tract. PURPOSE: This systematic review aims to provide an integrative understanding of the abnormal functional brain activity, visceral sensation, dyspeptic symptoms, and psychological changes of FD. Electronic and hand searches were conducted to identify functional neuroimaging studies involving FD patients. Sixteen studies were selected and divided into three categories: 10 resting state studies, three visceral distention studies, and three acupuncture studies. Changes were reported in several brain areas in FD patients including the frontal cortex, somatosensory cortex, insula, anterior cingulate cortex, thalamus, hippocampus, and amygdala. These brain activity changes were associated with visceral hypersensitivity, dyspeptic symptoms, poorer quality of life, anxiety, and depression. The results show that FD is associated with functional abnormalities in sensory and pain modulation, emotion, saliency, and homeostatic processing regions. The diversity of conditions, heterogeneous results, poorly standardized diagnoses of FD, and various comorbidities may be responsible for the variability in the results.

Gastric ghrelin, GOAT, leptin, and leptinR expression as well as peripheral serotonin are dysregulated in humans with obesity.

BACKGROUND: Gastrointestinal hormone release and the regulation of appetite and body weight are thought to be dysbalanced in obesity. However, human data investigating the expression of gastrointestinal hormones in the obese are rare. We studied the expression of ghrelin, leptin, and the serotonergic system in stomach tissue and serum of obese and non-obese individuals. METHODS: Gastric tissue and serum were collected from 29 adult obese (BMI 48.7 ± 10.6 kg/m(2) ; mean ± SD) who underwent laparoscopic sleeve gastrectomy. Gastric biopsies, surgery specimen or serum was obtained from 35 adult non-obese humans (BMI 22.7 ± 1.9 kg/m(2) ). Ghrelin, ghrelin O-acyl transferase (GOAT), leptin, leptin receptor, and tryptophan hydroxylase 1 (TPH1) mRNA expression were measured by qRT-PCR. Serotonin (5HT) and leptin protein concentration were quantified in tissue extracts and serum; GOAT and ghrelin-positive cells were immunohistologically quantified in tissue. Additionally, 21 blood immune markers were analyzed. KEY RESULTS: In gastric tissue, GOAT-positive cells were reduced (p < 0.01), but ghrelin-positive cells and mRNA were increased (both p < 0.05) in obese compared with non-obese individuals. Gastric leptin (p < 0.001) and leptin receptor (p < 0.001) mRNA expression, as well as leptin concentrations in serum (p < 0.001), were increased in obese compared with non-obese individuals. Serum 5HT was reduced (p < 0.05), while tissue 5HT and TPH1 mRNA were reduced only by trend. Interleukin 1 receptor a (IL1Ra), IL-8, IL-12, and monocyte chemoattractant protein 1 (IL1Ra) were increased and IL1Ra correlated negatively with serum leptin. CONCLUSIONS & INFERENCES: Our data indicate that obesity causes a dysregulation of gastrointestinal hormones at the tissue level and serum, including a negative correlation with an increased marker of subclinical inflammation.

Postinfectious irritable bowel syndrome after travelers' diarrhea--a cohort study.

BACKGROUND: There is sound evidence for the role of gastrointestinal infections in the development of postinfectious irritable bowel syndrome (PI-IBS), but understanding the interaction between mental factors and the infection remains incomplete. This study aims to (i) assess the occurrence of PI-IBS in a cohort of patients with self-reported travelers' diarrhea (TD), (ii) assess risk factors for PI-IBS development, and (iii) investigate the prognosis of PI-IBS after 1 year. METHODS: Patients consulting the travel clinic at the University Hospital Tuebingen, Germany (in 2009 and 2010) were identified from records and questioned in follow-ups in 2011 and 2012. We used the Rome III modular questionnaire to assess IBS, the Hospital Anxiety and Depression Scale to assess anxiety and depression, and the Patient Health Questionnaire to assess somatization. KEY RESULTS: We identified 529 eligible subjects from the clinical records. Of 135 subjects (age: 36.6 ± 14.6 years, 58.5% female) included in the study sample 6.7% (95% CI 3.0-11.1) had PI-IBS. We found more females (88.9% vs 56.3%, p = 0.08) and younger age subjects (mean 29.3 vs 37.1 years, p = 0.02) among the PI-IBS subjects. A multivariable regression model revealed vomiting at baseline and high somatization scores as strong and independent PI-IBS risk factors. One year later PI-IBS occurrence decreased to 3.3% (three cases of 90). CONCLUSIONS & INFERENCES: Our findings underline the close linkage of mental and somatic processes for the manifestation of PI-IBS. Screening for psychiatric comorbidities in patients with severe gastrointestinal infections may allow identifying groups at high risk for PI-IBS.

Systematic review with meta-analysis: post-infectious irritable bowel syndrome after travellers' diarrhoea.

BACKGROUND: Gastrointestinal infection is known as a risk factor for the development of the irritable bowel syndrome (post-infectious irritable bowel syndrome, PI-IBS). The incidence of PI-IBS ranges between 3% and over 30% of people after infectious gastroenteritis. AIM: To perform a meta-analysis pools and report data concerning the relative risk (RR) of PI-IBS after TD. METHODS: Database search using Medline through PubMed, Scopus, EBM Reviews (Cochrane Database of Systematic Reviews) and PsycINFO was performed to identify relevant studies. Those that met the inclusion criteria were pooled. A random effects model (Mantel-Haenszel) was performed. RESULTS: Six eligible studies were found. In three of six studies, the authors reported a statistically significant association of TD and PI-IBS. The pooled RR was 3.35 (95% CI: 2.22-5.05) with a significant overall effect (P < 0.00001). Overall PI-IBS incidence was 5.4% in TD subjects and 1.4% in healthy subjects. There was no significant heterogeneity within the pooled studies (I(2)  = 5%). Self-reported TD alone resulted in an over 1.5-fold RR for PI-IBS compared to laboratory-confirmed TD [RR 3.90 (95% CI: 2.35-6.49) vs. RR 2.42 (95% CI: 1.22-4.78)]. CONCLUSIONS: There is a strong association between travellers' diarrhoea and post-infectious irritable bowel syndrome. Self-reports of exposure seem to result in a higher post-infectious irritable bowel syndrome occurrence than laboratory-confirmed cases of travellers' diarrhoea, but further studies are needed to confirm this finding. Finally, potential influences of the selection of an appropriate study population on post-infectious irritable bowel syndrome epidemiology are discussed.

[Psychophysiology of visceral pain]. / Psychophysiologische Grundlagen viszeraler Schmerzen.

The psychophysiology of visceral pain is--different from cardiac psychophysiology--much less well investigated due to the invasiveness of its methods and problems associated with reliably and reproducibly stimulating as well as recording of the gastrointestinal tract. Despite these problems, the last 30 years have documented a number of psychophysiological phenomena such as the perception (interoception) of visceral stimuli, the effect of emotions and stress on visceral sensations, and the effect of visceral processes on cortical processing. This was mainly due to the application of neurophysiological techniques (cortical imaging and stimulation) in these investigations.

Review article: Associations between Helicobacter pylori and obesity--an ecological study.

BACKGROUND: There is emerging debate over the effect of Helicobacter pylori infection on body mass index (BMI). A recent study demonstrated that individuals who underwent H. pylori eradication developed significant weight gain as compared to subjects with untreated H. pylori colonisation. AIM: To elucidate the association between H. pylori colonisation and the prevalence of overweight and obesity in developed countries. METHODS: The literature was searched for publications reporting data on H. pylori prevalence rates and obesity prevalence rates. Studies selected reported H. pylori prevalence in random population samples with sample sizes of more than 100 subjects in developed countries (GDP >25,000 US$/person/year). Corresponding BMI distributions for corresponding countries and regions were identified. Nonparametric tests were used to compare the association between H. pylori and overweight and obesity rates. RESULTS: Forty-nine studies with data from 10 European countries, Japan, the US and Australia were identified. The mean H. pylori rate was 44.1% (range 17-75%), the mean rates for obesity and overweight were 46.6 (± 16)% and 14.2 (± 8.9)%. The rate of obesity and overweight were inversely and significantly (r = 0.29, P < 0.001) correlated with the prevalence of H. pylori infection. CONCLUSIONS: There is an inverse correlation between H. pylori prevalence and rate of overweight/obesity in countries of the developed world. Thus, the gradual decrease of the H. pylori colonisation that has been observed in recent decades (or factors associated with decrease of) could be causally related to the obesity endemic observed in the Western world.

Perception and pain thresholds for cutaneous heat and cold, and rectal distension: associations and disassociations.

BACKGROUND: Hypersensitivity to somatic or visceral pain has been reported in numerous clinical conditions such as fibromyalgia or the irritable bowel syndrome, and general hypersensitivity has been proposed to be the underlying mechanism. However, cross-modal relationships especially between somatic and visceral pain have rarely been investigated even in healthy volunteers. Furthermore, psychological influences on pain have rarely been characterized across modalities. METHODS: Sixty-one healthy participants underwent testing of perception and pain thresholds for cutaneous thermode heat and cold, as well as for rectal balloon distension. Psychological testing for anxiety, depression, and pain experience (including catastrophizing and coping) as well as cardiac interoception was performed. Measurement quality and the correlations between the different modalities were examined. KEY RESULTS: Significant correlations existed between the perception thresholds for cold/heat (τB  = -0.28, p = 0.002) and cold/distension (τB  = -0.21, p = 0.03) and for the pain thresholds for cold/heat (r = -0.61, p < 0.001) and heat/distension (r = 0.33, p = 0.01). No association was found between pain thresholds and anxiety, depression, psychological experience with and processing of pain, or cardiac interoception. Retest reliabilities for pain measurements were satisfying after short intertrial intervals (all intraclass correlation coefficients >0.8), but less so after longer intervals. The individuals contributing to the respective correlations differ between measurements. CONCLUSIONS & INFERENCES: Moderate associations were found for pain thresholds across modalities. The strength of the associations and their stability over time warrants further investigation and might serve to increase the understanding of conditions affecting multiple pain modalities.

Effects of a 48-h fast on heart rate variability and cortisol levels in healthy female subjects.

BACKGROUND/OBJECTIVES: The physiological changes that occur during fasting are not completely understood, regardless of the cause for fasting (for example, medical, lifestyle, religious, political or famine). The purpose of this study was to examine the effects of a 48-h fast on heart rate variability (HRV) and cortisol levels in healthy young female volunteers. SUBJECTS/METHODS: A total of 16 young healthy female volunteers underwent 48 h of total fasting under 24-h medical surveillance. Psychological (subjective feeling of hunger) as well as physiological data (HRV, diurnal cortisol profiles) were measured upon admission (Day 1), and after 24 (Day 2) and 48 h (Day 3) of fasting. RESULTS: There was a measured weight loss from Day 1 to Day 3 that resulted in significant body mass index (BMI) reduction across all subjects (P<0.001). The slope of the diurnal cortisol profile significantly shifted towards lower values from baseline to the end of experiment (P=0.002). HRV during resting showed a significant (P<.001) decrease in standard deviation of the normal-to-normal interval (SDNN) and root mean square of successive differences (RMSSDs) from Day 1 to Day 3 of the experiment, with a small increase after 24 h that did not reach statistical significance. A 48 h of fasting also induced a significant (P<.001) decrease of mean interbeat intervals (IBIs), SDNN, RMSSD and log high-frequency (HF) power during head-up tilt testing. CONCLUSIONS: An acute (48 h) total fast induced parasympathetic withdrawal with simultaneous sympathetic activation. These changes appear to reflect stress. Further studies are needed to demonstrate the specificity of these changes to fasting.

Heart rate variability in the irritable bowel syndrome: a review of the literature.

BACKGROUND: Patients with irritable bowel syndrome (IBS) often present with disturbances of bowel habits (diarrhea, constipation) and abdominal pain/discomfort that are modulated by the autonomic nerve system (ANS). In this narrative review, we analyzed studies that measured ANS functioning in IBS by means of heart rate variability (HRV). METHODS: The PUBMED was searched with the keywords 'irritable bowel syndrome' AND ('heart rate variability' OR 'autonomic function'). We included only papers that used 'traditional' HRV indices and diagnosed IBS based on Manning or Rome criteria. Studies were sub-grouped according to methodological features of HRV analysis (24-h monitoring, short-term laboratory records, records during sleep). KEY RESULTS: Most studies reported no difference in HRV when the IBS population was compared to healthy controls. Dividing the IBS sample into subgroups--according to their predominant bowel symptoms, the severity of clinical course, the presence of depressive symptoms, or a history of abuse in the past--revealed changes in autonomic functioning. CONCLUSIONS & INFERENCES: Patients with IBS appear to experience symptoms that may be the result of changes in ANS functioning. HRV measures in clinical routine may allow assessing these changes, but further studies performed in a standardized fashion should improve the validity of HRV measures for clinical research first.

A vegan or vegetarian diet substantially alters the human colonic faecal microbiota.

BACKGROUND/OBJECTIVES: Consisting of ≈10(14) microbial cells, the intestinal microbiota represents the largest and the most complex microbial community inhabiting the human body. However, the influence of regular diets on the microbiota is widely unknown. SUBJECTS/METHODS: We examined faecal samples of vegetarians (n=144), vegans (n=105) and an equal number of control subjects consuming ordinary omnivorous diet who were matched for age and gender. We used classical bacteriological isolation, identification and enumeration of the main anaerobic and aerobic bacterial genera and computed absolute and relative numbers that were compared between groups. RESULTS: Total counts of Bacteroides spp., Bifidobacterium spp., Escherichia coli and Enterobacteriaceae spp. were significantly lower (P=0.001, P=0.002, P=0.006 and P=0.008, respectively) in vegan samples than in controls, whereas others (E. coli biovars, Klebsiella spp., Enterobacter spp., other Enterobacteriaceae, Enterococcus spp., Lactobacillus spp., Citrobacter spp. and Clostridium spp.) were not. Subjects on a vegetarian diet ranked between vegans and controls. The total microbial count did not differ between the groups. In addition, subjects on a vegan or vegetarian diet showed significantly (P=0.0001) lower stool pH than did controls, and stool pH and counts of E. coli and Enterobacteriaceae were significantly correlated across all subgroups. CONCLUSIONS: Maintaining a strict vegan or vegetarian diet results in a significant shift in the microbiota while total cell numbers remain unaltered.