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Aims/hypothesis We hypothesised that type 1 diabetic patients with established diabetic sensorimotor polyneuropathy (DSPN) would have segmental and/or pan-enteric dysmotility in comparison to healthy age-matched controls. We aimed to investigate the co-relationships between gastrointestinal function, degree of DSPN and clinical symptoms. Methods An observational comparison was made between 48 patients with DSPN (39 men, mean age 50 years, range 29–71 years), representing the baseline data of an ongoing clinical trial (representing a secondary analysis of baseline data collected from an ongoing double-blind randomised controlled trial investigating the neuroprotective effects of liraglutide) and 41 healthy participants (16 men, mean age 49 years, range 30–78) who underwent a standardised wireless motility capsule test to assess gastrointestinal transit. In patients, vibration thresholds, the Michigan Neuropathy Screening Instrument and Patient Assessment of Upper Gastrointestinal Symptom questionnaires were recorded. Results Compared with healthy controls, patients showed prolonged gastric emptying (299 ± 289 vs 179 ± 49 min; p =  0.01), small bowel transit (289 ± 107 vs 224 ± 63 min; p  = 0.001), colonic transit (2140, interquartile range [IQR] 1149–2799 min vs 1087, IQR 882–1650 min; p  = 0.0001) and whole-gut transit time (2721, IQR 1196–3541 min vs 1475 (IQR 1278–2214) min; p  < 0.0001). Patients also showed an increased fall in pH across the ileocaecal junction (−1.8 ± 0.4 vs −1.3 ± 0.4 pH; p  < 0.0001), which was associated with prolonged colonic transit ( r  = 0.3, p  = 0.001). Multivariable regression, controlling for sex, disease duration and glycaemic control, demonstrated an association between whole-gut transit time and total GCSI ( p =  0.02). Conclusions/interpretation Pan-enteric prolongation of gastrointestinal transit times and a more acidic caecal pH, which may represent heightened caecal fermentation, are present in patients with type 1 diabetes. The potential implication of delayed gastrointestinal transit on the bioavailability of nutrition and on pharmacotherapeutic and glycaemic control warrants further investigation. Trial registration EUDRA CT: 2013-004375-12

Background Constipation, a prevalent gastrointestinal disorder, affects 10%–15% of adults in the USA and approximately 8.2% of China’s general population. Slow transit constipation (STC), accounting for 15%–42% of constipation cases, is defined by impaired colonic motility. For patients refractory to conservative treatment who experience chronic, intractable symptoms and diminished quality of life, surgical intervention becomes the treatment of last resort. The primary surgical approach for STC has traditionally been total colectomy with ileorectal anastomosis (TC-IRA). However, over the past two decades, subtotal colectomy with cecorectal anastomosis (SC-CRA) has gained increasing attention among clinicians due to its potential to reduce postoperative diarrhea. Despite this advantage, SC-CRA is also associated with concerns regarding an increased risk of recurrent constipation. The debate surrounding which approach is superior persists. This study aims to resolve this controversy through a comparative analysis of TC-IRA and SC-CRA, evaluating their therapeutic efficacy and safety profiles in refractory STC. Methods The STOPS trial is a prospective, randomized, multicenter-controlled clinical trial to compare the effectiveness of TC-IRA versus SC-CRA in treating patients with STC. After screening for eligibility and obtaining informed consent, a total of 252 adult patients will be randomized into two groups in a 1:1 ratio after assuring that none of the exclusion criteria is present. The primary outcome is the Wexner Constipation Score. The secondary outcomes include operative time, conversion rates, blood loss, short- and long-term complications, bowel movements, abdominal pain, bloating, straining, enema use, laxative use, Wexner Incontinence Score, gastrointestinal quality of life index (GIQLI), 36-item Short Form Health Survey (SF-36), and satisfaction. Outcomes will be assessed at baseline and at 1, 3, 6, 12, 24, and 36 months postoperatively. Discussion This trial will be the first and largest randomized clinical trial to assess whether TC-IRA or SC-CRA should be the standardized surgical treatment for STC in terms of WCS outcomes. We hope that its findings will not only demonstrate the value of the surgical procedure in the treatment of STC, but also provide more reliable clinical evidence for further standardization of STC surgical treatment. Trial registration STOPS Trial: A Multicentre Prospective Randomised Clinical Trial Comparing Total Colectomy with Ileorectal Anastomosis Versus Subtotal Colectomy with Cecal-rectal Anastomosis for Slow Transit Constipation ( http://clinicaltrials.gov/ct2/show/NCT05352074 ). Registry identifier: NCT05352074. Registration date: April 3, 2022.

ObjectivesRecent studies using the lactulose hydrogen breath test (LHBT) suggest most patients with irritable bowel syndrome (IBS) have small intestinal bacterial overgrowth (SIBO). However, the validity of the LHBT has been questioned, particularly as this test could reflect changes in oro-caecal transit. Therefore, we combined oro-caecal scintigraphy with LHBT in 40 patients who were Rome II positive for IBS to determine if the increase in hydrogen is due to the test meal reaching the caecum.DesignPatients ingested the test meal containing 99mTc and 10 g lactulose and simultaneous measurements of the location of the test meal using scintigraphic scanning and breath hydrogen levels were obtained every 10 min for 3 h. The LHBT was considered positive when the rise in H2 above baseline was >20 ppm within 90 and/or 180 min. The combined test was negative for SIBO if ≥5% of the test meal was in the caecum at the time the LHBT was positive.Results63% had an abnormal LHBT at 180 min and 35% at 90 min. The oro-caecal transit time based on scintigraphic scanning ranged from 10 to 220 min and correlated with IBS sub-type. At the time of increase in H2, the % accumulation of 99mTc in the caecum was ≥5% in 88% of cases (22/25).ConclusionsThese findings demonstrate that an abnormal rise in H2 measured in the LHBT can be explained by variations in oro-caecal transit time in patients with IBS and therefore do not support the diagnosis of SIBO.

Background and aims:Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes.Methods:Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation.Results:Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota.Conclusion:We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism, contributing to the improvement of gut barrier functions during obesity and diabetes.

In adult patients with Duchenne muscular dystrophy (DMD) life-threatening constipation has been reported. Since gastrointestinal function in DMD has not been rigorously studied we investigated objective and subjective manifestations of gastrointestinal disturbances in DMD patients. In 33 patients with DMD, age 12-41 years, eating behavior and gastrointestinal symptoms were evaluated by questionnaires. Gastric emptying half time (T1/2) and oro-cecal transit time (OCTT) were evaluated by analyzing 13CO2 exhalation curves after ingestion of 13C labeled test meals. Colonic transit time (CTT) was measured by abdominal radiography following ingestion of radiopaque markers. The median (quartiles) T1/2 was 187 (168, 220) minutes, the OCTT was 6.3 (5.0, 7.9) hours, both substantially longer than normal data (Goetze 2005, T1/2: 107±10; Geypens 1999, OCTT 4.3±0.1 hours). The median CTT was 60 (48, 82) hours despite extensive use of laxative measures (Meier 1995, upper limit of normal: 60 hours). T1/2 and OCTT did not correlate with symptoms evaluated by the Gastroparesis Cardinal Symptom Index (GCSI) (Spearman r = -0.3, p = 0.1; and r = -0.15, p = 0.4, respectively). CTT was not correlated with symptoms of constipation assessed by ROME III criteria (r = 0.12, p = 0.5). DMD patients have a markedly disturbed gastrointestinal motor function. Since objective measures of impaired gastrointestinal transport are not correlated with symptoms of gastroparesis or constipation our findings suggest that measures assuring adequate intestinal transport should be taken independent of the patient's perception in order to prevent potentially life threatening constipation, particularly in older DMD patients.

Renal dysfunction is one of the most common complications of septic injury. One critical contributor to septic injury-induced renal dysfunction is renal vascular dysfunction. Protein palmitoylation serves as a novel regulator of vascular function. Here, we examined whether palmitoyl acyltransferase (PAT)-DHHC21 contributes to septic injury-induced renal dysfunction through regulating renal hemodynamics. Multispectral optoacoustic imaging showed that cecal ligation and puncture (CLP)-induced septic injury caused impaired renal excretion, which was improved in DHHC21 functional deficient ( Zdhhc21 dep/dep ) mice. DHHC21 deficiency attenuated CLP-induced renal pathology, characterized by tissue structural damage and circulating injury markers. Importantly, DHHC21 loss-of-function led to better-preserved renal perfusion and oxygen saturation after CLP. The CLP-caused reduction in renal blood flow was also ameliorated in Zdhhc21 dep/dep mice. Next, CLP promoted the palmitoylation of vascular α1-adrenergic receptor (α1AR) and the activation of its downstream effector ERK, which were blunted in Zdhhc21 dep/dep mice. Vasoreactivity analysis revealed that renal arteries from Zdhhc21 dep/dep mice displayed reduced constriction response to α1AR agonist phenylephrine compared to those from wild-type mice. Consistently, inhibiting PATs with 2-bromopalmitate caused a blunted vasoconstriction response to phenylephrine in small arteries isolated from human kidneys. Therefore, DHHC21 contributes to impaired renal perfusion and function during septic injury via promoting α1AR palmitoylation-associated vasoconstriction.

Survivors of sepsis often experience long-term cognitive and functional decline. Previous studies utilizing lipopolysaccharide injection and cecal ligation and puncture in rodent models of sepsis have demonstrated changes in depressive-like behavior and learning and memory after sepsis, as well as evidence of myeloid inflammation and cytokine expression in the brain, but the long-term course of neuroinflammation after sepsis remains unclear. Here, we utilize cecal ligation and puncture with greater than 80% survival as a model of sepsis. We found that sepsis survivor mice demonstrate deficits in extinction of conditioned fear, but no acquisition of fear conditioning, nearly two months after sepsis. These cognitive changes occur in the absence of neuronal loss or changes in synaptic density in the hippocampus. Sepsis also resulted in infiltration of monocytes and neutrophils into the CNS at least two weeks after sepsis in a CCR2 independent manner. Cellular inflammation is accompanied by long-term expression of pro-inflammatory cytokine and chemokine genes, including TNFα and CCR2 ligands, in whole brain homogenates. Gene expression analysis of microglia revealed that while microglia do express anti-microbial genes and damage-associated molecular pattern molecules of the S100A family of genes at least 2 weeks after sepsis, they do not express the cytokines observed in whole brain homogenates. Our results indicate that in a naturalistic model of infection, sepsis results in long-term neuroinflammation, and that this sustained inflammation is likely due to interactions among multiple cell types, including resident microglia and peripherally derived myeloid cells.

The complex microbiome of the ceca of chickens plays an important role in nutrient utilization, growth and well-being of these animals. Since we have a very limited understanding of the capabilities of most species present in the cecum, we investigated the role of the microbiome by comparative analyses of both the microbial community structure and functional gene content using random sample pyrosequencing. The overall goal of this study was to characterize the chicken cecal microbiome using a pathogen-free chicken and one that had been challenged with Campylobacter jejuni. Comparative metagenomic pyrosequencing was used to generate 55,364,266 bases of random sampled pyrosequence data from two chicken cecal samples. SSU rDNA gene tags and environmental gene tags (EGTs) were identified using SEED subsystems-based annotations. The distribution of phylotypes and EGTs detected within each cecal sample were primarily from the Firmicutes, Bacteroidetes and Proteobacteria, consistent with previous SSU rDNA libraries of the chicken cecum. Carbohydrate metabolism and virulence genes are major components of the EGT content of both of these microbiomes. A comparison of the twelve major pathways in the SEED Virulence Subsystem (metavirulome) represented in the chicken cecum, mouse cecum and human fecal microbiomes showed that the metavirulomes differed between these microbiomes and the metavirulomes clustered by host environment. The chicken cecum microbiomes had the broadest range of EGTs within the SEED Conjugative Transposon Subsystem, however the mouse cecum microbiomes showed a greater abundance of EGTs in this subsystem. Gene assemblies (32 contigs) from one microbiome sample were predominately from the Bacteroidetes, and seven of these showed sequence similarity to transposases, whereas the remaining sequences were most similar to those from catabolic gene families. This analysis has demonstrated that mobile DNA elements are a major functional component of cecal microbiomes, thus contributing to horizontal gene transfer and functional microbiome evolution. Moreover, the metavirulomes of these microbiomes appear to associate by host environment. These data have implications for defining core and variable microbiome content in a host species. Furthermore, this suggests that the evolution of host specific metavirulomes is a contributing factor in disease resistance to zoonotic pathogens.

Nuclear factor κB (NF-κB) plays a pivotal role in sepsis. Activation of NF-κB is initiated by the signal-induced ubiquitylation and subsequent degradation of inhibitors of kappa B (IκBs) primarily via activation of the IκB kinase (IKK). This study was designed to investigate the effects of IKK inhibition on sepsis-associated multiple organ dysfunction and/or injury (MOD) and to elucidate underlying signaling mechanisms in two different in vivo models: male C57BL/6 mice were subjected to either bacterial cell wall components [lipopolysaccharide and peptidoglycan (LPS/PepG)] or underwent cecal ligation and puncture (CLP) to induce sepsis-associated MOD. At 1 hour after LPS/PepG or CLP, mice were treated with the IKK inhibitor IKK 16 (1 mg/kg body weight). At 24 hours, parameters of organ dysfunction and/or injury were assessed in both models. Mice developed a significant impairment in systolic contractility (echocardiography), and significant increases in serum creatinine, serum alanine aminotransferase and lung myeloperoxidase activity, thus indicating cardiac dysfunction, renal dysfunction, hepatocellular injury and lung inflammation, respectively. Treatment with IKK 16 attenuated the impairment in systolic contractility, renal dysfunction, hepatocellular injury and lung inflammation in LPS/PepG-induced MOD and in polymicrobial sepsis. Compared with mice that were injected with LPS/PepG or underwent CLP, immunoblot analyses of heart and liver tissues from mice that were injected with LPS/PepG or underwent CLP and were also treated with IKK 16 revealed: (1) significant attenuation of the increased phosphorylation of IκBα; (2) significant attenuation of the increased nuclear translocation of the NF-κB subunit p65; (3) significant attenuation of the increase in inducible nitric oxide synthase (iNOS) expression; and (4) a significant increase in the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). Here, we report for the first time that delayed IKK inhibition reduces MOD in experimental sepsis. We suggest that this protective effect is (at least in part) attributable to inhibition of inflammation through NF-κB, the subsequent decrease in iNOS expression and the activation of the Akt-eNOS survival pathway.

Age/gender may likely influence the course of septic complications after trauma. We aimed to characterize the influence of age/gender on the response of circulating cytokines, cells and organ function in post-traumatic sepsis. We additionally tested whether post-traumatic responses alone can accurately predict outcomes in subsequent post-traumatic sepsis. A mouse 2-hit model of trauma/hemorrhage (TH, 1(st) hit) and cecal ligation and puncture (CLP, 2(nd) hit) was employed. 3, 15 and 20 month (m) old female (♀) and male (♂) CD-1 mice underwent sublethal TH followed by CLP 2 days later. Blood was sampled daily until day 6 post-TH and survival was followed for 16 days. To compare general response patterns among groups, we calculated two scores: the inflammatory response (including KC, MIP-1α, TNFα, MCP-1, IFNγ, IL-1β,-5,-6,-10) and the organ dysfunction score (Urea, ALT, AST and LDH). Moreover, mice were retrospectively divided into survivors (SUR) and dying (DIE) based on post-CLP outcome. In general, females survived better than males and their survival did not correspond to any specific estrus cycle phase. Pre-CLP phase: the post-TH inflammatory score was weakest in 3 m♂ but there were no changes among remaining groups (similar lack of differences in the organ dysfunction score). TH induced a 40% increase of IFNγ, MIP-1α and IL-5 in 15 m♂ SUR (vs. DIE) but predictive accuracy for post-CLP outcomes was moderate. Post-CLP phase: while stable in males, inflammatory response score in 15 m and 20 m females decreased with age at day 1 and 2 post-CLP. SUR vs. DIE differences in inflammatory and organ dysfunction score were evident but their magnitude was comparable across age/gender. Nearly identical activation of the humoral inflammatory and organ function compartments, both across groups and according to sepsis severity, suggests that they are not directly responsible for the age/gender-dependent disparity in TH-CLP survival in the studied young-to-mature population.