Metabolic independence drives gut microbial colonization and resilience in health and disease.

BACKGROUND: Changes in microbial community composition as a function of human health and disease states have sparked remarkable interest in the human gut microbiome. However, establishing reproducible insights into the determinants of microbial succession in disease has been a formidable challenge. RESULTS: Here we use fecal microbiota transplantation (FMT) as an in natura experimental model to investigate the association between metabolic independence and resilience in stressed gut environments. Our genome-resolved metagenomics survey suggests that FMT serves as an environmental filter that favors populations with higher metabolic independence, the genomes of which encode complete metabolic modules to synthesize critical metabolites, including amino acids, nucleotides, and vitamins. Interestingly, we observe higher completion of the same biosynthetic pathways in microbes enriched in IBD patients. CONCLUSIONS: These observations suggest a general mechanism that underlies changes in diversity in perturbed gut environments and reveal taxon-independent markers of "dysbiosis" that may explain why widespread yet typically low-abundance members of healthy gut microbiomes can dominate under inflammatory conditions without any causal association with disease.

Transient Suppression of Bacterial Populations Associated with Gut Health is Critical in Success of Exclusive Enteral Nutrition for Children with Crohn's Disease.

BACKGROUND AND AIMS: Exclusive enteral nutrition [EEN] is a dietary intervention to induce clinical remission in children with active luminal Crohn's disease [CD]. While changes in the gut microbial communities have been implicated in achieving this remission, a precise understanding of the role of microbial ecology in the restoration of gut homeostasis is lacking. METHODS: Here we reconstructed genomes from the gut metagenomes of 12 paediatric subjects who were sampled before, during and after EEN. We then classified each microbial population into distinct 'phenotypes' or patterns of response based on changes in their relative abundances throughout the therapy on a per-individual basis. RESULTS: Our data show that children achieving clinical remission during therapy were enriched with microbial populations that were either suppressed or that demonstrated a transient bloom as a function of EEN. In contrast, this ecosystem-level response was not observed in cases of EEN failure. Further analysis revealed that populations that were suppressed during EEN were significantly more prevalent in healthy children and adults across the globe compared with those that bloomed ephemerally during the therapy. CONCLUSIONS: These observations taken together suggest that successful outcomes of EEN are marked by a temporary emergence of microbial populations that are rare in healthy individuals, and a concomitant reduction in microbes that are commonly associated with gut homeostasis. Our work is a first attempt to highlight individual-specific, complex environmental factors that influence microbial response in EEN. This model offers a novel, alternative viewpoint to traditional taxonomic strategies used to characterize associations with health and disease states.

Histopathology of Colectomy Specimens Predicts Endoscopic Pouch Phenotype in Patients with Ulcerative Colitis.

BACKGROUND: The endoscopic appearance in patients with "pouchitis" after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) can be quite heterogenous. Patients with an endoscopic phenotype resembling Crohn's disease (CD) are at high risk of pouch loss. AIMS: We aimed to assess how the histopathology of colectomy specimens predicts endoscopic pouch phenotypes in UC. METHODS: We retrospectively assessed pouchoscopies from patients with UC who underwent IPAA and classified pouch findings into 7 main phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted ≥ 6 months from ileostomy takedown. We assessed the clinical and pathological data including deep, focal inflammation, granulomas, and terminal ileal involvement in the colectomy specimens. Logistic regression analysis was performed to identify contributing factors to each phenotype. RESULTS: This study included 1,203 pouchoscopies from 382 patients with UC. On multivariable analysis, deep inflammation was significantly associated with pouch fistulas (Odds ratio 3.27; 95% confidence interval 1.65-6.47; P = 0.0007). Of the 75 patients with deep inflammation, only two patients (2.7%) were diagnosed with CD based on pathology review. Terminal ileal involvement significantly increased the risk of afferent limb involvement (Odds ratio 2.96; 95% confidence interval 1.04-8.47; P = 0.04). There were no significant associations between other microscopic features and phenotypes. CONCLUSIONS: We identify histologic features of colectomy specimens in UC that predict subsequent pouch phenotypes. Particularly, deep inflammation in the resected colon was significantly associated with pouch fistulas, a pouch phenotype with poor prognosis.

Outcomes of Ileoanal Pouch Anastomosis in Pediatric Ulcerative Colitis Are Worse in the Modern Era: A Time Trend Analysis Outcomes Following Ileal Pouch-Anal Anastomosis in Pediatric Ulcerative Colitis.

BACKGROUND: Despite significant differences in surgical outcomes between pediatric and adult patients with ulcerative colitis (UC) undergoing colectomy, counseling on pediatric outcomes has largely been guided by data from adults. We compared differences in pouch survival between pediatric and adult patients who underwent total proctocolectomy with ileal pouch-anal anastomosis (IPAA). METHODS: This was a retrospective single-center study of patients with UC treated with IPAA who subsequently underwent pouchoscopy between 1980 and 2019. Data were collected via electronic medical records. We stratified the study population based on age at IPAA. Differences between groups were assessed using t tests and chi-square tests. Kaplan-Meier curves were used to compare survival probabilities. Differences between groups were assessed using a log-rank test. RESULTS: We identified 53 patients with UC who underwent IPAA before 19 years of age and 329 patients with UC who underwent IPAA at or after 19 years of age. Subjects who underwent IPAA as children were more likely to require anti-tumor nerosis factor (TNF) postcolectomy compared with adults (41.5% vs 25.8%; P < .05). Kaplan-Meier estimates revealed that pediatric patients who underwent IPAA in the last 10 years had a 5-year pouch survival probability that was 28% lower than that of those who underwent surgery in the 1990s or 2000s (72% vs 100%; P < .001). Further, children who underwent IPAA and received anti-TNF therapies precolectomy had the most rapid progression to pouch failure when compared with anti-TNF-naive children and with adults who were either exposed or naive precolectomy (P < .05). CONCLUSIONS: There are lower rates of pouch survival for children with UC who underwent IPAA following the uptake of anti-TNF therapy compared with both historical pediatric control subjects and contemporary adults.

Ileal pouch­anal anastomosis is the most common surgical approach for patients with ulcerative colitis undergoing total proctocolectomy. Outcomes are informed by heterogeneous adult data cohorts often predating anti-tumor necrosis factor uptake. We find that for children in the modern era pouch loss occurs at higher rates.

Endoscopic Phenotype of the J Pouch in Patients With Inflammatory Bowel Disease: A New Classification for Pouch Outcomes.

BACKGROUND & AIMS: Pouchitis is a common complication of ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis who have undergone colectomy. Pouchitis has been considered a single entity despite a broad array of clinical and endoscopic patterns. We developed a novel classification system based on the pattern of inflammation observed in pouches and evaluated the contributing factors and prognosis of each phenotype. METHODS: We identified 426 patients (384 with ulcerative colitis) treated with proctocolectomy and IPAA who subsequently underwent pouchoscopies at the University of Chicago between June 1997 and December 2019. We retrospectively reviewed 1359 pouchoscopies and classified them into 7 main pouch phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted 6 months after ileostomy takedown. Logistic regression analysis was used to assess factors contributing to each phenotype. Pouch survival was estimated by the log-rank test and the Cox proportional hazards model. RESULTS: Significant contributing factors for afferent limb involvement were a body mass index of 25 or higher and hand-sewn anastomosis, for inlet involvement the significant contributing factor was male sex; for diffuse inflammation the significant contributing factors were extensive colitis and preoperative use of anti-tumor necrosis factor drugs, for cuffitis the significant contributing factors were stapled anastomosis and preoperative Clostridioides difficile infection. Inlet stenosis, diffuse inflammation, and cuffitis significantly increased the risk of pouch excision. Diffuse inflammation was associated independently with pouch excision (hazard ratio, 2.69; 95% CI, 1.34-5.41; P = .005). CONCLUSIONS: We describe 7 unique IPAA phenotypes with different contributing factors and outcomes, and propose a new classification system for pouch management and future interventional studies.

COVID-19 and Gastrointestinal and Hepatobiliary Diseases.

Since its initial onset in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread quickly across the globe, resulting in the potentially life-threatening respiratory coronavirus disease 2019 (COVID-19). Although less commonly reported, COVID-19 has also been associated with gastrointestinal and hepatic manifestations, which may occur more frequently in children. This has also led to concern about the susceptibility of children to the SARS-CoV-2 virus who have underlying chronic digestive disease and may be treated with immune suppression. As such, recommendations and expert consensus regarding the management of chronic gastrointestinal and hepatobiliary disease have been of great interest during the pandemic and international database reporting has informed our understanding. The impact of COVID-19 on the gastrointestinal tract and its influence on the management of pediatric digestive disease is reviewed in this article. [Pediatr Ann. 2021;50(8):e315-e319.].

Pediatric Digestive Health and the Gut Microbiome: Existing Therapies and a Look to the Future.

The human gut is host to trillions of microbes that from birth begin interacting with our immune system. Over time this relationship is thought to shape critical aspects of human function such as metabolism, brain development, immune response, and overall gut health. Recent advances in technology have allowed us to begin understanding this complex relationship and have demonstrated that microbes within the gut ecosystem can be influenced by a variety of factors including mode of delivery, diet, and medication exposure, all of which can impact host health in either positive or detrimental ways. Perturbations of gut homeostasis have been implicated in many forms of digestive disease such as inflammatory bowel disease, irritable bowel syndrome, Helicobacter pylori infection, and even in cases of antibiotic-associated diarrhea. As such, researchers have sought methods to either restore gut homeostasis or prevent dysregulation of the gut community, also known as dysbiosis, through an emerging field known as microbial therapeutics. Examples of existing modalities are reviewed here such as prebiotics, probiotics, fecal microbial transplantation, and dietary therapy. As these therapies become further substantiated through research and increasingly desired by patients and their families, there is a need for providers caring for children to familiarize themselves with the existing data and indications for use. As we look to the future, machine-learning algorithms and more readily available next-generation sequencing of fecal samples may allow us to harness data from a person's gut microbiota to predict response to a particular intervention and tailor therapeutic options with an aim toward precision medicine. [Pediatr Ann. 2021;50(8):e336-e342.].

Devastating Postpartum Complications in an Adolescent Linked to New-Onset Inflammatory Bowel Disease and Antiphospholipid Antibody Syndrome.

Pregnancy can affect the severity of inflammatory bowel disease (IBD), and pregnant women with IBD are at a higher risk for venous thromboembolism compared with the general population. We report a previously healthy 16-year-old female who developed bloody diarrhea and venous thromboembolism following childbirth, with further evaluation revealing IBD and antiphospholipid antibody syndrome. This case highlights the impact pregnancy can have on IBD and other immunological disorders, and the potentially life-threatening risk of thrombosis in pregnant women with IBD.

A Narrow Window: Booming Gluten-free Market and Fostering Healthy Dietary Habits in Children With Celiac Disease.

An expanding gluten-free marketplace has left children with celiac disease and their families with a host of new dietary options. The quality of these foods is inconsistent and processed items may be high in caloric content while lacking nutritional value. Assessing the dietary preferences of a cohort of children with celiac disease via cross-sectional survey, we find that these processed food items have become a staple of the gluten-free diet, and in many cases, these foods are consumed to the exclusion of healthy alternatives. Furthermore, children with celiac disease and their families become less interested in dietary education over time, indicating that the greatest opportunity for imparting a healthy diet may occur at the time of diagnosis.

Refeeding Syndrome.

Refeeding syndrome describes the metabolic disturbances and clinical sequelae that occur in response to nutritional rehabilitation of patients who are moderate to severely malnourished. When risk factors are not identified and nutrition therapy is not managed appropriately, devastating consequences such as electrolyte depletion and imbalances, fluid overload, arrhythmia, seizure, encephalopathy, and death may occur. As this entity is often unrecognized, especially in pediatrics, becoming familiar with the pathophysiology, clinical manifestations, and management strategies will help clinicians caring for children avoid unnecessary morbidity and mortality. [Pediatr Ann. 2019;48(11):e448-e454.].

Hypophosphatemia in a Malnourished Child: When Renal Fanconi Syndrome Does Not Stand for Refeeding Syndrome.

Refeeding syndrome is diagnosed based on the onset of multiple laboratory abnormalities (most commonly hypophosphatemia) and clinical signs in the setting of nutrition rehabilitation of malnourished patients. Because definitions are not uniform, a broad differential diagnosis should always include renal tubular dysfunction. Our report details a 3 year-old child with undiagnosed renal tubular dysfunction who presented with the clinical picture of refeeding syndrome with refractory electrolyte abnormalities. A diagnosis of renal Fanconi syndrome was made after urinalysis that revealed glucosuria and urine electrolyte losses. Thus, urinalysis can aid in making a positive diagnosis of refeeding syndrome.

Hepatobiliary Manifestations in Systemic Disease.

Liver disease in children occurs via a multitude of primary illnesses such as autoimmune hepatopathy, biliary atresia, and nonalcoholic fatty liver disease. However, jaundice, hepatitis, and alterations in liver tests can often be a manifestation of systemic diseases. The liver is involved in many critical functions such as circulation, immunity, toxin clearance, and metabolism; when the heart, lungs, gastrointestinal tract, immune system, or endocrine systems are compromised, the liver will be affected. This article reviews common causes of liver injury as well as highlights key associations that should not be missed when diagnosing and managing children with liver disease. Becoming familiar with patterns of liver injury and arranging clues in the context of a thorough history and physical examination can help providers navigate the broad differential diagnosis of secondary liver disease. [Pediatr Ann. 2018;47(11):e458-e464.].