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Medication is a major determinant of human gut microbiome structure, and its overuse increases the risks of morbidity and mortality. However, effects of certain commonly prescribed drugs and multiple medications on the gut microbiome are still underinvestigated.We performed shotgun metagenomic analysis of fecal samples from 4198 individuals in the Japanese 4D (Disease, Drug, Diet, Daily life) microbiome project. A total of 759 drugs were profiled, and other metadata, such as anthropometrics, lifestyles, diets, physical activities, and diseases, were prospectively collected. Second fecal samples were collected from 243 individuals to assess the effects of drug initiation and discontinuation on the microbiome.We found that numerous drugs across different treatment categories influence the microbiome; more than 70% of the drugs we profiled had not been examined before. Individuals exposed to multiple drugs, polypharmacy, showed distinct gut microbiome structures harboring significantly more abundant upper gastrointestinal species and several nosocomial pathobionts due to additive drug effects. Polypharmacy was also associated with microbial functions, including the reduction of short-chain fatty acid metabolism and increased bacterial stress responses. Even nonantibiotic drugs were significantly correlated with an increased antimicrobial resistance potential through polypharmacy. Notably, a 2-time points dataset revealed the alteration and recovery of the microbiome in response to drug initiation and cessation, corroborating the observed drug-microbe associations in the cross-sectional cohort.Our large-scale metagenomics unravels extensive and disruptive impacts of individual and multiple drug exposures on the human gut microbiome, providing a drug-microbe catalog as a basis for a deeper understanding of the role of the microbiome in drug efficacy and toxicity.

Case-control studies have shown that patients with Crohn's disease (CD) have a microbial composition different from healthy individuals. Although the causes of CD are unknown, epidemiologic studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters (DCs) are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives (FDRs) of patients with CD.As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy FDRs of patients with CD. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters.DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota.Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases.

To identify gut and oral metagenomic signatures that accurately predict pancreatic ductal carcinoma (PDAC) and to validate these signatures in independent cohorts.We conducted a multinational study and performed shotgun metagenomic analysis of fecal and salivary samples collected from patients with treatment-naïve PDAC and non-PDAC controls in Japan, Spain, and Germany. Taxonomic and functional profiles of the microbiomes were characterized, and metagenomic classifiers to predict PDAC were constructed and validated in external datasets.Comparative metagenomics revealed dysbiosis of both the gut and oral microbiomes and identified 30 gut and 18 oral species significantly associated with PDAC in the Japanese cohort. These microbial signatures achieved high area under the curve values of 0.78 to 0.82. The prediction model trained on the Japanese gut microbiome also had high predictive ability in Spanish and German cohorts, with respective area under the curve values of 0.74 and 0.83, validating its high confidence and versatility for PDAC prediction. Significant enrichments of Streptococcus and Veillonella spp and a depletion of Faecalibacterium prausnitzii were common gut signatures for PDAC in all the 3 cohorts. Prospective follow-up data revealed that patients with certain gut and oral microbial species were at higher risk of PDAC-related mortality. Finally, 58 bacteriophages that could infect microbial species consistently enriched in patients with PDAC across the 3 countries were identified.Metagenomics targeting the gut and oral microbiomes can provide a powerful source of biomarkers for identifying individuals with PDAC and their prognoses. The identification of shared gut microbial signatures for PDAC in Asian and European cohorts indicates the presence of robust and global gut microbial biomarkers.

Background. The pathogenesis of chronic inflammatory bowel disease (IBD) is still not fully clarified. It is known that disorders of the intestinal microbiota lead to an increased intestinal permeability, activation of mucous and adaptive immunity, impaired production and intestinal absorption of short-chain fatty acids (SCFA). The ratio of acetic, propionic, butyric acids is an important indicator of the integrity of the intestinal microbial community. Thus, the study of the composition of the intestinal microbiota and the concentrations of fecal SCFA is a very promi­sing approach to broadening the understanding of IBD pathoge­nesis. The purpose of our study was to determine the features of the production of fecal SCFA and the composition of colon microbiota in patients with IBD. Materials and methods. The study, which was carried out at the Department of Intestinal Diseases of the Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine, involved 74 patients with IBD with an average age of (43.2 ± 1.8) years, who according to nosology were divided into 2 groups: group I — those with ulcerative colitis (UC) (n = 66), group II — individuals with Crohn’s disease (CD) (n = 8). The diagnoses of CD and UC were established accor­ding to generally accepted diagnostic standards in gastroenterology. Determination of fecal SCFA was carried out by chromatographic method with the use of hardware-software complex for medical researches on the basis of the gas chromatographer Chromateс Crystal 5000. The intestinal microflora was evaluated using a microbiological study of the colon content. Results. Patients with IBD had significant changes in the spectrum of SCFA, which were similar in both UC and CD: a decrease in acetic acid in the UC group by 5.7 times, in the CD group by 10.5 times (p, Актуальність. Патогенез хронічних запальних захворювань кишечника (ХЗЗК) досі залишається до кінця не вивченим. Відомо, що порушення мікробіоти кишечника призводять до підвищеної проникності кишечника, порушення продукції та кишкового всмоктування коротколанцюгових жирних кислот (КЖК), співвідношення яких є важливим показником цілісності мікробної спільноти кишечника. Таким чином, вивчення складу мікробіоти кишечника і концентрацій фекальних КЖК є дуже перспективним підходом до розширення розуміння патогенезу ХЗЗК. Метою дослідження було визначити особливості продукції фекальних КЖК та складу мікробіоти товстої кишки у хворих на ХЗЗК. Матеріали та методи. У дослідження, що проводилось у відділенні захворювань кишечника ДУ «Інститут гастроентерології НАМН України», були залучені 74 пацієнти з ХЗЗК, які були розподілені на 2 групи: І група — хворі на неспецифічний виразковий коліт (НВК) (n = 66), II — хворі на хворобу Крона (ХК) (n = 8). Діагнози ХК та НВК були встановлені згідно із загальноприйнятими стандартами діагностики в гастроентерології. Проведене визначення фекальних КЖК, дослідження видового та кількісного складу мікрофлори вмісту кишечника. Результати. У хворих на ХЗЗК виявлені значні зміни в спектрі КЖК, які були аналогічними як при НВК, так і при ХК: зменшення вмісту оцтової кислоти в групі НВК у 5,7 раза і в групі ХК у 10,5 раза (р

Background. Lactase deficiency (LD) is the most common pathology of small intestine characterized by the development of maldigestion and malabsorbtion syndromes associated with the absence or lack of the enzyme lactase activity. Objective: to study the features of various LD clinical forms in children. Materials and methods. We have examined 40 children (21 boys and 19 girls) of different age groups diagnosed with lactate deficiency. The follo­wing studies were conducted: stool analysis, pH determination, total carbohydrate content, lactose load, and urinary lactose content. The probability assessment was performed using Student’s t-test. Results. Four clinical groups have been identified depending on the form of LD: the first group — LD with complete absence of the enzyme (alactasia, 4 persons), the second — LD with partial deficiency of the enzyme (hypolactasia, 10 individuals), the third — LD with lactosuria (4 patients), the fourth — transient LD (22 people). The clinical picture manifested by liquid (100 %), foamy (83.3 %), with acidic smell (83.3 %) feces. One-third of children with LD experienced regurgitation, 75.0 % — abdominal colic. All children had weight deficit and deficiency anemia. Conclusions. Transient (secondary) lactase deficiency is most common, it occurs in mild form in children of different age categories. Alactasia is typical for children under 1 year of age, it occurs with significant clinical signs against a background of deficiency of weight deficit and anemia. Hypolactasia occurs with mild clinical symptoms. LN with lactosuria is characteristic of premature infants.

В статье рассматриваются вопросы патогенеза синдрома раздраженного кишечника. Проведен короткий анализ вероятных факторов развития синдрома раздраженного кишечника. Отдельно рассмотрена роль кишечной микрофлоры и вклад короткоцепочечных жирных кислот в процессы, происходящие при синдроме раздраженного кишечника. Проанализованы исследования различных авторов относительно короткоцепочечных жирных кислот. Показаны результаты собственных исследований, в которых опеределялось содержание в кале короткоцепочечных жирных кислот у больных с синдромом раздраженного кишечника. Было выявлено существенное повышение содержания короткоцепочечных жирных кислот, особенно при диарейной форме синдрома раздраженного кишечника.

Background. Today, the development and implementation of non-invasive methods for the diagnosis of ulcerative colitis is certainly an actual task of the scientific community, the solution of which will allow us to prescribe the adequate treatment in time and to improve the quality of life of patients. Given that the differences between women and men in the parameters determining the state of health are generally recognized, the purpose of the work was to determine the gender characteristics of the level of biological markers of intestinal inflammation in patients with ulcerative colitis. Materials and methods. Sixty patients with ulcerative colitis were examined, among them there were 31 (51.7 %) men and 29 (48.3 %) women with mean age of (40.28 ± 1.34) years. The comparison group consisted of 20 patients with irritable bowel syndrome. By means of enzyme immunoassay using a StatFax 303 Plus analyzer (USA) with Immundiagnostik (Germany) test kit, we determined the level of fecal myeloperoxidase, the content of α1-antitrypsin in the blood serum and feces, and the level of fecal calprotectin using a Buhlmann test kit (Switzerland). Results. Fecal myeloperoxidase and calprotectin are specific markers of intestinal inflammation, which is confirmed by established correlations between the endoscopic activity of intestinal inflammation and its content: r = 0.632; p < 0.05, and r = 0.532; p < 0.05, respectively. The concentration of α1-antitrypsin in the feces of men is 3 times higher than that in women (p < 0.05), and, on the contrary, the level of α1-antitrypsin in the blood is higher in female patients compared to men (p < 0.05). The discovered correlation between the content of α1-antitrypsin in the feces and the male gender (r = 0.528; p

Background and Aims Increasing evidence supports the role of early-life gut microbiota in developing atopic diseases, but ecological changes to gut microbiota during infancy in relation to food sensitization remain unclear. We aimed to characterize and associate these changes with the development of food sensitization in children. Methods In this observational study, using 16S rRNA amplicon sequencing, we characterized the composition of 2844 fecal microbiota in 1422 Canadian full-term infants. Atopic sensitization outcomes were measured by skin prick tests at age 1 year and 3 years. The association between gut microbiota trajectories, based on longitudinal shifts in community clusters, and atopic sensitization outcomes at age 1 and 3 years were determined. Ethnicity and early-life exposures influencing microbiota trajectories were initially examined, and post-hoc analyses were conducted. Results Four identified developmental trajectories of gut microbiota were shaped by birth mode and varied by ethnicity. The trajectory with persistently low Bacteroides abundance and high Enterobacteriaceae/Bacteroidaceae ratio throughout infancy increased the risk of sensitization to food allergens, particularly to peanuts at age 3 years by 3-fold (adjusted odds ratio [OR] 2.82, 95% confidence interval [CI] 1.13–7.01). A much higher likelihood for peanut sensitization was found if infants with this trajectory were born to Asian mothers (adjusted OR 7.87, 95% CI 2.75–22.55). It was characterized by a deficiency in sphingolipid metabolism and persistent Clostridioides difficile colonization. Importantly, this trajectory of depleted Bacteroides abundance mediated the association between Asian ethnicity and food sensitization. Conclusions This study documented an association between persistently low gut Bacteroides abundance throughout infancy and sensitization to peanuts in childhood. It is the first to show a mediation role for infant gut microbiota in ethnicity-associated development of food sensitization.

Background and Aims Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress. Methods We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies. Results We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo. Conclusions Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation.

Background & aims This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). Methods This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor–naive patients with active ulcerative colitis (total Mayo score 6–12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220–450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. Results Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37–1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. Conclusions The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

Background & Aims Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown. Methods We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs). Results Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC–colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice. Conclusions We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.

BACKGROUND & AIMS: Establishment of the gastrointestinal microbiota during infancy affects immune system development and oral tolerance induction. Perturbations in the microbiome during this period can contribute to development of immune-mediated diseases. We monitored microbiota maturation and associations with subsequent development of allergies in infants and children. METHODS: We collected 1453 stool samples, at 5, 13, 21, and 31weeks postpartum (infants), and once at school age (6-11 years), from 440 children (49.3% girls, 24.8% born by cesarean delivery; all children except for 6 were breastfed for varying durations; median 40 weeks; interquartile range, 30-53 weeks). Microbiota were analyzed by amplicon sequencing. Children were followed through 3 years of age for development of atopic dermatitis; data on allergic sensitization and asthma were collected when children were school age. RESULTS: Diversity of fecal microbiota, assessed by Shannon index, did not differ significantly among children from 5 through 13 weeks after birth, but thereafter gradually increased to 21 and 31 weeks. Most bacteria within the Bacteroidetes and Proteobacteria phyla were already present at 5 weeks after birth, whereas many bacteria of the Firmicutes phylum were acquired at later times in infancy. At school age, many new Actinobacteria, Firmicutes, and Bacteroidetes bacterial taxa emerged. The largest increase in microbial diversity occurred after 31 weeks. Vaginal, compared with cesarean delivery, was most strongly associated with an enrichment of Bacteroides species at 5 weeks through 31 weeks. From 13 weeks onward, diet became the most important determinant of microbiota composition; cessation of breast-feeding, rather than solid food introduction, was associated with changes. For example, Bifidobacteria, staphylococci, and streptococci significantly decreased on cessation of breastfeeding, whereas bacteria within the Lachnospiraceae family (Pseudobutyrivibrio, Lachnobacterium, Roseburia, and Blautia) increased. When we adjusted for confounding factors, we found fecal microbiota composition to be associated with development of atopic dermatitis, allergic sensitization, and asthma. Members of the Lachnospiraceae family, as well as the genera Faecalibacterium and Dialister, were associated with a reduced risk of atopy. CONCLUSIONS: In a longitudinal study of fecal microbiota of children from 5 weeks through 6 to 11 years, we tracked changes in diversity and composition associated with the development of allergies and asthma.

Background & Aims Sulfur-metabolizing microbes, which convert dietary sources of sulfur into genotoxic hydrogen sulfide (H2S), have been associated with development of colorectal cancer (CRC). We identified a dietary pattern associated with sulfur-metabolizing bacteria in stool and then investigated its association with risk of incident CRC using data from a large prospective study of men. Methods We collected data from 51,529 men enrolled in the Health Professionals Follow-up Study since 1986 to determine the association between sulfur-metabolizing bacteria in stool and risk of CRC over 26 years of follow-up. First, in a subcohort of 307 healthy men, we profiled serial stool metagenomes and metatranscriptomes and assessed diet using semiquantitative food frequency questionnaires to identify food groups associated with 43 bacterial species involved in sulfur metabolism. We used these data to develop a sulfur microbial dietary score. We then used Cox proportional hazards modeling to evaluate adherence to this pattern among eligible individuals (n = 48,246) from 1986 through 2012 with risk for incident CRC. Results Foods associated with higher sulfur microbial diet scores included increased consumption of processed meats and low-calorie drinks and lower consumption of vegetables and legumes. Increased sulfur microbial diet scores were associated with risk of distal colon and rectal cancers, after adjusting for other risk factors (multivariable relative risk, highest vs lowest quartile, 1.43; 95% confidence interval 1.14–1.81; P-trend = .002). In contrast, sulfur microbial diet scores were not associated with risk of proximal colon cancer (multivariable relative risk 0.86; 95% CI 0.65–1.14; P-trend = .31). Conclusions In an analysis of participants in the Health Professionals Follow-up Study, we found that long-term adherence to a dietary pattern associated with sulfur-metabolizing bacteria in stool was associated with an increased risk of distal CRC. Further studies are needed to determine how sulfur-metabolizing bacteria might contribute to CRC pathogenesis.

The enteric mycobiota is a major component of the human gut microbiota, but its role in colorectal cancer (CRC) remains largely elusive. We conducted a meta-analysis to uncover the contribution of the fungal mycobiota to CRC.We retrieved fecal metagenomic data sets from 7 previous publications and established an additional in-house cohort, totaling 1329 metagenomes (454 with CRC, 350 with adenoma, and 525 healthy individuals). Mycobiota composition and microbial interactions were analyzed. Candidate CRC-enriched fungal species (Aspergillus rambellii) was functionally validated in vitro and in vivo.Multicohort analysis revealed that the enteric mycobiota was altered in CRC. We identified fungi that were associated with patients with CRC or adenoma from multiple cohorts. Signature CRC-associated fungi included 6 enriched (A rambellii, Cordyceps sp. RAO-2017, Erysiphe pulchra, Moniliophthora perniciosa, Sphaerulina musiva, and Phytophthora capsici) and 1 depleted species (A kawachii). Co-occurrent interactions among CRC-enriched fungi became stronger in CRC compared with adenoma and healthy individuals. Moreover, we reported the transkingdom interactions between enteric fungi and bacteria in CRC progression, of which A rambellii was closely associated with CRC-enriched bacteria Fusobacterium nucleatum. A rambellii promoted CRC cell growth in vitro and tumor growth in xenograft mice. We further identified that combined fungal and bacterial biomarkers were more accurate than panels with pure bacterial species to discriminate patients with CRC from healthy individuals (the area under the curve relative change increased by 1.44%-10.60%).This study reveals enteric mycobiota signatures and pathogenic fungi in stages of colorectal tumorigenesis. Fecal fungi can be used, in addition to bacteria, for noninvasive diagnosis of patients with CRC.

The COVID-19 pandemic has affected clinical services globally, including colorectal cancer (CRC) screening and diagnostic testing. We investigated the pandemic's impact on fecal immunochemical test (FIT) screening, colonoscopy utilization, and colorectal neoplasia detection across 21 medical centers in a large integrated health care organization.We performed a retrospective cohort study in Kaiser Permanente Northern California patients ages 18 to 89 years in 2019 and 2020 and measured changes in the numbers of mailed, completed, and positive FITs; colonoscopies; and cases of colorectal neoplasia detected by colonoscopy in 2020 vs 2019.FIT kit mailings ceased in mid-March through April 2020 but then rebounded and there was an 8.7% increase in kits mailed compared with 2019. With the later mailing of FIT kits, there were 9.0% fewer FITs completed and 10.1% fewer positive tests in 2020 vs 2019. Colonoscopy volumes declined 79.4% in April 2020 compared with April 2019 but recovered to near pre-pandemic volumes in September through December, resulting in a 26.9% decline in total colonoscopies performed in 2020. The number of patients diagnosed by colonoscopy with CRC and advanced adenoma declined by 8.7% and 26.9%, respectively, in 2020 vs 2019.The pandemic led to fewer FIT screenings and colonoscopies in 2020 vs 2019; however, after the lifting of shelter-in-place orders, FIT screenings exceeded, and colonoscopy volumes nearly reached numbers from those same months in 2019. Overall, there was an 8.7% reduction in CRC cases diagnosed by colonoscopy in 2020. These data may help inform the development of strategies for CRC screening and diagnostic testing during future national emergencies.

Key Points Question What 3-year clinical outcomes are associated with expanding fecal immunochemical test (FIT)–based colorectal cancer screening participation during the COVID-19 pandemic? Findings In this modeling study, increasing FIT use from 15% to 22% over a 3-year period to offset COVID-19–related declines in colonoscopy screening was associated with an additional 655 825 colorectal cancer screenings and 2715 colorectal cancer diagnoses, of which 72% were early stage. Meaning These findings suggest that increasing FIT use for colorectal cancer screening during the COVID-19 pandemic may mitigate the consequences of reduced screening rates caused by the pandemic for colorectal cancer outcomes., This modeling study estimates COVID-19–related changes in rates of colorectal cancer screenings and associated outcomes and estimates the degree to which expanded fecal immunochemical testing could potentially mitigate these outcomes., Importance COVID-19 has decreased colorectal cancer screenings. Objective To estimate the degree to which expanding fecal immunochemical test–based colorectal cancer screening participation during the COVID-19 pandemic is associated with clinical outcomes. Design, Setting, and Participants A previously developed simulation model was adopted to estimate how much COVID-19 may have contributed to colorectal cancer outcomes. The model included the US population estimated to have completed colorectal cancer screening pre–COVID-19 according the American Cancer Society. The model was designed to estimate colorectal cancer outcomes between 2020 and 2023. This analysis was completed between July and December 2020. Exposures Adults screened for colorectal cancer and colorectal cancer cases detected by stage. Main Outcomes and Measures Estimates of colorectal cancer outcomes across 4 scenarios: (1) 9 months of 50% colorectal cancer screenings followed by 21 months of 75% colorectal cancer screenings; (2) 18 months of 50% screening followed by 12 months of 75% screening; (3) scenario 1 with increased use of fecal immunochemical tests; and (4) scenario 2 with increased use of fecal immunochemical tests. Results In our simulation model, COVID-19–related reductions in care utilization resulted in an estimated 1 176 942 to 2 014 164 fewer colorectal cancer screenings, 8346 to 12 894 fewer colorectal cancer diagnoses, and 6113 to 9301 fewer early-stage colorectal cancer diagnoses between 2020 and 2023. With an abbreviated period of reduced colorectal cancer screenings, increasing fecal immunochemical test use was associated with an estimated additional 588 844 colorectal cancer screenings and 2836 colorectal cancer diagnoses, of which 1953 (68.9%) were early stage. In the event of a prolonged period of reduced colorectal cancer screenings, increasing fecal immunochemical test use was associated with an estimated additional 655 825 colorectal cancer screenings and 2715 colorectal cancer diagnoses, of which 1944 (71.6%) were early stage. Conclusions and Relevance These results suggest that the increased use of fecal immunochemical tests during the COVID-19 pandemic was associated with increased colorectal cancer screening participation and more colorectal cancer diagnoses at earlier stages. If our estimates are borne out in real-world clinical practice, increasing fecal immunochemical test–based colorectal cancer screening participation during the COVID-19 pandemic could mitigate the consequences of reduced screening rates during the pandemic for colorectal cancer outcomes.

Studies have reported abnormal gut microbiota or circulating metabolome associated with colorectal cancer (CRC), but it remains a challenge to capture the CRC-relevant features consistent across geographic regions. This is particularly the problem for metabolic traits of CRC because the analyses generally use different platforms and laboratory methods, which poses a barrier to cross-dataset examination. In light of this, we sought to elucidate the microbial and metabolic signatures of CRC with broad population relevance.In this integrated metagenomic (healthy controls [HC], n = 91; colorectal adenoma [CRA], n = 63; CRC, n = 71) and metabolomic (HC, n = 34; CRA, n = 31; CRC, n = 35) analysis, CRC-associated features and microbe-metabolite correlations were first identified from a Shanghai cohort. A gut microbial panel was trained in the in-house cohort and cross-validated in 7 published metagenomic datasets of CRC. The in-house metabolic connections to the cross-cohort microbial signatures were used as evidence to infer serum metabolites with potentially external relevance. In addition, a combined microbe-metabolite panel was produced for diagnosing CRC or adenoma.CRC-associated alterations were identified in the gut microbiome and serum metabolome. A composite microbe-metabolite diagnostic panel was developed and yielded an area under the curve of 0.912 for adenoma and 0.994 for CRC. We showed that many CRC-associated metabolites were linked to cross-cohort gut microbiome signatures of the disease, including CRC-enriched leucylalanine, serotonin, and imidazole propionate; and CRC-depleted perfluorooctane sulfonate, 2-linoleoylglycerol (18:2), and sphingadienine.We generated cross-cohort metagenomic signatures of CRC, some of which linked to in-house CRC-associated serum metabolites. The microbial and metabolic shifts may have wide population relevance.

There has been an increase in the burden of Clostridioides difficile infection (CDI),1 especially in high-risk populations such as patients with inflammatory bowel disease (IBD).2 The prevalence of CDI in the IBD population is up to 8-fold higher than comparable controls, with increased rates of recurrence and CDI-associated mortality.3 In addition, CDI may induce an IBD flare, and worsen disease severity and clinical course.4 Fecal microbiota transplantation (FMT) is a guideline recommended therapy for recurrent CDI5; however, supportive randomized trials excluded patients with IBD. In retrospective trials of patients with IBD, FMT failure rates had been reported to be approximately 25% to 30%.6 In addition, Khoruts and colleagues reported that patients with IBD and CDI were more likely to fail FMT,7 leading to further uncertainty regarding the safety and efficacy of FMT in IBD patients with concurrent CDI. Accordingly, we conducted the first prospective study examining the efficacy of FMT among patients with IBD and CDI. Methods We conducted an open-label, prospective, single-arm, multicenter cohort study at 4 tertiary care FMT referral centers (Brigham and Women’s Hospital, Indiana University, Brown University, and Mount Sinai Hospital; NCT03106844). Patients with a confirmed diagnosis of IBD and 2 or more confirmed CDI episodes within 12 months, including the most recent episode occurring within 3 months, were enrolled. In keeping with CDI clinical guidelines,5 polymerase chain reaction or glutamate dehydrogenase with toxin enzyme immunoassay were permitted for the qualifying CDI episode. Patients with a total or subtotal colectomy, isolated ileal or small bowel Crohn’s disease, those pregnant or breastfeeding, those treated with vancomycin or metronidazole for more than 60 days, or those who had undergone a prior FMT within 12 months were excluded. Baseline IBD and CDI data were collected. All patients underwent a single FMT via colonoscopy. Four robustly screened healthy donors were used (OpenBiome, Cambridge, MA).8 Stool testing, including glutamate dehydrogenase, toxin enzyme immunoassay ,and polymerase chain reaction, was performed 1, 8, and 12 weeks post-FMT regardless of symptoms to assess for CDI and C. difficile colonization rates. All stool testing was performed at a central laboratory. The primary outcome was FMT failure through week 8, defined as diarrhea (3 or more loose stools daily for 3 or more days) and stool testing positive for C. difficile via 2-step testing using glutamate dehydrogenase and toxin enzyme immunoassay. Patients who met the criteria for failure underwent a second FMT. Secondary outcomes included C. difficile colonization defined as patients without diarrhea whose stool remained positive via polymerase chain reaction post-FMT. Results Fifty participants were enrolled (August 2017 to October 2019) among whom 15 had Crohn’s disease and 35 had ulcerative colitis (Table 1). The mean age of participants was 43 years (range 21–91) and the cohort was primarily female (58%). A total of 49 patients received treatment. One patient withdrew before treatment and was not replaced. Among the 49 participants, 1 patient was lost to follow-up after the week 1 visit and was treated as an FMT failure. Baseline CDI characteristics: 48% had 2 CDI episodes before entry, among whom 87.5% (21/24) were diagnosed via polymerase chain reaction at the qualifying episode; 38% had 3 confirmed episodes, among whom 78.9% (15/19) were diagnosed via polymerase chain reaction; and 14% had 4 prior CDI episodes among whom 71% were diagnosed via polymerase chain reaction (5/7).

Most patients with gastric cancer (GCa) are diagnosed at an advanced stage. We aimed to investigate novel fecal signatures for clinical application in early diagnosis of GCa.This was an observational study that included 1043 patients from 10 hospitals in China. In the discovery cohort, 16S ribosomal RNA gene analysis was performed in paired samples (tissues and feces) from patients with GCa and chronic gastritis (ChG) to determine differential abundant microbes. Their relative abundances were detected using quantitative real-time polymerase chain reaction to test them as bacterial candidates in the training cohort. Their diagnostic efficacy was validated in the validation cohort.Significant enrichments of Streptococcus anginosus (Sa) and Streptococcus constellatus (Sc) in GCa tumor tissues (P.05) and feces (P.0001) were observed in patients with intraepithelial neoplasia, early and advanced GCa. Either the signature parallel test Sa∪Sc or single signature Sa/Sc demonstrated superior sensitivity (Sa: 75.6% vs 72.1%, P.05; Sc: 84.4% vs 64.0%, P.001; and Sa∪Sc: 91.1% vs 81.4%, P.01) in detecting early GCa compared with advanced GCa (specificity: Sa: 84.0% vs 83.9%, Sc: 70.4% vs 82.3%, and Sa∪Sc: 64.0% vs 73.4%). Fecal signature Sa∪Sc outperformed Sa∪CEA/Sc∪CEA in the discrimination of advanced GCa (sensitivity: 81.4% vs 74.2% and 81.4% vs 72.3%, P.01; specificity: 73.4% vs 81.0 % and 73.4% vs 81.0%). The performance of Sa∪Sc in the diagnosis of both early and advanced GCa was verified in the validation cohort.Fecal Sa and Sc are noninvasive, accurate, and sensitive signatures for early warning in GCa. (ClinicalTrials.gov, Number: NCT04638959).

Epidemiologic and murine studies suggest that dietary emulsifiers promote development of diseases associated with microbiota dysbiosis. Although the detrimental impact of these compounds on the intestinal microbiota and intestinal health have been demonstrated in animal and in vitro models, impact of these food additives in healthy humans remains poorly characterized.To examine this notion in humans, we performed a double-blind controlled-feeding study of the ubiquitous synthetic emulsifier carboxymethylcellulose (CMC) in which healthy adults consumed only emulsifier-free diets (n = 9) or an identical diet enriched with 15 g per day of CMC (n = 7) for 11 days.Relative to control subjects, CMC consumption modestly increased postprandial abdominal discomfort and perturbed gut microbiota composition in a way that reduced its diversity. Moreover, CMC-fed subjects exhibited changes in the fecal metabolome, particularly reductions in short-chain fatty acids and free amino acids. Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition.These results support the notion that the broad use of CMC in processed foods may be contributing to increased prevalence of an array of chronic inflammatory diseases by altering the gut microbiome and metabolome (ClinicalTrials.gov, number NCT03440229).

The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update Commentary is to review the available evidence and provide expert advice regarding the approach to using noninvasive colorectal cancer (CRC) screening options, including evidence for their effectiveness, selection of individuals for whom these tests are appropriate, implications of a positive non-colonoscopy screening test, and opportunities to enhance the quality of noninvasive CRC screening programs. This Clinical Practice Update was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. This expert commentary reflects recently published studies in this field, as well as the experiences of the authors who are gastroenterologists with high-level expertise in CRC screening and prevention.

Background & Aims SARS-CoV-2 infection is associated with altered gut microbiota composition. Phylogenetic groups of gut bacteria involved in the metabolism of short chain fatty acids were depleted in SARS-CoV-2-infected patients. We aimed to characterize functional profile of gut microbiome in patients with COVID-19 before and after disease resolution. Methods We performed shotgun metagenomic sequencing on fecal samples from 66 antibiotics-naïve patients with COVID-19 and 70 non-COVID-19 controls. Serial fecal samples were collected (up to 6 times points) during hospitalization and beyond one month after discharge. We assessed gut microbial pathways in association with disease severity and blood inflammatory markers. We also determined changes of microbial functions in fecal samples before and after disease resolution and validated these functions using targeted analysis of fecal metabolites. Results Compared with non-COVID-19 controls, COVID-19 patients with severe/critical illness showed significant alterations in gut microbiome functionality (P < .001), characterized by impaired capacity of gut microbiome for short chain fatty acid (SCFA) and L-isoleucine biosynthesis and enhanced capacity for urea production. Impaired SCFA and L-isoleucine biosynthesis in gut microbiome persisted beyond 30 days after recovery in COVID-19 patients. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs and L-isoleucine in COVID-19 patients before and after disease resolution. Lack of SCFA and L-isoleucine biosynthesis significantly correlated with disease severity and increased plasma concentrations of CXCL-10, NT-proBNP, C-reactive protein (CRP) (all P < .05). Conclusions Gut microbiome of COVID-19 patients displayed impaired capacity for SCFA and L-isoleucine biosynthesis which persisted even after disease resolution. These two microbial functions correlated with host immune response underscoring the importance of gut microbial functions in SARS-CoV-2 infection pathogenesis and outcome., Graphical abstract

Background & Aims This study compared the effectiveness of the Specific Carbohydrate Diet (SCD) to the Mediterranean diet (MD) as treatment for Crohn's disease (CD) with mild to moderate symptoms. Methods Adult patients with CD and with mild-to-moderate symptoms were randomly assigned 1:1 to consume the MD or SCD for 12 weeks. For the first 6 weeks, participants received prepared meals and snacks according to their assigned diet. After 6 weeks, participants were instructed to follow the diet independently. The primary outcome was symptomatic remission at week 6. Key secondary outcomes at week 6 included fecal calprotectin (FC) response (FC 50% among those with baseline FC >250 μg/g) and C-reactive protein (CRP) response (high-sensitivity CRP 50% reduction from baseline among those with high-sensitivity CRP >5 mg/L). Results The study randomized 194 patients, and 191 were included in the efficacy analyses. The percentage of participants who achieved symptomatic remission at week 6 was not superior with the SCD (SCD, 46.5%; MD, 43.5%; P = .77). FC response was achieved in 8 of 23 participants (34.8%) with the SCD and in 4 of 13 participants (30.8%) with the MD (P = .83). CRP response was achieved in 2 of 37 participants (5.4%) with the SCD and in 1 of 28 participants (3.6%) with the MD (P = .68). Conclusions The SCD was not superior to the MD to achieve symptomatic remission, FC response, and CRP response. CRP response was uncommon. Given these results, the greater ease of following the MD and other health benefits associated with the MD, the MD may be preferred to the SCD for most patients with CD with mild to moderate symptoms. ClinicalTrials.gov Identifier: NCT03058679

Background & Aims To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD). Methods Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. Results Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation–free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD. Conclusions The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC. publishedVersion