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.

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.

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.

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.

Heart rate variability in anorexia nervosa and the irritable bowel syndrome.

BACKGROUND: Many studies have reported disturbances of heart rate variability (HRV) in patients with psychosomatic disorders such as anorexia nervosa (AN) and the irritable bowel syndrome (IBS). However, both have never been directly compared. METHODS: We compared HRV in AN (n = 21) and in IBS (n = 21) (all females) with 42 healthy female control subjects who were matched for age and in IBS to body mass index (BMI). Recovery periods between different cardiac load tests were compared with baseline recordings and tilt test to estimate time [mean successive difference (MSD)] and frequency domain (Goldberger dimension, frequency of HF peak location and HF power, log HF power) values and to assess general reactivity of the autonomic nervous system (ANS). KEY RESULTS: Significantly longer inter-beat intervals (IBIs) in AN patients and lower values of MSD in IBS patients were found in comparison with respective controls; both were independent from experimental conditions and are found in baseline recordings only. Both effects were independent of age and BMI. We also demonstrate a significant relationship between age, BMI and some HRV parameters. CONCLUSIONS & INFERENCES: Opposite autonomic patterns were found in AN and IBS: stronger vagal withdrawal in IBS and weaker vagal inhibition in AN patients. Records made at rest and without any autonomic load may be representative for assessment of ANS function. Age and BMI should be taken into consideration during assessment of HRV data.

The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells.

Galectin-3 is a member of the beta-galactoside-binding protein family shown to be involved in tumor progression and metastasis. It has a unique primary structure consisting of three domains: a 12-amino acid leader sequence containing a casein kinase I serine phosphorylation site, which is preceded by a collagenase-sensitive Pro-Gly-rich motif, and a COOH-terminal half encompassing the carbohydrate-binding site. To study the functional role of the unusual leader sequence of galectin-3, a mutant cDNA that causes an 11-amino acid deletion in the NH2-terminal region was generated and expressed in galectin-3-null BT-549 human breast carcinoma cells. Deletion of the NH2 terminus resulted in abolition of the secretion of truncated galectin-3, loss of nuclear localization, and reduced carbohydrate-mediated functions compared with the wild-type protein. When green fluorescent protein was fused to the galectin-3 leader sequence and transiently transfected into BT-549 cells, the uniform cellular distribution of native green fluorescent protein was changed mainly to a nuclear pattern. To further investigate whether the functional changes observed in a galectin-3 with the 11 NH2-terminal amino acids deleted were due to loss of phosphorylation at Ser6, two point mutations were created at this serine: Ser6-->Ala and Ser6-->Glu. No obvious difference was observed in cellular localization between wild-type and Ser6-mutated transfectants. These results suggest a structural role for the NH2 terminus leader motif of galectin-3 in determining its cellular targeting and biological functions independent of phosphorylation.