Glutamine supplementation as a novel metabolic therapeutic strategy for LIG3-dependent chronic intestinal pseudo-obstruction.

BACKGROUND AND AIMS: We recently identified a recessive syndrome due to LIG3 mutations in patients with chronic intestinal pseudo-obstruction, leukoencephalopathy and neurogenic bladder. LIG3 mutations affect mitochondrial DNA (mtDNA) maintenance, leading to defective energy production. We aimed at identifying altered molecular pathways and develop possible targeted treatments to revert / ameliorate the cellular energy impairment. METHODS: Whole transcriptome analysis was performed on patients' derived fibroblasts total RNA and controls. Mitochondrial function, mitophagy, L-Glutamine (L-Gln) supplementation effects were analyzed by live cell analysis, immunostaining and western blot. Patients were treated with Dipeptiven according to standard protocols. Patients' symptoms were analyzed by the Gastrointestinal Symptom Rating Scale questionnaire. RESULTS: We identified deregulated transcripts in mutant fibroblasts vs. controls, including overexpression of genes involved in extracellular matrix development and remodeling and mitochondrial functions. Gut biopsies of LIG3-mutant patients documented collagen and elastic fiber accumulation. Mutant fibroblasts exhibited impaired mitochondrial mitophagy indicative of dysfunctional turnover and altered Ca2+ homeostasis. L-Gln supplementation (6 mM), previously shown to increase mtDNA-defective cell survival, improved growth rate and ATP production in LIG3-mutant fibroblasts. These data led us to provide parenterally a dipeptide containing L-Gln to three siblings carrying biallelic LIG3 mutations. Compared to baseline, gastrointestinal and extra-gastrointestinal symptoms significantly improved after 8 months of treatment. CONCLUSIONS: LIG3 deficiency leads to mitochondrial dysfunction. High levels L-Gln supplementation was beneficial in LIG3-mutant cells and improved symptom severity without noticeable side effects. Our results provide a proof-of-concept to design ad hoc clinical trials with L-Gln in LIG3-mutant patients.

The Long Noncoding RNA Cardiac Mesoderm Enhancer-Associated Noncoding RNA (Carmn) Is a Critical Regulator of Gastrointestinal Smooth Muscle Contractile Function and Motility.

BACKGROUND & AIMS: Visceral smooth muscle cells (SMCs) are an integral component of the gastrointestinal (GI) tract that regulate GI motility. SMC contraction is regulated by posttranslational signaling and the state of differentiation. Impaired SMC contraction is associated with significant morbidity and mortality, but the mechanisms regulating SMC-specific contractile gene expression, including the role of long noncoding RNAs (lncRNAs), remain largely unexplored. Herein, we reveal a critical role of Carmn (cardiac mesoderm enhancer-associated noncoding RNA), an SMC-specific lncRNA, in regulating visceral SMC phenotype and contractility of the GI tract. METHODS: Genotype-Tissue Expression and publicly available single-cell RNA sequencing (scRNA-seq) data sets from embryonic, adult human, and mouse GI tissues were interrogated to identify SMC-specific lncRNAs. The functional role of Carmn was investigated using novel green fluorescent protein (GFP) knock-in (KI) reporter/knock-out (KO) mice. Bulk RNA-seq and single nucleus RNA sequencing (snRNA-seq) of colonic muscularis were used to investigate underlying mechanisms. RESULTS: Unbiased in silico analyses and GFP expression patterns in Carmn GFP KI mice revealed that Carmn is highly expressed in GI SMCs in humans and mice. Premature lethality was observed in global Carmn KO and inducible SMC-specific KO mice due to GI pseudo-obstruction and severe distension of the GI tract, with dysmotility in cecum and colon segments. Histology, GI transit, and muscle myography analysis revealed severe dilation, significantly delayed GI transit, and impaired GI contractility in Carmn KO vs control mice. Bulk RNA-seq of GI muscularis revealed that loss of Carmn promotes SMC phenotypic switching, as evidenced by up-regulation of extracellular matrix genes and down-regulation of SMC contractile genes, including Mylk, a key regulator of SMC contraction. snRNA-seq further revealed SMC Carmn KO not only compromised myogenic motility by reducing contractile gene expression but also impaired neurogenic motility by disrupting cell-cell connectivity in the colonic muscularis. These findings may have translational significance, because silencing CARMN in human colonic SMCs significantly attenuated contractile gene expression, including MYLK, and decreased SMC contractility. Luciferase reporter assays showed that CARMN enhances the transactivation activity of the master regulator of SMC contractile phenotype, myocardin, thereby maintaining the GI SMC myogenic program. CONCLUSIONS: Our data suggest that Carmn is indispensable for maintaining GI SMC contractile function in mice and that loss of function of CARMN may contribute to human visceral myopathy. To our knowledge this is the first study showing an essential role of lncRNA in the regulation of visceral SMC phenotype.

Chronic intestinal pseudo-obstruction: associations with gut microbiota and genes expression of intestinal serotonergic pathway.

BACKGROUND: Pediatric chronic intestinal pseudo-obstruction (PIPO) is a rare disease characterized by symptoms and radiological signs suggestive of intestinal obstruction, in the absence of lumen-occluding lesions. It results from an extremely severe impairment of propulsive motility. The intestinal endocrine system (IES) jointly with the enteric nervous system (ENS) regulates secreto-motor functions via different hormones and bioactive messengers/neurotransmitters. The neurotransmitter 5-hydroxytryptamine (5-HT) (or serotonin) is linked to intestinal peristalsis and secretory reflexes. Gut microbiota and its interplay with ENS affect 5-HT synthesis, release, and the subsequent serotonin receptor activation. To date, the interplay between 5-HT and gut microbiota in PIPO remains largely unclear. This study aimed to assess correlations between mucosa associated microbiota (MAM), intestinal serotonin-related genes expression in PIPO. To this purpose, biopsies of the colon, ileum and duodenum have been collected from 7 PIPO patients, and 7 age-/sex-matched healthy controls. After DNA extraction, the MAM was assessed by next generation sequencing (NGS) of the V3-V4 region of the bacterial RNA 16 S, on an Illumina Miseq platform. The expression of genes implicated in serotoninergic pathway (TPH1, SLC6A4, 5-HTR3 and 5-HTR4) was established by qPCR, and correlations with MAM and clinical parameters of PIPO have been evaluated. RESULTS: Our results revealed that PIPO patients exhibit a MAM with a different composition and with dysbiosis, i.e. with a lower biodiversity and fewer less connected species with a greater number of non-synergistic relationships, compared to controls. qPCR results revealed modifications in the expression of serotonin-related intestinal genes in PIPO patients, when compared to controls. Correlation analysis do not reveal any kind of connection. CONCLUSIONS: For the first time, we report in PIPO patients a specific MAM associated to underlying pathology and an altered intestinal serotonin pathway. A possible dysfunction of the serotonin pathway, possibly related to or triggered by an altered microbiota, may contribute to dysmotility in PIPO patients. The results of our pilot study provide the basis for new biomarkers and innovative therapies targeting the microbiota or serotonin pathways in PIPO patients.

Acute colonic pseudo-obstruction: a retrospective review of the surgical outcomes.

PURPOSE: Limited data exist regarding the surgical outcomes of acute colonic pseudo-obstruction (ACPO), commonly referred to as Ogilvie syndrome, in modern clinical practice. The prevailing belief is that surgery should be avoided due to previously reported high mortality rates. We aimed to describe the surgical results of ACPO treated within our institution. METHODS: Our prospectively maintained colorectal surgery registry was queried for patients diagnosed with ACPO, who underwent surgery between 2009 and 2022. Postoperative complications were graded according to Clavien-Dindo (CD) classification. The primary outcome was postoperative mortality. RESULTS: A total of 32 patients who underwent surgery for ACPO were identified. Overall, nonoperative therapy was initially administered to 21 patients (65.6%). The surgeries performed included total abdominal colectomy (15, 43.1%), ascending colectomy with end ileostomy (8, 25%), transverse colostomy (5, 15.6%), ileostomy and transverse colostomy (3, 9.4%), and Hartmann's operation (1, 3.1%). Severe postoperative complications (CD grade 3 or 4) occurred in five patients (15.6%). No recurrence of ACPO was observed and no patient required reoperation. The average postoperative length of stay was 14.5 days, 30-day mortality was 6.3% (n = 2), and 90-day mortality was 15.6% (n = 5) due to complications of underlying comorbidities. CONCLUSIONS: Surgical treatment was effective for patients with ACPO refractory to medical therapy or presenting with acute complications. Although postoperative complications were frequent, both the 30- and 90-day mortality rates were lower than previously documented in the literature. Further investigations are warranted to determine the optimal surgical strategy, which may involve total or segmental colectomy, or diversion alone without resection.

Loss-of-function variants within LMOD1 actin-binding site 2 cause pediatric intestinal pseudo-obstruction by impairing protein stability and actin nucleation.

The leiomodin1 (LMOD1) gene, encoding a potent actin nucleator, was recently reported as a potential pathogenic gene of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, OMIM 619362). However, only a single patient has been reported to have LMOD1 mutations, and the underlying pathogenic mechanism remains unknown. Here, we described a male infant with LMOD1 mutations presenting typical symptoms of pediatric intestinal pseudo-obstruction (PIPO) but without megacystis and microcolon. Two compound heterozygous missense variants (c.1106C>T, p.T369M; c.1262G>A, p.R421H) were identified, both affecting highly conserved amino acid residues within the second actin-binding site (ABS2) domain of LMOD1. Expression analysis showed that both variants resulted in significantly reduced protein amounts, especially for p.T369M, which was almost undetectable. The reduction was only partially rescued by the proteasome inhibitor MG-132, indicating that there might be proteasome-independent pathways involved in the degradation of the mutant proteins. Molecular modeling showed that variant p.T369M impaired the local protein conformation of the ABS2 domain, while variant p.R421H directly impaired the intermolecular interaction between ABS2 and actin. Accordingly, both variants significantly damaged LMOD1-mediated actin nucleation. These findings provide further human genetic evidence supporting LMOD1 as a pathogenic gene underlying visceral myopathy including PIPO and MMIHS, strengthen the critical role of ABS2 domain in LMOD1-mediated actin nucleation, and moreover, reveal an unrecognized role of ABS2 in protein stability.

Acute Colonic Pseudo-obstruction: Colonoscopy Versus Neostigmine First?

INTRODUCTION: Neostigmine (NEO) and decompressive colonoscopy (COL) are two efficacious treatment modalities for acute colonic pseudo-obstruction (ACPO). We hypothesize that a COL first strategy is associated with better outcomes compared to a NEO first strategy. METHODS: A single-center retrospective analysis was performed from 2013 to 2020. Patients ≥18 y with a diagnosis of ACPO were included. The outcome was a composite measure of acute operative intervention, 30-day readmission with ACPO, and 30-day ACPO-related mortality. A P-value of ≤ 0.05 indicated statistical significance. RESULTS: Of 910 encounters in 849 patients, 50 (5.5%) episodes of ACPO in 39 patients were identified after exclusion of one patient with colon perforation on presentation. The median (interquartile range) age was 68 (62-84) y. NEO and COL were administered in 21 and 25 episodes, respectively. In 16 (32%) episodes, no NEO or COL was administered. When patients were given NEO first, COL or additional NEO was required in 12/18 (67%) compared with a COL first strategy where a second COL and/or NEO was given in 5/16 (32%) (P = 0.05). Both strategies had similar outcomes (NEO, 4/18 versus COL, 4/16, P = 0.85). Twenty-two (44%) episodes had an early intervention (≤48 h) with NEO and/or COL. There was no difference in outcome between those that received an early intervention and those who did not (5/22 versus 5/28, P = 0.71). CONCLUSIONS: For patients failing conservative measures, a COL first approach was associated with fewer subsequent interventions, but with similar composite outcomes compared to a NEO first approach. Early (≤48 h) intervention with NEO and/or COL was not associated with improved outcomes.

Update on the Diagnosis and Management of Acute Colonic Pseudo-obstruction (ACPO).

PURPOSE OF REVIEW: Acute Colonic Pseudo-obstruction (ACPO) is a cause of large intestinal dilation and obstruction without any physical transition point. It remains difficult to diagnose and treat. We review the recent updates on diagnosis and management of ACPO. RECENT FINDINGS: Recent guidelines have posited that conservative management can be tried in most cases of ACPO, but that early decompression and surgery should be considered. Use of neostigmine is still a viable option but there is also promising data on pyridostigmine as well as prucalopride. Resolution of ACPO should be followed by daily use of polyethylene glycol (PEG) to help prevent recurrence. ACPO warrants early and accurate diagnosis with exclusion of alternate causes of large bowel dilation. Conservative management can be attempted for 48-72 h in those with cecal diameters < 12 cm and without signs of peritonitis and perforation. Early escalation of management should be attempted with neostigmine followed by endoscopy and/or surgery as needed, given that longer periods of dilation are associated with worse outcomes. There is promising new evidence for use of pyridostigmine and prucalopride, but further trials are needed prior to incorporating them into regular use. Finally, studies are lacking regarding prevention of ACPO after initial resolution.

Histopathological, Ultrastructural, and Immunohistochemical Findings in MYH11-Variant Visceral Myopathy.

BACKGROUND: Pathogenic mutations in the smooth muscle myosin heavy chain gene, MYH11, cause megacystis megacolon intestinal hypoperistalsis syndrome and other forms of chronic intestinal pseudo-obstruction. Evaluation of intestinal tissues from affected patients is often performed before mutational analysis, but the pathological findings of MYH11-variant visceral myopathy have not been well defined. METHODS: Light microscopic, immunohistochemical, and ultrastructural findings from multiple intestinal samples from 2 patients with MYH11-variant visceral myopathy were reviewed, including MYH11-specific immunohistochemistry. The findings were compared with intestinal samples from patients with gamma-smooth muscle actin (ACTG2)-variant visceral myopathy and non-pseudo-obstruction controls. RESULTS: Apart from non-specific changes (e.g., muscle hypertrophy and distension-related muscularis propria necrosis), no alterations were identified by routine histopathological evaluation or electron microscopy. Immunohistochemistry with antibodies against a battery of smooth muscle proteins, including MYH11, revealed indistinguishable patterns of immunoreactivity in the muscularis propria of both patients and controls. CONCLUSIONS: Myopathic morphological or immunohistochemical changes may not be present in intestinal specimens from patients with MYH11-variant visceral myopathy. Molecular genetic studies should be considered for patients with chronic intestinal pseudo-obstruction and normal or non-specific pathology findings.

Percutaneous endoscopic cecostomy for management of Ogilvie's syndrome: a case series and literature review with an update on current guidelines (with video).

INTRODUCTION: Percutaneous endoscopic cecostomy (PEC) is a viable treatment option for patients with persistent or recurrent acute colonic pseudo-obstruction (ACPO; Ogilvie's syndrome). It should be generally considered in patients that are refractory to pharmacologic and endoscopic decompression, especially those not amenable to surgical intervention due to an increased perioperative risk. Physicians are rather unfamiliar with this approach given the limited number of reports in the literature and paucity of guideline resources, although guidelines concerning ACPO and covering the role of endoscopy were recently published by three major expert societies, all within the last 2 years. PATIENTS AND METHODS: We retrospectively identified three consecutive patients who underwent PEC placement at a Czech tertiary referral center between May 2018 and December 2021: all for recurrent ACPO. In addition, we summarized the current guidelines in order to present the latest knowledge related both to the procedure and management approach in patients with ACPO. RESULTS: The placement of PEC was successful and resulted in clinical improvement in all cases without any adverse events. CONCLUSION: The results of our experience are in line with previous reports and suggest that PEC may become a very useful tool in the armamentarium of modalities utilized to treat ACPO. Furthermore, the availability of guideline resources now offers comprehensive guidance for informed decision-making and the procedural aspects.

Multi-disciplinary Insights from the First European Forum on Visceral Myopathy 2022 Meeting.

Visceral myopathy is a rare, life-threatening disease linked to identified genetic mutations in 60% of cases. Mostly due to the dearth of knowledge regarding its pathogenesis, effective treatments are lacking. The disease is most commonly diagnosed in children with recurrent or persistent disabling episodes of functional intestinal obstruction, which can be life threatening, often requiring long-term parenteral or specialized enteral nutritional support. Although these interventions are undisputedly life-saving as they allow affected individuals to avoid malnutrition and related complications, they also seriously compromise their quality of life and can carry the risk of sepsis and thrombosis. Animal models for visceral myopathy, which could be crucial for advancing the scientific knowledge of this condition, are scarce. Clearly, a collaborative network is needed to develop research plans to clarify genotype-phenotype correlations and unravel molecular mechanisms to provide targeted therapeutic strategies. This paper represents a summary report of the first 'European Forum on Visceral Myopathy'. This forum was attended by an international interdisciplinary working group that met to better understand visceral myopathy and foster interaction among scientists actively involved in the field and clinicians who specialize in care of people with visceral myopathy.

Nicotinamide Riboside Improves Enteric Neuropathy in Streptozocin-Induced Diabetic Rats Through Myenteric Plexus Neuroprotection.

BACKGROUND: Diabetes Mellitus causes a systemic oxidative stress due in part to the hyperglycemia and the reactive oxygen species generated. Up to 75% of diabetic patients present with an autonomic neuropathy affecting the Enteric Nervous System. Deficits in the human population are chronic dysmotilities with either increased (i.e., constipation) or decreased (i.e., diarrhea) total gastrointestinal transit times. These are recapitulated in the streptozocin-induced diabetic rat, which is a model of Type I Diabetes Mellitus. AIMS: Examine the effects that a precursor of nicotinamide adenosine dinucleotide (NAD), nicotinamide riboside (NR), had on the development of dysmotility in induced diabetic rats and if fecal microbiota transplant (FMT) could produce the same results. MATERIALS AND METHODS: Utilizing a 6-week treatment paradigm, NR was administered intraperitoneally every 48 h. Total gastrointestinal transit time was assessed weekly utilizing the carmine red method. Three weeks following hyperglycemic induction, FMT was performed between NR-treated animals and untreated animals. SIGNIFICANT RESULTS: There is improvement in overall gastrointestinal transit time with the use of NR. 16S microbiome sequencing demonstrated decreased alpha and beta diversity in induced diabetic rats without change in animals receiving FMT. Improvements in myenteric plexus ganglia density in small and large intestines in diabetic animals treated with NR were seen. CONCLUSIONS: NR treatment led to functional improvement in total gastrointestinal transit time in induced diabetic animals. This was associated with neuroprotection in the myenteric plexuses of both small and large intestines of induced diabetic rats. This represents an important first step in showing NR's benefit as a treatment for diabetic enteric neuropathy. Streptozocin-induced diabetic rats have improved transit times and increased myenteric plexus ganglia density when treated with intraperitoneal nicotinamide riboside.

Acute intestinal pseudo-obstruction secondary to Sjogren's syndrome in pregnancy: a case report and literature review.

BACKGROUND: Intestinal pseudo-obstruction (IPO) is a rare disease, and its clinical manifestations can resemble mechanical intestinal obstruction leading to unnecessary and potentially harmful surgery. Certain autoimmune diseases have been associated with IPO, however, cases secondary to Sjögren's syndrome (SjS) are especially rare. CASE PRESENTATION: We described the first case of SjS-associated acute IPO in pregnancy, which was successfully treated with combined immunosuppressive therapy and resulted in an uneventful caesarean delivery. CONCLUSIONS: Women with SjS is likely to experience more complications during pregnancy, and IPO rather than the classic symptoms could be the first sign of SjS flares. IPO should be suspected in patients with unrelenting symptoms of small bowel obstruction, and a multidisciplinary approach can provide optimal management of such high-risk pregnancies.

When you are living and dying at the same time: A qualitative exploration of living with gastrointestinal motility disorders.

BACKGROUND: An expanding base of evidence indicates that chronic gastrointestinal disorders not only impact physical wellbeing, but also affect many psychosocial aspects of life. However, less is known about gastrointestinal motility disorders. The present study aimed to explore how individuals experience gastrointestinal motility disorders and their impact on daily living. METHODS: Eleven people with a gastrointestinal motility disorder participated in semi-structured interviews face-to-face or via telephone. The interviews explored how participants came to be diagnosed, their experiences with health professionals, as well as the impact of dysmotility on enjoyment of food, socialising, eating out and quality of life (QoL). Interviews were tape-recorded, transcribed and analysed using an inductive thematic analysis approach. RESULTS: Analysis revealed an overarching theme of frustration that stemmed from three subthemes: (1) feeling misunderstood, judged and dismissed by health professionals leading to delayed diagnosis, misdiagnosis and multiple diagnoses; (2) severity and unpredictability of undesirable gastrointestinal symptoms; and (3) reduced QoL because of physical and social limitations, impairing their ability to have normal life experiences, including education, work and social activities. CONCLUSIONS: Dysmotility is a complex illness that impacts almost all aspects of a person's life. In addition to managing reported physical symptoms, the social and psychological burden associated with dysmotility needs to be addressed to improve outcomes and QoL.

Cutting-edge regenerative therapy for Hirschsprung disease and its allied disorders.

Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy. Notably, HSCR involving the small intestine, isolated hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction, and megacystis-microcolon-intestinal hypoperistalsis syndrome carry a poor prognosis. Ultimately, small-bowel transplantation (SBTx) is necessary for refractory cases, but it is highly invasive and outcomes are less than optimal, despite advances in surgical techniques and management. Thus, regenerative therapy has come to light as a potential form of treatment involving regeneration of the enteric nervous system, mesenchyme, and smooth muscle in affected areas. We review the cutting-edge regenerative therapeutic approaches for managing HSCR and AD-HSCR, including the use of enteric nervous system progenitor cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells as cell sources, the recipient intestine's microenvironment, and transplantation methods. Perspectives on the future of these treatments are also discussed.

Risk factors for acute colonic pseudo-obstruction after caesarean section: A retrospective case-control study.

BACKGROUND: Pregnancy and caesarean section are known to predispose to the development of acute colonic pseudo-obstruction (ACPO), a rare form of functional ileus of the distal large bowel. Pathogenesis of ACPO is likely influenced by pregnancy and childbirth and subsequent changes to hormonal, autonomic and metabolic physiology. Identifying pregnancy risk factors will assist with early identification, as the insidious onset postpartum often leads to delayed diagnosis and bowel ischaemia, perforation and sepsis. AIMS: To establish pregnancy risk factors associated with the development of ACPO after caesarean section. MATERIALS AND METHODS: A retrospective case-control study included 19 121 women undergoing caesarean between 1 January 2008 and 31 December 2016 at a tertiary referral hospital. Twenty-three cases of computerised tomography (CT)-diagnosed ACPO post-caesarean were identified from hospital medical records and imaging databases. Controls were matched for gestational and maternal age within one week of delivery with a ratio of 1:3. RESULTS: The incidence of ACPO was one in 800 caesarean sections. ACPO was significantly more likely to occur in women who had been administered opioid analgesia in labour (odds ratio (OR) 4.67, P = 0.04), and a trend for increased estimated blood loss (OR 1.01, P = 0.01). There was no increased risk associated with emergency or elective caesarean classification, previous abdominal surgery, type of anaesthesia, duration of labour, oxytocin augmentation, intrapartum fever, hypertensive disorders, diabetes in pregnancy, antepartum haemorrhage, multiple gestation, fetal presentation or birthweight. CONCLUSIONS: Risk factors for developing ACPO post-caesarean include opioid analgesia in labour and a trend for increased blood loss.

Aldosterone up-regulates basolateral Na+ -K+ -2Cl- cotransporter-1 to support enhanced large-conductance K+ channel-mediated K+ secretion in rat distal colon.

Na+ -K+ -2Cl- cotransporter-1 (NKCC1) facilitates basolateral K+ and Cl- uptake, supporting their efflux across mucosal membranes of colonic epithelial cells. NKCC1 activity has also been shown to be critical for electrogenic K+ secretion induced by aldosterone, which is known to stimulate large-conductance K+ (BK) channel expression in mucosal membranes. This study was aimed to (1) identify whether aldosterone enhances NKCC1 expression specifically to support BK-mediated K+ secretion and (2) to determine whether increased NKCC1 supports electrogenic Cl- secretion in parallel to K+ secretion. Dietary Na+ depletion was used to induce secondary hyperaldosteronism in rats, or aldosterone was administered ex vivo to rat distal colonic mucosae. NKCC1-dependent electrogenic K+ or Cl- secretion was measured as a function of short circuit current (ISC ). qRT-PCR, western blot, and immunofluorescence analyses were performed using standard techniques. Aldosterone enhanced NKCC1 and BKα expression and electrogenic K+ secretion in the distal colon, which was inhibited by either serosal bumetanide (NKCC1 inhibitor) or mucosal iberiotoxin (IbTX; BK channel blocker), but not TRAM-34 (IK channel blocker). Expression of NKCC1 and BKα proteins was enhanced in crypt cells of hyper-aldosterone rats. However, neither NKCC1-dependent Cl- secretion nor CFTR (apical Cl- channel) expression was enhanced by aldosterone. We conclude that aldosterone enhances NKCC1 to support BK-mediated K+ secretion independently of Cl- secretion in the distal colon. The regulation of NKCC1 expression/K+ secretion by aldosterone may be a therapeutic target in treating gastrointestinal disorders associated with alterations in colonic K+ transport, such as colonic pseudo-obstruction, and hyperkalemia associated with renal disease.

Colostomy as a definitive treatment in an ALS patient with acute colonic Pseudo-obstruction refractory to medical management, a case report.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, and ALS patients may experience disturbed gastrointestinal motility often resulting in acute colonic pseudo-obstruction (ACPO). There is currently a paucity in the literature to guide the treatment of patients with both ALS and ACPO. CASE PRESENTATION: Here we describe a 39-year-old male patient with advanced ALS who developed ACPO. His condition was refractory to both medical and procedural managements including polyethylene glycol, senna, and docusate suppository, metoclopramide, linaclotide, erythromycin, prucalopride, neostigmine, and repeated colonoscopies. He ultimately underwent successful colostomy for palliation. Here we report the peri-operative multidisciplinary approach taken with this case, the surgical procedures, the potential risks, and the outcome. CONCLUSION: The patient is delighted with the result and requested publication of this case to raise awareness of constipation in ALS patients and promote the consideration of colostomy as a treatment option for patients with ileus resistant to conservative management. Ultimately, a multidisciplinary team approach is required to properly assess the risks and benefits to achieve good clinical outcomes.

Systemic lupus erythematosus simultaneously presenting with visceral muscle dysmotility syndrome and mechanical intestinal obstruction clinically relieved by surgery: a case report and literature review.

BACKGROUND: Intestinal pseudo-obstruction (IPO) accompanied by hepatobiliary dilatation and ureterohydronephrosis is extremely rare in systemic lupus erythematosus (SLE). This triad is also called visceral muscle dysmotility syndrome (VMDS). Only 9 cases have been reported in the literature. Here, we report a rare case of VMDS with mechanical intestinal obstruction that was clinically relieved by surgery. CASE PRESENTATION: This report refers to a 31-year-old woman with SLE and gastrointestinal symptoms presented as abdominal pain, nausea and stoppage of the passage of flatus or stool without obvious reasons. The patient suffered from severe abdominal distension because of massive flatulence. Contrast-enhanced computed tomography (CT) of the abdomen performed in our hospital showed localized stenosis of the bowel, ureterohydronephrosis, and biliary tract dilatation. Endoscopy showed a stenotic segment located in the sigmoid colon. The colon biopsy samples suggested that the stenosis was caused by inflammatory tissues. Biochemical investigations showed hypoalbuminemia, electrolyte disturbance and decreased C3. Antinuclear antibody was positive. After careful assessment, transverse colostomy was performed for this patient. Gastrointestinal symptoms were clinically relieved after the surgery. CONCLUSION: To the best of our knowledge, no VMDS patients have presented with mechanical ileus before. This case is the first documented occurrence of SLE with VMDS and mechanical intestinal obstruction symptoms relieved by surgery. Due to the low incidence of this condition, no standard treatment regimen has been established. However, surgical treatment offers significant benefit in specific situations.

Preservation of native sigmoid colon for secondary continent cystostomy after multivisceral transplantation for chronic intestinal pseudo-obstruction.

Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe digestive +/- urinary dysmotility. If the conservative management fails, multivisceral transplantation (MVT) may be needed. However, urinary dysmotility remains after MVT and requires to continue urinary catheterizations and/or drainage. We report on a boy with severe CIPO complicated by (1) chronic intestinal obstruction requiring total parenteral nutrition, decompression gastrostomy, and ileostomy; (2) recurrent line infections; (3) hepatic fibrosis; and (4) distension of the bladder and upper urinary tract, and recurrent urinary infections, leading to non-continent cystostomy for urinary drainage. He underwent MVT at the age of 5 years. The transplant included the liver, stomach, duodenum and pancreas, small bowel, and right colon. The distal native sigmoid colon was preserved. Fifteen months later, he underwent a pull through of the transplanted right colon (Duhamel's procedure), together with a tube continent cystostomy (Monti's procedure) using the native sigmoid. Postoperative course was uneventful, and the remaining ileostomy was closed 3 months later. Five years post-transplant, he is alive and well. He is fed by mouth with complementary gastrostomy feeding at night. He has 3-6 stools per day, with occasional soiling. The cystostomy is used for intermittent urinary catheterization 4 times/day and continuous drainage at night. He is dry, with rare afebrile urinary infections, normal renal function, and un-dilated upper urinary tract. Conclusion: in severe CIPO with urinary involvement, preservation of the distal native sigmoid colon during MVT allows secondary creation of a continent tube cystostomy, which is useful to manage persistent urinary disease.

Chronic Intestinal Pseudo-Obstruction Is Associated with Intestinal Methanogen Overgrowth.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIP) is a rare motility disorder characterized by dilated small bowel in the absence of mechanical obstruction. CIP has a known association with small intestinal bacterial overgrowth (SIBO); however, data regarding association with specific subtypes such as methane-positive (M+) and hydrogen-positive (H+) SIBO are limited. Therefore, we conducted this study to characterize subtypes of SIBO in CIP and compare them with non-CIP patients. AIMS: The aim is to explore the association and prevalence of hydrogen and methane subtypes of SIBO in patients with CIP. METHODS: A retrospective chart review was conducted for 494 patients who underwent glucose breath tests (GBT) in 2019. CIP was diagnosed based on clinical suspicion and after ruling out mechanical obstruction. We also reviewed demographic data, including age, gender, body mass index, tobacco and alcohol history, medical comorbidities, use of proton pump inhibitors, and history of colectomy. RESULTS: Among 494 patients, 7.7% (38) had CIP. The prevalence of M+ GBT in CIP patients was higher compared with non-CIP patients, and it was significant [52.6% (20/38) versus 11.8% (54/456), p < 0.001]. The prevalence of H+ GBT in our cohort of CIP patients was similar to that of non-CIP patients [23.7% (9/38) versus 25.7% (117/456), p = 0.941]. CONCLUSION: The prevalence of methane-positive GBT was higher in CIP patients than in patients without CIP. This finding further strengthens the hypothesis that the relationship between motility disorders and methanogen overgrowth is facilitative.