Small intestinal bacterial overgrowth (SIBO) has been implicated in symptoms associated with functional gastrointestinal disorders (FGIDs), though mechanisms remain poorly defined and treatment ...involves non-specific antibiotics. Here we show that SIBO based on duodenal aspirate culture reflects an overgrowth of anaerobes, does not correspond with patient symptoms, and may be a result of dietary preferences. Small intestinal microbial composition, on the other hand, is significantly altered in symptomatic patients and does not correspond with aspirate culture results. In a pilot interventional study we found that switching from a high fiber diet to a low fiber, high simple sugar diet triggered FGID-related symptoms and decreased small intestinal microbial diversity while increasing small intestinal permeability. Our findings demonstrate that characterizing small intestinal microbiomes in patients with gastrointestinal symptoms may allow a more targeted antibacterial or a diet-based approach to treatment.
ObjectiveThe intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS.Design39 patients with IBS and 25 ...healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states.ResultsPatients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota.ConclusionA subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.
Background and Aim:
Irritable bowel syndrome (IBS) is a complex and heterogeneous disorder. Sensory, motor and barrier dysfunctions are the key physiological endophenotypes of IBS. Our aim is to ...review studies evaluating barrier dysfunction in adults and children with IBS, as well as to link those changes with IBS symptomatology and quality of life.
Methods:
A comprehensive and systematic review of multiple databases was performed up to March 2020 to identify studies comparing intestinal permeability in IBS patients with healthy controls. Both in vivo and in vitro studies were considered.
Results:
We identified 66 studies, of which 27 used intestinal probes to quantify barrier function. The prevalence of barrier dysfunction differed between PI-IBS (17–50%), IBS-D (37–62%) and IBS-C (4–25%). At a group level, permeability was increased compared with healthy controls in IBS-D (9/13 studies) and PI-IBS (4/4 studies), but only a minority of IBS-C (2/7 studies) and not in the only IBS-M study. All four studies in children with IBS demonstrated loss of barrier function. A heterogeneous set of tight junction genes were found to be altered in small and large intestines of adults with IBS, but these have not been evaluated in children. Positive associations were identified between barrier dysfunction and bowel disturbances (6/9 studies), abdominal pain (9/13 studies), overall symptom severity (1/6 studies), depression and anxiety (1/1 study) and quality of life (1/4 studies). Fecal slurry or supernatants of IBS patients were found to induce barrier disruption in animal models (5/6 studies).
Conclusions:
Barrier dysfunction is present in a significant proportion of adult and all pediatric IBS studies, especially in the IBS-D and PI-IBS subtype. The majority of studies indicated a positive association between loss of barrier function and symptoms such as abdominal pain and changes in the bowel function.
The aim of this study was to evaluate tolerability of and response to rituximab in children with myelin oligodendrocyte glycoprotein (MOG) antibody‐positive relapsing neuroinflammatory disease. This ...was an observational study of prospectively collected data on 12 consecutive children (eight females, four males; median age at onset 10y 6mo interquartile range {IQR} 7y 2mo–12y 5mo, median follow‐up 2y 1mo IQR 1y 7mo–2y 6mo) with central nervous system inflammation and persistent serum MOG immunoglobulin G positivity more than 12 weeks after clinical presentation. Patients received a standardized rituximab treatment protocol. MOG antibody testing was performed following standardized cell‐based methods. Median clinical follow‐up after rituximab induction was 2 years (IQR 1y 7mo–2y 10mo). The relapse rate in the first 12 months posttreatment was 0 (IQR 0–0). After rituximab, two patients relapsed during B‐cell suppression and four showed clinical or radiological disease recurrences at B‐cell reconstitution. Mild‐to‐moderate infusion related adverse events occurred in two patients. Leukopenia developed in seven patients and serum immunoglobulin suppression in five patients with no significant age effect on the risk of their development. None developed severe life‐threatening events. Rituximab‐induced B‐cell suppression was associated with absence of relapses in 10 patients who were MOG‐positive with recurrent disease. Rituximab was well tolerated. The most frequent adverse effects were hypogammaglobulinemia and leukopenia. We recommend monitoring of complete blood counts and immunoglobulins in this population.
What this paper adds
Rituximab appears to control disease in most anti‐myelin oligodendrocyte glycoprotein‐positive patients with relapsing neuroinflammatory disease.
Rituximab was associated with transitory, mild‐to‐moderate infusion‐related effects.
Half of patients treated with rituximab developed leukopenia or hypogammaglobulinemia.
No opportunistic infections were observed.
What this paper adds
Rituximab appears to control disease in most anti‐myelin oligodendrocyte glycoprotein‐positive patients with relapsing neuroinflammatory disease.
Rituximab was associated with transitory, mild‐to‐moderate infusion‐related effects.
Half of patients treated with rituximab developed leukopenia or hypogammaglobulinemia.
No opportunistic infections were observed.
This article is commented on by HACOHEN, MARIGNIER on page 273 of this issue.
To examine the longitudinal relationship between physical activity and fatigue and depression among youth with demyelinating conditions.
From September 2013 to March 2017, we performed a longitudinal ...study of consecutive youth diagnosed at their first visit with pediatric onset multiple sclerosis (POMS) or monophasic acquired demyelinating syndromes (mono-ADS) at a neuroinflammatory disorders clinic in a tertiary children's hospital. Fatigue was determined at each visit by the Pediatric Quality of Life Multidimensional Fatigue Scale, depressive symptoms by the Center of Epidemiologic Studies Depression Children Rating Scale, and physical activity level by the Godin Leisure Time Exercise Questionnaire. Mixed linear models were used to examine the associations of moderate-to-vigorous physical activity (MVPA) with fatigue and depression over time, adjusting for age, time from incident demyelination, sex, number of relapses, relapse within 30 days, and disability.
In 182 patients (48 POMS, age 15 ± 1.7 years, 35 female; and 134 mono-ADS, age 12 ± 3.6 years 67 female) with 538 visits (mean follow-up 3.6 ± 2.7 years and 4.2 ± 3.3 years, respectively), a trajectory of increased fatigue over time was observed in POMS (2.28 points/year, P = .008) and mono-ADS (1.33 points/year, P = .007) patients. Youth with POMS had more depressive symptoms (estimate = 11.4 points, P < .002) than mono-ADS. Depressive symptoms increased over time in female patients with POMS (estimate = 1.4 points/year, P < .02). MVPA was associated with lower depression (−0.09, P < .001) and general fatigue (0.13, P = .02) over time in POMS.
Youth with POMS who have higher levels of MVPA demonstrate lesser depressive symptoms and lower fatigue over time. Our results may inform future interventions to manage mood and fatigue in POMS.
Objectives To investigate physical activity levels in youth with multiple sclerosis and monophasic acquired demyelinating syndromes (mono-ADS, ie, children without relapsing disease) compared with ...healthy controls and to determine factors that contribute to engagement in physical activity. We hypothesized that greater physical activity goal setting and physical activity self-efficacy would be associated with greater levels of vigorous physical activity in youth with multiple sclerosis. Study design A total of 68 consecutive patients (27 multiple sclerosis, 41 mono-ADS) and 37 healthy controls completed fatigue, depression, Physical Activity Self-Efficacy Scale, perceived disability, Exercise Goal-Setting scale, and physical activity questionnaires, and wore an accelerometer for 7 days. All patients had no ambulatory limitations (Expanded Disability Status Scale, scores all <4). Results Youth with multiple sclerosis engaged in fewer minutes per day of vigorous ( P = .009) and moderate and vigorous physical activity ( P = .048) than did patients with mono-ADS and healthy controls. A lower proportion of the group with multiple sclerosis (63%) reported participating in any strenuous physical activity than the mono-ADS (85%) and healthy control (89%) groups ( P = .020). When we adjusted for age and sex, the Physical Activity Self-Efficacy Scale and Exercise Goal-Setting scale were associated positively with vigorous physical activity in the group with multiple sclerosis. Fatigue and depression did not predict physical activity or accelerometry metrics. Conclusions Youth with multiple sclerosis participate in less physical activity than their counterparts with mono-ADS and healthy controls. Physical activity self-efficacy and exercise goal setting serve as potentially modifiable correlates of physical activity, and are measures suited to future interventions aimed to increase physical activity in youth with multiple sclerosis.
Objective To investigate differences in fertilization, clinical pregnancy, and miscarriage rates between men with a markedly high sperm DNA fragmentation index (DFI) (>50%) and those with low DFI ...(≤15%) in couples matched by female partner age and ovarian reserve as determined by antimüllerian hormone (AMH) level. Design Retrospective cohort study. Setting University-affiliated fertility center. Patient(s) Men undergoing intracytoplasmic sperm injection (ICSI) cycles who had low (n = 114) or markedly high (n = 36) DNA damage. Intervention(s) None. Main Outcome Measure(s) Sperm DNA damage evaluated by acridine orange flow cytometry and expressed as the DFI, with the potential confounders of ovarian reserve and age controlled for by multivariable logistic regression analysis. Result(s) The fertilization and clinical pregnancy rates were not different between the two groups. We observed a trend toward a higher miscarriage rate with the high DFI group, but it did not reach statistical significance. Conclusion(s) Intracytoplasmic sperm injection in men with a high DFI with sperm selected by movement and morphology characteristics resulted in a similar pregnancy rate compared with the controls with a normal DFI. However, the trend observed of an increase in miscarriages suggests that any potential negative impact may appear later in development. Future studies involving a larger cohort may determine if the miscarriage trend reaches statistical significance.
OBJECTIVE:To evaluate the association between physical activity (PA) and multiple sclerosis (MS) disease activity, depression, and fatigue in a cohort of children with MS and monophasic acquired ...demyelinating syndrome (mono-ADS).
METHODS:In this cross-sectional study of consecutive patients attending a specialized pediatric MS clinic, we administered the PedsQL Multidimensional Fatigue Scale, Center for Epidemiological Studies Depression Scale, and Godin Leisure-Time Exercise Questionnaire. Quantitative MRI analysis was performed to obtain whole brain and T2 lesion volume in a subset of participants (n = 60).
RESULTS:A total of 110 patients (79 mono-ADS; 31 MS; 5–18 years; M:F 1:1.2) were included. Patients with MS reported less strenuous (33.21 ± 31.88 metabolic equivalents METs vs 15.97 ± 22.73 METs, p = 0.002) and total (44.48 ± 39.35 METs vs 67.28 ± 59.65 METs; p = 0.0291) PA than those with mono-ADS. Patients with MS who reported greater amounts of moderate PA METs had fewer sleep/rest fatigue symptoms (r = −0.4). Participation in strenuous PA was associated with smaller T2 lesion volumes (r = −0.66) and lower annualized relapse rate (r = −0.66). No associations were found between total brain volume and participation in PA.
CONCLUSIONS:Children with MS are less physically active than children with mono-ADS. Reasons for this are unclear, but may be related to ongoing disease activity, perceived limitations, or symptoms such as depression or fatigue. Children with MS reporting higher levels of strenuous PA had lower T2 lesion volumes and lower relapse rates, suggesting a potential protective effect of strenuous PA in this population. Further longitudinal studies are needed to establish the relationship of PA to MS symptoms and disease activity in this population.
ABSTRACT
Intestinal barrier function and microbiota are integrally related and play critical roles in maintenance of host physiology. Sex is a key biologic variable for several disorders. Our aim was ...to determine sex‐based differences in response to perturbation and subsequent recovery of intestinal barrier function and microbiota in healthy humans. Twenty‐three volunteers underwent duodenal biopsies, mucosal impedance, and in vivo permeability measurement. Permeability testing was repeated after administration of indomethacin, then 4 to 6 wk after its discontinuation. Duodenal and fecal microbiota composition was determined using 16S rRNA amplicon sequencing. Healthy women had lower intestinal permeability and higher duodenal and fecal microbial diversity than healthy men. Intestinal permeability increases after indomethacin administration in both sexes. However, only women demonstrated decreased fecal microbial diversity, including an increase in Prevotella abundance, after indomethacin administration. Duodenal microbiota composition did not show sex‐specific changes. The increase in permeability and microbiota changes normalized after discontinuation of indomethacin. In summary, women have lower intestinal permeability and higher microbial diversity. Intestinal permeability is sensitive to perturbation but recovers to baseline. Gut microbiota in women is sensitive to perturbation but appears to be more stable in men. Sex‐based differences in intestinal barrier function and microbiome should be considered in future studies.—Edogawa, S., Peters, S. A., Jenkins, G. D., Gurunathan, S. V., Sundt, W. J., Johnson, S., Lennon, R. J., Dyer, R. B., Camilleri, M., Kashyap, P. C., Farrugia, G., Chen, J., Singh, R. J., Grover, M. Sex differences in NSAID‐induced perturbation of human intestinal barrier function and microbiota. FASEB J. 32, 6615–6625 (2018). www.fasebj.org
Background:
Adherence to disease-modifying therapies (DMTs) in pediatric multiple sclerosis (MS) is not well understood. We examined the prevalence and risk factors for poor adherence in pediatric ...MS.
Methods:
This cross-sectional study recruited youth with MS from 12 North American pediatric MS clinics. In addition to pharmacy-refill data, patients and parents completed self-report measures of adherence and quality of life. Additionally, patients completed measures of self-efficacy and well-being. Factor analysis and linear regression methods were used.
Results:
A total of 66 youth (mean age, 15.7 years) received MS DMTs (33% oral, 66% injectable). Estimates of poor adherence (i.e. missing >20% of doses) varied by source: pharmacy 7%, parent 14%, and patient 41%. Factor analysis yielded two composites: adherence summary and parental involvement in adherence. Regressions revealed that patients with better self-reported physical functioning were more adherent. Parents were more likely to be involved in adherence when their child had worse parent-reported PedsQL School Functioning and lower MS Self-Efficacy Control. Oral DMTs were associated with lesser parental involvement in adherence.
Conclusion:
Rates of non-adherence varied by information source. Better self-reported physical functioning was the strongest predictor of adherence. Parental involvement in adherence was associated with worse PedsQL School Functioning and lower MS Self-Efficacy-measured confidence in controlling MS.
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