Kaleido Biosciences

Relative abundances of bacterial species in the gut microbiome have been linked to many diseases. Species of gut bacteria are ecologically differentiated by their abilities to metabolize different glycans, making glycan delivery a powerful way to alter the microbiome to promote health. Here, we study the properties and therapeutic potential of chemically diverse synthetic glycans (SGs). Fermentation of SGs by gut microbiome cultures results in compound-specific shifts in taxonomic and metabolite profiles not observed with reference glycans, including prebiotics. Model enteric pathogens grow poorly on most SGs, potentially increasing their safety for at-risk populations. SGs increase survival, reduce weight loss, and improve clinical scores in mouse models of colitis. Synthetic glycans are thus a promising modality to improve health through selective changes to the gut microbiome.

Sugar nucleotides are essential glycosylation donors in carbohydrate metabolism. In their Research Article (DOI: 10.1002/anie.202115696), Liuqing Wen and co‐workers developed a general strategy for the efficient preparation of rare sugar nucleotides. Complex de novo biosynthesis of rare sugar nucleotides was recognized as cascade reactions. The cascade reactions were driven toward the formation of the target sugar nucleotides through cofactor regeneration system (CRS), thus resulting in a clean conversion.

Zuckernukleotide sind wichtige Glykosylierungsdonoren im Kohlenhydratstoffwechsel. In ihrem Forschungsartikel (DOI: 10.1002/ange.202115696) beschreiben Liuqing Wen und Mitarbeiter eine allgemeine Strategie für die effiziente Herstellung seltener Zuckernukleotide. Die komplexe Biosynthese von seltenen Zuckernukleotiden wurde als Kaskadenreaktion erkannt. Die Kaskadenreaktionen werden durch ein Cofaktor‐Regenerationssystem (CRS) zur Bildung der Ziel‐Zuckernukleotide angetrieben, was zu einer sauberen Umwandlung führte.

Glycosylation is catalyzed by glycosyltransferases using sugar nucleotides or occasionally lipid‐linked phosphosugars as donors. However, only very few common sugar nucleotides that occur in humans can be obtained readily, while the majority of sugar nucleotides that exist in bacteria, plants, archaea, or viruses cannot be synthesized in sufficient quantities by either enzymatic or chemical synthesis. The limited availability of such rare sugar nucleotides is one of the major obstacles that has greatly hampered progress in glycoscience. Herein we describe a general cofactor‐driven cascade conversion strategy for the efficient synthesis of sugar nucleotides. The described strategy allows the large‐scale preparation of rare sugar nucleotides from common sugars in high yields and without the need for tedious purification processes.

Glycosylation is catalyzed by glycosyltransferases using sugar nucleotides or occasionally lipid‐linked phosphosugars as donors. However, only very few common sugar nucleotides that occur in humans can be obtained readily, while the majority of sugar nucleotides that exist in bacteria, plants, archaea, or viruses cannot be synthesized in sufficient quantities by either enzymatic or chemical synthesis. The limited availability of such rare sugar nucleotides is one of the major obstacles that has greatly hampered progress in glycoscience. Herein we describe a general cofactor‐driven cascade conversion strategy for the efficient synthesis of sugar nucleotides. The described strategy allows the large‐scale preparation of rare sugar nucleotides from common sugars in high yields and without the need for tedious purification processes.

Background Ulcerative colitis (UC) pathogenesis involves genetic susceptibility, immune-mediated tissue injury, and gut microbiota disturbances. Most approved therapies modify host immunity, rather than directly targeting the microbiota. Faecal microbiota transplantation provides encouraging evidence for the therapeutic potential of gut microbiome modulation. Gastrointestinal tract bacteria are ecologically differentiated by their ability to use specific glycans as growth substrates, making glycans a promising and safe alternative to target the microbiome. To explore this, we used an ex vivo faecal microbiota culture system to identify a synthetic glycan (KB295) with desirable microbiological activity and conducted a proof of principle study (NCT04508413) of safety and tolerability of KB295 in patients with UC. Methods In ex vivo studies, faecal microbial communities from healthy subjects were incubated anaerobically (negative control) ± KB295. Taxa counts from shotgun metagenomic sequencing data were used to evaluate microbial response to KB295. Short-chain fatty acid (SCFA) levels were also assessed. KB295 was evaluated in an open-label single-arm study in adult patients with mild to moderate UC. KB295 was ingested over an 8-wk period. Objectives included KB295 safety (primary) and effect on gut microbiota composition and faecal biomarkers. Results In ex vivo studies, KB295 increased SCFA levels across 10 faecal samples to a median of 47.0 vs 15.2 mM with negative control, including increases in acetate, propionate, and butyrate levels. Metagenomic sequencing showed pathobiont depletion in the family Enterobacteriaceae with KB295 to a median relative abundance of 10.8% vs 38.2% with negative control. Pathobiont depletion was associated with enrichments of diverse genera in the phyla Bacteroidetes and Firmicutes. In patients with UC (n=12), KB295 was well tolerated with generally mild adverse events (AEs). The most frequently occurring AEs were bowel habit changes, flatulence, and headache. Median faecal calprotectin and lactoferrin levels decreased by 69.0% (n=11) and 86.0% (n=6), respectively, from screening to end of the KB295 intake. Consistent with our ex vivo results, of the patients for whom we have data to date, the relative abundance of the faecal pathobiont family Enterobacteriaceae decreased in 5 of 5 participants, and the commensal genus Parabacteroides was enriched in 4 of 5 participants. Conclusion Our results establish a proof of principle for the glycan modulation of gut microbiome composition and function and provide insight into the potential utility of this strategy in patients with UC. The safety and tolerability of KB295, along with evidence of reduced inflammation, support a phase 2 study, which is planned.

Chronic kidney disease is a major public health concern that affects millions of people globally. Alterations in gut microbiota composition have been observed in patients with chronic kidney disease. Nevertheless, the correlation between the gut microbiota and disease severity has not been investigated. In this study, we performed shot-gun metagenomics sequencing and identified several taxonomic and functional signatures associated with disease severity in patients with chronic kidney disease. We noted that 19 microbial genera were significantly associated with the severity of chronic kidney disease. The butyrate-producing bacteria were reduced in patients with advanced stages of chronic kidney diseases. In addition, functional metagenomics showed that two-component systems, metabolic activity and regulation of co-factor were significantly associated with the disease severity. Our study provides valuable information for the development of microbiota-oriented therapeutic strategies for chronic kidney disease.

Objectives These 2 parallel studies (K031 and K032) aim to evaluate the safety of KB109 in addition to supportive self-care (SSC) compared with SSC alone in outpatients with mild to moderate coronavirus disease 2019 (COVID-19). KB109 is a novel synthetic glycan that was formulated to modulate the gut microbiome composition and metabolic output in order to increase beneficial short-chain fatty acid (SCFA) production in the gut. The K031 study is designed to evaluate the safety of KB109 and characterize its impact on the natural progression of COVID-19 in patients with mild to moderate disease. The K032 study is evaluating the effect of KB109 on the gut microbiota structure and function in this same patient population. Additionally, both studies are evaluating measures of health care utilization, quality of life (QOL), laboratory indices, biomarkers of inflammation, and serological measures of immunity in patients who received SSC alone or with KB109. Noteworthy aspects of these outpatient studies include study design measures aimed at limiting in-person interactions to minimize the risk of infection spread, such as use of online diaries, telemedicine, and at-home sample collection. Study design K031 and K032 are randomized, controlled, open-label, clinical food studies. Participants Inclusion Criteria: • Adults ≥18 years of age • Patients willing and able to give informed consent • Screening/randomization telemedicine visit within 2 days of testing positive test for COVID-19 In K031 study, symptomatic patients at COVID-19 testing must report new or worsening symptoms at baseline that have not been present for more than 5 days ▪ Cardinal COVID-19 symptoms include fever, chills/repeated shaking with chills, cough, shortness of breath, headache, muscle pain, anosmia/ageusia, and sore throat. The 5 additional symptoms include gastrointestinal (GI) disturbance/symptoms (other than diarrhea), diarrhea, fatigue, nasal congestion, and chest tightness In K031, at COVID-19 testing, pre-symptomatic patients must report new cardinal COVID-19 symptoms within 7 days of a positive test and they must be screened and randomized within 5 days of developing symptoms • Mild to moderate COVID-19 and self-reported outpatient management In K032, mild to moderate COVID-19 was defined as having the following symptoms for no more than 72 hours before COVID-19 testing: a self- reported fever or cough (new or exacerbated) or presence of at least 2 of the following: anosmia, sore throat, or nasal congestion • Ability to adhere to the study visit schedule and other protocol requirements • Consistent internet or cell phone access with a data plan and access to a smartphone, tablet, or computer • The K031 and K032 studies are currently being conducted at 17 clinical institutions throughout the United States. Exclusion Criteria: • In the primary investigator’s (PI) judgement, patients likely to require hospitalization for COVID-19 • Patients who are hospitalized for in-patient treatment or currently being evaluated for potential hospitalization at the time of informed consent for conditions other than COVID-19 • History of chronic lung disease with chronic hypoxia • History of documented cirrhosis or end-stage liver disease • Ongoing requirement for oxygen therapy • Shortness of breath in resting position • Diagnosis of sleep apnea requiring bilevel positive airway pressure (BIPAP)/continuous positive airway pressure (CPAP) • Female patients who are pregnant, trying to become pregnant, or lactating • Concurrent use of immunomodulatory agent within 12 months; systemic antibiotics, antifungals, or antivirals for treatment of active infection within 28 days; systemic immunosuppressive therapy within 3 months; or drugs or other compounds that modulate GI motility (eg, stool softeners, laxatives, or fiber supplements) taken currently, or within 7 days. Antacid (histamine 2 blockers and proton pump inhibitors) and antidiarrheal agents are not prohibited • History of GI surgery (6 months prior to randomization), including but not limited to bariatric surgery and bowel resection, or history of, or active GI disease(s) that may affect assessment of tolerability, including but not limited to inflammatory bowel disease, irritable bowel syndrome, autoimmune disease, or GI malignancy • Participation in an interventional clinical trial or use of any investigational agent within 30 days before randomization • Clinically significant or uncontrolled concomitant medical condition that would put the patient at risk or jeopardize the objectives of the study in the opinion of the PI • In the opinion of the PI, patient unlikely for any reason to be able to comply with study procedures • Contraindications, sensitivities, or known allergy to the use of the study product or its components Intervention and comparator Patients will be randomized (1,1) to receive either SSC and KB109 or SSC alone. During SSC, patients should follow the steps as instructed by their healthcare provider to care for themselves and protect other people in the home and community from potentially contracting COVID-19. Management of COVID-19-related symptoms with over-the-counter cough, cold, and anti-pyretic medications by patients is permitted in accordance with the medications’ respective drug facts label or as instructed by the patient’s healthcare provider. Following randomization, patients assigned to receive KB109 and SSC will receive a Kaleido Biosciences, Inc at-home study kit including a thermometer, pulse oximeter, and KB109. During the Intake Period (days 1–14), KB109 will be reconstituted in water by the patient and consumed by the patient twice daily (at least 8 hours apart), following an up-titration dosing schedule: Days 1 to 2: 9 g twice daily for a total daily dose of 18 g Days 3 to 4: 18 g twice daily for a total daily dose of 36 g Days 5 to 14: 36 g twice daily for a total daily dose of 72 g During the intake period, patients will record their daily COVID-19–related symptoms, selected COVID-19 signs (as self-measured using the provided thermometer and pulse oximeter), responses to questions related to QOL measures, health care use measures, and concomitant medications taken in the previous 24 hours. Wellness visits by telephone will be conducted between days 1 and 14 to follow up on patient’s health status and to ascertain compliance with KB109 and completion of questions. On day 14, all patients will undergo a telemedicine visit where the following will be conducted: abbreviated physical examination, assessment of safety and other protocol-specified measures of health, and an evaluation of whether follow-up treatment is recommended owing to a progression of COVID-19 symptoms. If feasible, blood samples for clinical chemistries, biomarkers and serological measure of immunity, and nasal/oropharyngeal swabs for quantitative viral load assessments will be collected. Beginning on day 15, patients in both groups will enter the follow-up period (days 15–35) where COVID-19 signs, symptoms, and health care use indices will be collected. Wellness visits by telephone will be conducted on days 21, 28, and 35 to follow-up on the patient’s health status. On day 35, all patients will undergo a telemedicine visit where the same information as the day 14 telemedicine visit will be collected, including any blood samples. Main outcomes The primary outcome for the K031 and K032 studies is to evaluate the safety of KB109 in addition to SSC compared with SSC alone in outpatients with mild to moderate COVID-19 by assessing the number of patients experiencing KB109-related treatment-emergent adverse events (TEAEs) during the study. K031 will also evaluate duration of symptoms among outpatients with mild to moderate COVID-19. This will be as an assessment made during the intake and/or follow-up periods of the following: • Time to resolution of the 13 overall and the 8 cardinal COVID-19–related symptoms from day 1 until the day at which the composite score of the 13 overall and 8 cardinal COVID-19–related symptoms becomes 0 or 1 and remains at 0 or 1 for the rest of the intake period and for the follow-up period • Proportion of patients with a reduction from baseline in each of the 13 overall COVID-19–related symptoms • Proportion of patients in whom symptoms (present at baseline) become absent for each of the 13 overall COVID-19–related symptoms • Change from baseline in the overall composite score of the 13 overall COVID-19–related symptoms and the 8 cardinal COVID-19–related symptoms • Time to resolution of fever (defined as from day 1 until the day at which a patient’s daily maximum temperature achieves and remains below 100.4°F without antipyretic medication) • Proportion of patients with oxygen saturation <95% and <98% on days 14 and 35 • Measures collected from the health care provider wellness visits • Proportion of patients experiencing hospital admissions (all cause and COVID-19–related) • Health care use K032 will evaluate the effect of KB109 in addition to SSC compared with SSC alone on the gut microbiota structure and function in outpatients with mild to moderate COVID-19. Before days 1, 14, and 35, microbiota structure (eg, magnitude of change in gut microbiome structure, composition of gut microbiome) will be analysed by methods such as nucleic acid sequencing and gut microbiome function will be analysed via levels of stool inflammatory biomarkers (eg, lipocalin) and gut microbiome metabolites (eg, SCFA). The health of outpatients with mild to moderate COVID-19 will be evaluated during the intake and follow- up periods by: measures of QOL; measures collected from the healthcare provider wellness visits; the proportion of patients experiencing hospital admissions; health care use, the proportions of patients with oxygen saturation <95% and <98%, and the proportion of patients with temperature below 100.4 °F without an anti-pyretic medication. Potential exploratory outcome measures may include: changes from baseline (day 1) in laboratory measures, specific biomarkers of infection, serology, inflammation (eg, D-dimer, lipocalin, cytokines, IgM/IgG sero-conversion, and neutralization assays), and viral load in outpatients with mild to moderate COVID-19 in the presence and absence of KB109. Randomisation All patients deemed eligible for the studies will be randomized in a 1:1 ratio to KB109 in addition to SSC or SSC alone group using an interactive response technology system. Randomization will be stratified by study site/center, age groups (≥18–<45 years, ≥45–<65 years, ≥65 years), and comorbidity status (yes, no). Blinding (masking) These studies are open-label; therefore, no blinding is necessary. Numbers to be randomised (sample size) K031 will enroll approximately 350 to 400 (175–200 patients per group) whereas K032 will enroll approximately 50 patients (25 per group). Study status K031 protocol version 4, December 9, 2020; recruitment started in August, 2020, and the study is estimated to be completed in March 2021. This study is active and enrollment was completed in January, 2021. K032 protocol version 2, June 30, 2020; recruitment is estimated to start in July, 2020. This study is recruiting and the study is estimated to be completed in March 2021. Study registration K031 is registered with the US National Library of Medicine, Identifier NCT04414124 as of June 4, 2020. K032 is registered with the US National Library of Medicine, Identifier NCT04486482 as of July 24, 2020. Full protocol The full protocols are attached as additional files (Additional files 1 and 2), accessible from the ClinicalTrials.gov website. In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocols. The study protocols have been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional files 3 and 4).

An amendment to this paper has been published and can be accessed via the original article.

Background With increasing concerns about the impact of frequent antibiotic usage on the human microbiome, it is important to characterize the potential for such effects in early antibiotic drug development clinical trials. In a randomised Phase 2a clinical trial study that evaluated the pharmacokinetics of repeated oral doses of gepotidacin, a first-in-chemical-class triazaacenaphthylene antibiotic with a distinct mechanism of action, in adult females with uncomplicated urinary tract infections for gepotidacin (GSK2140944) we evaluated the potential changes in microbiome composition across multiple time points and body-sites ( ClinicalTrials.gov : NCT03568942). Results Samples of gastrointestinal tract (GIT), pharyngeal cavity and vaginal microbiota were collected with consent from 22 patients at three time points relative to the gepotidacin dosing regimen; Day 1 (pre-dose), Day 5 (end of dosing) and Follow-up (Day 28 ± 3 days). Microbiota composition was determined by DNA sequencing of 16S rRNA gene variable region 4 amplicons. By Day 5, significant changes were observed in the microbiome diversity relative to pre-dose across the tested body-sites. However, by the Follow-up visit, microbiome diversity changes were reverted to compositions comparable to Day 1. The greatest range of microbiome changes by body-site were GIT followed by the pharyngeal cavity then vagina. In Follow-up visit samples we found no statistically significant occurrences of pathogenic taxa. Conclusion Our findings suggest that gepotidacin alteration of the human microbiome after 5 days of dosing is temporary and rebound to pre-dosing states is evident within the first month post-treatment. We recommend that future antibiotic drug trials include similar exploratory investigations into the duration and context of microbiome modification and recovery. Trial registration NCT03568942 . Registered 26 June 2018.

Metabolites produced in the human gut are known modulators of host immunity. However, large-scale identification of metabolite–host receptor interactions remains a daunting challenge. Here, we employed computational approaches to identify 983 potential metabolite–target interactions using the Inflammatory Bowel Disease (IBD) cohort dataset of the Human Microbiome Project 2 (HMP2). Using a consensus of multiple machine learning methods, we ranked metabolites based on importance to IBD, followed by virtual ligand-based screening to identify possible human targets and adding evidence from compound assay, differential gene expression, pathway enrichment, and genome-wide association studies. We confirmed known metabolite–target pairs such as nicotinic acid–GPR109a or linoleoyl ethanolamide–GPR119 and inferred interactions of interest including oleanolic acid–GABRG2 and alpha-CEHC–THRB. Eleven metabolites were tested for bioactivity in vitro using human primary cell-types. By expanding the universe of possible microbial metabolite–host protein interactions, we provide multiple drug targets for potential immune-therapies.

Objectives These 2 parallel studies (K031 and K032) aim to evaluate the safety of KB109 in addition to supportive self-care (SSC) compared with SSC alone in outpatients with mild to moderate coronavirus disease 2019 (COVID-19). KB109 is a novel synthetic glycan that was formulated to modulate the gut microbiome composition and metabolic output in order to increase beneficial short-chain fatty acid (SCFA) production in the gut. The K031 study is designed to evaluate the safety of KB109 and characterize its impact on the natural progression of COVID-19 in patients with mild to moderate disease. The K032 study is evaluating the effect of KB109 on the gut microbiota structure and function in this same patient population. Additionally, both studies are evaluating measures of health care utilization, quality of life (QOL), laboratory indices, biomarkers of inflammation, and serological measures of immunity in patients who received SSC alone or with KB109. Noteworthy aspects of these outpatient studies include study design measures aimed at limiting in-person interactions to minimize the risk of infection spread, such as use of online diaries, telemedicine, and at-home sample collection.

Introduction and objectives Hepatic encephalopathy (HE) is a complication of cirrhosis linked to the microbiome. We aimed to characterize the fecal microbiome of patients with prior and future overt HE, and explore the relationship between fecal species, short-chain fatty acids (SCFAs) and ammonia on HE pathogenesis. Materials and methods Consecutive inpatients and outpatients with cirrhosis were recruited. A single stool sample was collected and underwent shallow shotgun sequencing, and SCFA and ammonia quantification. Patients were followed until the end of the study period. Prior and new overt HE was diagnosed by the treating hepatologist. Results Forty-nine patients with cirrhosis, mean MELD-Na 20 (SD = 9) and 33 (67%) with a history of OHE provided a stool sample. Over a median 85 days of follow up (interquartile range 34 to 181 days), 16 developed an OHE episode. Eight fecal bacterial species were associated with a history of OHE, and no species predicted future OHE. Bacterial species positively associated with SCFA content were inversely related to cirrhosis disease severity. Patients with a history of OHE had lower concentrations of 6 fecal SCFAs. Fecal ammonia concentrations were similar between those with and without a history of OHE (273 μmol/g ± 214 vs. 327 ± 234, P = 0.43). Conclusions We found 8 fecal species and 6 SCFAs linked to OHE. Many of the species inversely linked to OHE also have an association with SCFA production. Further work is needed to detail this relationship and to develop targeted interventions to treat HE.

Background The prevention and treatment of bacterial infections is a human health challenge. A disadvantage of antibiotics is that they often kill beneficial commensal, bacteria in addition to, pathogenic bacteria. Indiscriminate killing disrupts the homeostasis between commensal bacteria and the host gut epithelium allowing colonization of the gut by pathogenic bacteria and increases susceptibility to infections. This research was done to develop a non-antibiotic modality to prevent bacterial infections by growing, rather than killing, commensal bacteria in the gut. Gut commensal bacteria grown on carbohydrates produce short-chain fatty acids (SCFAs) that support gut homeostasis maintenance and promote resistance to bacterial colonization. SCFAs have direct and indirect effects on the gut and lung mucosal immune system. They have also been linked to respiratory viral infection reduction and shown to influence macrophage function to mitigate pro-inflammatory neutrophil-mediated tissue damage. Methods A library of over 1,500 synthetic proprietary glycans, termed Microbiome Metabolic Therapies (MMT™), was synthesized using different chemical and enzymatic approaches. An ex vivo platform using fecal bacterial communities from human subjects was devised to screen MMTs for their abilities to deplete pathogenic bacteria, and modulate multiple aspects of bacterial metabolism. Results KB109 was identified based on its ability to reduce the relative abundance of a diversity of pathogens including clinically relevant Gram-negative and Gram-positive bacteria in human fecal communities. KB109 also increased the relative abundance of prevalent commensal bacteria. Monoculture experiments demonstrated that KB109 promotes the growth of commensal bacteria, but not pathogens. Ex vivo screening revealed that KB109 consistently increased SFCA production across multiple fecal communities. Conclusion KB109 represents an appealing activity profile and offers an opportunity to prevent enteric and systemic bacterial infections by promoting gut homeostasis and colonization resistance, and ameliorating respiratory viral infections by stimulating immune homeostasis. KB109 is under evaluation in two COVID-19 clinical studies. Disclosures Jeffrey Meisner, PhD, Kaleido Biosciences (Employee, Shareholder) Jackson Lee, PhD, Kaleido Biosciences (Employee, Shareholder) Jonathan Lawrence, PhD, Kaleido Biosciences (Employee, Shareholder) Megan Roed, BA, Kaleido Biosciences (Employee, Shareholder) Johan van Hylckama Vlieg, PhD, Kaleido Biosciences (Employee, Shareholder)

Background: This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short bowel syndrome–associated intestinal failure (SBS–IF). Methods: Safety data from teduglutide‐treated patients in 4 clinical trials were pooled. The completed 12‐week and 24‐week phase III core studies (NCT01952080/EudraCT 2013‐004588‐30 and NCT02682381/EudraCT 2015‐002252‐27) enrolled children aged 1–17 years with SBS–IF. Patients could elect to enroll in ongoing open‐label extensions (NCT02949362/EudraCT 2016‐000863‐17 and NCT02954458/EudraCT 2016‐000849‐30). Interim data from ongoing studies were included. Results: Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0–94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty‐five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, D‐lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred. Conclusion: Based on integrated data from 4 clinical studies, including long‐term follow‐up for ≤161 weeks, teduglutide had a safety profile consistent with the individual core pediatric studies and as expected for pediatric patients with SBS–IF who never received teduglutide. The most frequent AEs reflected treatment with teduglutide, complications of the underlying disease, and typical childhood illnesses. This article is protected by copyright. All rights reserved

Background: Dietary glycans, widely used as food ingredients and not directly digested by humans, are of intense interest for their beneficial roles in human health through shaping the microbiome. Characterizing the consistency and temporal responses of the gut microbiome to glycans is critical for rationally developing and deploying these compounds as therapeutics. Methods: We investigated the effect of two chemically distinct glycans (fructooligosaccharides and polydextrose) through three clinical studies conducted with 80 healthy volunteers. Stool samples, collected at dense temporal resolution (~ 4 times per week over 10 weeks) and analyzed using shotgun metagenomic sequencing, enabled detailed characterization of participants' microbiomes. For analyzing the microbiome time-series data, we developed MC-TIMME2 (Microbial Counts Trajectories Infinite Mixture Model Engine 2.0), a purpose-built computational tool based on nonparametric Bayesian methods that infer temporal patterns induced by perturbations and groups of microbes sharing these patterns. Results: Overall microbiome structure as well as individual taxa showed rapid, consistent, and durable alterations across participants, regardless of compound dose or the order in which glycans were consumed. Significant changes also occurred in the abundances of microbial carbohydrate utilization genes in response to polydextrose, but not in response to fructooligosaccharides. Using MC-TIMME2, we produced detailed, high-resolution temporal maps of the microbiota in response to glycans within and across microbiomes. Conclusions: Our findings indicate that dietary glycans cause reproducible, dynamic, and differential alterations to the community structure of the human microbiome.

Biomedical scientists often search databases of therapeutic molecules to answer a set of drug-related queries. In this paper, we present a novel network algorithm called MolecRank that is specialized in searching and ranking molecules using a biomedical literature. Starting with a disease-related set of publications (e.g., depression), a feature extraction step is performed to identify the biological features associated with the drugs of study. The MolecRank is a network centrality algorithm that is specialized in deriving a rank when specificity is in question. The algorithm’s promise is two folds (a) an interesting search-and-rank tool that demonstrated its importance in the drug discovery research, (b) a theoretical network centrality measure that is based on the notion of specificity. We performed our experiments against a depression-related literature dataset. The results shows an interesting order that is significantly different from well-advertised drugs (e.g., Cymbalta#10 though well-advertised). We conclude that not all well-advertised drugs are most specific. This striking evidence highlights the significance of specificity as an important measure in discovering new drugs.