ABSTRACT
Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic stem cell transplantation (SCT), and severe intestinal manifestation is the major cause of early mortality. Intestinal microbiota control MHC class II (MHC-II) expression by ileal intestinal epithelial cells (IECs) that promote GVHD. Here, we demonstrated that genetically identical mice of differing vendor origins had markedly different intestinal microbiota and ileal MHC-II expression, resulting in discordant GVHD severity. We utilized cohousing and antibiotic treatment to characterize the bacterial taxa positively and negatively associated with MHC-II expression. A large proportion of bacterial MHC-II inducers were vancomycin sensitive, and peri-transplant oral vancomycin administration attenuated CD4+ T cell-mediated GVHD. We identified a similar relationship between pre-transplant microbes, HLA class II expression, and both GVHD and mortality in a large clinical SCT cohort. These data highlight therapeutically tractable mechanisms by which pre-transplant microbial taxa contribute to GVHD independently of genetic disparity.
Subject(s)
Gastrointestinal Microbiome , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Mice , Animals , Vancomycin , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Transplantation, Homologous/adverse effectsABSTRACT
To understand how different diets, the consumers' gut microbiota, and the enteric nervous system (ENS) interact to regulate gut motility, we developed a gnotobiotic mouse model that mimics short-term dietary changes that happen when humans are traveling to places with different culinary traditions. Studying animals transplanted with the microbiota from humans representing diverse culinary traditions and fed a sequence of diets representing those of all donors, we found that correlations between bacterial species abundances and transit times are diet dependent. However, the levels of unconjugated bile acids-generated by bacterial bile salt hydrolases (BSH)-correlated with faster transit, including during consumption of a Bangladeshi diet. Mice harboring a consortium of sequenced cultured bacterial strains from the Bangladeshi donor's microbiota and fed a Bangladeshi diet revealed that the commonly used cholekinetic spice, turmeric, affects gut motility through a mechanism that reflects bacterial BSH activity and Ret signaling in the ENS. These results demonstrate how a single food ingredient interacts with a functional microbiota trait to regulate host physiology.
Subject(s)
Diet , Gastrointestinal Motility , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/physiology , Models, Animal , Travel , Animals , Bangladesh , Bile Acids and Salts/metabolism , Curcuma/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Microbiota , Specific Pathogen-Free OrganismsABSTRACT
Colorectal cancer (CRC) is among the most common cancers globally and a major cause of cancer-related deaths. The American Cancer Society estimates that CRC will kill 1 in 60 Americans, and CRC screening is recommended for all Americans ≥45 years of age. Current CRC screening methods are effective for preventing CRC and have been shown to reduce CRC-related mortality. However, none of the currently available tests is ideal, and many people are not compliant with screening recommendations. Novel screening tests based on advances in CRC molecular biology, genetics, and epigenetics, combined with developments in sequencing technologies and computational analytic methods, have been developed to address the shortcomings of current CRC screening tests. These emerging tests include blood-based assays that use plasma-derived circulating tumor DNA and serum proteins to detect early CRC and advanced adenomas, assays that use stool DNA or mRNA, and methods for profiling the gut microbiome. Here we review current screening modalities, and we discuss the principles behind the most promising emerging CRC screening tests and the data supporting their potential to be used in clinical practice.
Subject(s)
Circulating Tumor DNA , Colorectal Neoplasms , Humans , Colonoscopy , Early Detection of Cancer/methods , Colorectal Neoplasms/diagnosis , Mass Screening/methodsABSTRACT
The American Gastroenterological Association's Center for Gastrointestinal Innovation and Technology convened a consensus conference in December 2018, entitled, "Colorectal Cancer Screening and Surveillance: Role of Emerging Technology and Innovation to Improve Outcomes." The goal of the conference, which attracted more than 60 experts in screening and related disciplines, including the authors, was to envision a future in which colorectal cancer (CRC) screening and surveillance are optimized, and to identify barriers to achieving that future. This White Paper originates from that meeting and delineates the priorities and steps needed to improve CRC outcomes, with the goal of minimizing CRC morbidity and mortality. A one-size-fits-all approach to CRC screening has not and is unlikely to result in increased screening uptake or desired outcomes owing to barriers stemming from behavioral, cultural, and socioeconomic causes, especially when combined with inefficiencies in deployment of screening technologies. Overcoming these barriers will require the following: efficient utilization of multiple screening modalities to achieve increased uptake; continued development of noninvasive screening tests, with iterative reassessments of how best to integrate new technologies; and improved personal risk assessment to better risk-stratify patients for appropriate screening testing paradigms.
Subject(s)
Colorectal Neoplasms , Early Detection of Cancer , Colonoscopy , Colorectal Neoplasms/diagnosis , Humans , Mass Screening , Risk Assessment , United StatesSubject(s)
Colorectal Neoplasms/diagnosis , Consensus Development Conferences as Topic , Early Detection of Cancer/methods , Gastroenterology/methods , Mass Screening/methods , Biomedical Technology , Canada , Colonoscopy/instrumentation , Colonoscopy/methods , Colorectal Neoplasms/epidemiology , Diffusion of Innovation , Early Detection of Cancer/instrumentation , Epidemiological Monitoring , Humans , Inventions , Mass Screening/instrumentation , Societies, Medical , United StatesABSTRACT
The multitude of barriers between the mouth and colon may eliminate swallowed oral bacteria. Ascertaining the presence of the same bacteria in the mouth and colon is methodologically challenging partly because 16S rRNA gene sequencing - the most commonly used method to characterize the human microbiota - has low confidence in taxonomic assignments deeper than genus for most bacteria. As different species of the same genus can have low-level variation across the same 16S rRNA gene region, shotgun sequencing is needed to identify a true overlap. We analyzed a curated, multi-cohort, shotgun metagenomic database with species-level taxonomy and clade-specific marker genes to fill this knowledge gap. Using 500 paired fecal/oral (4 oral sites) samples from 4 healthy adult cohorts, we found a minute overlap between the two niches. Comparing marker genes between paired oral and fecal samples with species-level overlap, the pattern of overlap in only 7 individuals was consistent with same-strain colonization. These findings argue against ectopic colonization of oral bacteria in the distal gut in healthy adults.
Subject(s)
Gastrointestinal Microbiome , Microbiota , Adult , Humans , Gastrointestinal Microbiome/genetics , Metagenome , Microbiota/genetics , Mouth/microbiology , RNA, Ribosomal, 16S/geneticsABSTRACT
Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.
Subject(s)
Precancerous Conditions , Humans , Precancerous Conditions/genetics , Precancerous Conditions/pathology , Risk FactorsABSTRACT
BACKGROUND: The gut microbiome is altered in Crohn's disease. Although individual taxa have been correlated with post-operative clinical course, global trends in microbial diversity have not been described in this context. METHODS: We collected mucosal biopsies from the terminal ileum and ascending colon during surgery and post-operative colonoscopy in 6 Crohn's patients undergoing ileocolic resection (and 40 additional Crohn's and healthy control patients undergoing either surgery or colonoscopy). Using next-generation sequencing technology, we profiled the gut microbiota in order to identify changes associated with remission or recurrence of inflammation. RESULTS: We performed 16S ribosomal profiling using 101 base-pair single-end sequencing on the Illumina GAIIx platform with deep coverage, at an average depth of 1.3 million high quality reads per sample. At the time of surgery, Crohn's patients who would remain in remission were more similar to controls and more species-rich than Crohn's patients with subsequent recurrence. Patients remaining in remission also exhibited greater stability of the microbiota through time. CONCLUSIONS: These observations permitted an association of gut microbial profiles with probability of recurrence in this limited single-center study. These results suggest that profiling the gut microbiota may be useful in guiding treatment of Crohn's patients undergoing surgery.
Subject(s)
Colon/microbiology , Crohn Disease/microbiology , Ileum/microbiology , Microbiota , RNA, Bacterial/analysis , RNA, Ribosomal, 16S/analysis , Adult , Case-Control Studies , Crohn Disease/drug therapy , Crohn Disease/surgery , Female , Humans , Ileum/surgery , Male , Middle Aged , Recurrence , Remission Induction , Treatment OutcomeABSTRACT
BACKGROUND: The oral and colonic microbiota are distinct in healthy individuals. However, this distinction is diminished in common diseases such as colon cancer and inflammatory bowel disease, suggesting a potential pathogenic role for oral bacteria when ectopically colonized in the gut. A key mechanism for the segregation of oral and colonic microbiota niches is thought to be microbiota-mediated colonization resistance whereby the commensal gut microbiota outcompete and eliminate the ingested oral bacteria. METHODS: We tested this theory by analyzing exact amplicon sequence variants generated from concurrent fecal and oral samples from healthy volunteers exposed to a brief course of a single antibiotic (cohort 1), acute leukemia patients (cohort 2), and stem cell transplant recipients (cohort 3). Cohorts 2 and 3 represent extreme clinical scenarios with respect to antibiotic pressure and severity of gut microbiota injury. RESULTS: While mild antibiotic exposure in cohort 1 was not sufficient for colonization of any oral bacteria in the gut, even with extreme antibiotic pressure and severe gut microbiota disruptions in cohorts 2 and 3, only one oral species in each cohort colonized the gut. CONCLUSIONS: Colonization resistance is dispensable for segregation of oral and colonic microbiota in humans. This finding implies that the presence of oral bacteria in the distal gut in diseases such as colon cancer and inflammatory bowel disease is not driven by impaired colonization resistance.
Subject(s)
Colonic Neoplasms , Gastrointestinal Microbiome , Inflammatory Bowel Diseases , Humans , Anti-Bacterial Agents/therapeutic use , Feces/microbiology , BacteriaABSTRACT
BACKGROUND: Despite pharmacological treatment, individuals with inflammatory bowel disease (IBD) experience a variety of symptoms, including abdominal pain, fatigue, anxiety, and depression. Few nonmedical self-management interventions are available for people with IBD. A validated comprehensive self-management (CSM) intervention is effective for patients with irritable bowel syndrome who can have symptoms similar to those of individuals with IBD. We created a modified CSM intervention tailored to individuals with IBD (CSM-IBD). The CSM-IBD is an 8-session program delivered over 8-12 weeks with check-ins with a registered nurse. OBJECTIVE: The primary objective of this pilot study is to determine the feasibility and acceptability of study procedures and the CSM-IBD intervention and to evaluate preliminary efficacy on quality of life and daily symptoms for a future randomized controlled trial. Additionally, we will examine the association of socioecological, clinical, and biological factors with symptoms at baseline and response to intervention. METHODS: We are conducting a pilot randomized controlled trial of the CSM-IBD intervention. Participants aged 18-75 years who are experiencing at least 2 symptoms are eligible for inclusion. We plan to enroll 54 participants who will be randomized (2:1) into the CSM-IBD program or usual care. Patients in the CSM-IBD program will have 8 intervention sessions. Primary study outcomes include the feasibility of recruitment, randomization, and data or sample collection, as well as the acceptability of study procedures and interventions. Preliminary efficacy outcome variables include quality of life and symptoms. Outcomes data will be assessed at baseline, immediately post intervention, and 3 months post intervention. Participants in the usual care group will have access to the intervention after study participation. RESULTS: This project is funded by the National Institutes of Nursing Research and reviewed by the University of Washington's institutional review board. Recruitment began in February 2023. As of April 2023, we have enrolled 4 participants. We expect the study to be completed by March 2025. CONCLUSIONS: This pilot study will evaluate the feasibility and efficacy of a self-management intervention (a web-based program with weekly check-ins with a registered nurse) that aims to improve symptom management in individuals with IBD. In the long term, we aim to validate a self-management intervention to improve patient quality of life, reduce direct and indirect costs related to IBD, and be culturally appropriate and accessible, particularly in rural and underserved communities. TRIAL REGISTRATION: ClinicalTrials.gov NCT05651542; https://clinicaltrials.gov/ct2/show/NCT05651542. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/46307.
ABSTRACT
Here, we describe the isolation and genomic annotation of two novel siphovirus species of bacteriophages that infect Bacteroides uniformis: Bacteroides phage EMB1 and Bacteroides phage EMB2. EMB1 has a 34,204-bp genome with 48 coding sequences, and EMB2 has a 34,008-bp genome with 47 coding sequences.
ABSTRACT
BACKGROUND: The design of a randomized pilot trial evaluating the feasibility of two doses of a digital health intervention promoting changes in nutrition and physical activity in breast cancer (BC) survivors is described. METHODS: Eligible women were adults with history of early-stage breast cancer and > 60 days post-treatment, consumed <5 servings/day of fruits/vegetables and/or engaged in <150 min/week of aerobic moderate-to-vigorous physical activity, and had internet access. Participants were randomized to 6 months of either a "low" (1 session) or "high" (12 sessions) dose digital health intervention. Zoom-delivered sessions focused on improving diet and physical activity through didactic and experiential classes delivered by a registered dietitian, chef, exercise physiologist, and culinary educator. All study participants received weekly motivational texts, a Fitbit, and study website access. Diet, accelerometry, anthropometric, psychosocial, and biospecimen data were collected remotely at baseline and six months. Primary outcome was feasibility measured via accrual rate, adherence, retention, and acceptability. RESULTS: Recruitment began in December 2019, was suspended in March 2020 due to the COVID-19 pandemic, resumed September 2020, and concluded in January 2021. Women were identified from the local BC registry and flyers posted in the oncology clinic. Of 929 women recruited, 321 completed the screening assessment, and of these, 138 were eligible. A total of 74 women were enrolled and randomized to the study. CONCLUSION: BC survivors were successfully enrolled in a digital health nutrition and physical activity intervention. If feasible, this intervention will be tested in larger and more diverse populations of cancer survivors. TRIAL REGISTRATION: ClinicalTrials.govNCT04200482.
Subject(s)
Breast Neoplasms , COVID-19 , Cancer Survivors , Adult , Female , Humans , Cancer Survivors/psychology , Breast Neoplasms/therapy , Breast Neoplasms/psychology , Feasibility Studies , Pandemics , Survivors , Exercise , Pilot ProjectsABSTRACT
Gastrointestinal motility is regulated by a variety of environmental factors including gut microbes and metabolites. The ability to interrogate mouse models of gut motility has enabled elucidation of these relationships. Here we describe integration of the red carmine dye and fluorescence isothiocyanate-dextran marker-based assays for characterizing gut transit with spatial resolution, along with an optional intracolonic infusion protocol for studying the effects of metabolites on colonic transit. These protocols can be adapted for use in gnotobiotic and conventional mouse models. For complete details on the use and execution of this protocol, please refer to Li et al. (2021).
Subject(s)
Disease Models, Animal , Gastrointestinal Transit/physiology , Animals , Biomarkers/metabolism , Feces/chemistry , Female , Gastrointestinal Tract/chemistry , Gastrointestinal Tract/metabolism , Germ-Free Life , Male , MiceABSTRACT
Gut motility is regulated by the microbiome via mechanisms that include bile acid metabolism. To localize the effects of microbiome-generated bile acids, we colonized gnotobiotic mice with different synthetic gut bacterial communities that were metabolically phenotyped using a functional in vitro screen. Using two different marker-based assays of gut transit, we inferred that bile acids exert effects on colonic transit. We validated this using an intra-colonic bile acid infusion assay and determined that these effects were dependent upon signaling via the bile acid receptor, TGR5. The intra-colonic bile acid infusion experiments further revealed sex-biased bile acid-specific effects on colonic transit, with lithocholic acid having the largest pro-motility effect. Transcriptional responses of the enteric nervous system (ENS) were stereotypic, regional, and observed in response to different microbiota, their associated bile acid profiles, and even to a single diet ingredient, evidencing exquisite sensitivity of the ENS to environmental perturbations.
ABSTRACT
COVID-19 (coronavirus disease 2019) patients exhibiting gastrointestinal symptoms are reported to have worse prognosis. Ace2 (angiotensin-converting enzyme 2), the gene encoding the host protein to which SARS-CoV-2 spike proteins bind, is expressed in the gut and therefore may be a target for preventing or reducing severity of COVID-19. Here we test the hypothesis that Ace2 expression in the gastrointestinal and respiratory tracts is modulated by the microbiome. We used quantitative PCR to profile Ace2 expression in germ-free mice, conventional raised specific pathogen-free mice, and gnotobiotic mice colonized with different microbiota. Intestinal Ace2 expression levels were significantly higher in germ-free mice compared to conventional mice. A similar trend was observed in the respiratory tract. Intriguingly, microbiota depletion via antibiotics partially recapitulated the germ-free phenotype, suggesting potential for microbiome-mediated regulation of Ace2 expression. Variability in intestinal Ace2 expression was observed in gnotobiotic mice colonized with different microbiota, partially attributable to differences in microbiome-encoded proteases and peptidases. Together, these data suggest that the microbiome may be one modifiable factor determining COVID-19 infection risk and disease severity.
Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Colon/enzymology , Gastrointestinal Microbiome , Intestine, Small/enzymology , Lung/enzymology , Adenomatous Polyposis Coli Protein/deficiency , Adenomatous Polyposis Coli Protein/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , Female , Gene Expression , Interleukin-10/deficiency , Interleukin-10/genetics , Male , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Growing evidence indicates a role for the gut microbiota in modulating anti-tumor treatment efficacy in human cancer. Here we study mucosa-associated invariant T (MAIT) cells to look for evidence of bacterial antigen recognition in human colon, lung, and kidney carcinomas. Using mass cytometry and single-cell mRNA sequencing, we identify a tumor-infiltrating MAIT cell subset expressing CD4 and Foxp3 and observe high expression of CD39 on MAIT cells from colorectal cancer (CRC) only, which we show in vitro to be expressed specifically after TCR stimulation. We further reveal that these cells are phenotypically and functionally exhausted. Sequencing data show high bacterial infiltration in CRC tumors and highlight an enriched species, Fusobacteria nucleatum, with capability to activate MAIT cells in a TCR-dependent way. Our results provide evidence of a MAIT cell response to microbial antigens in CRC and could pave the way for manipulating MAIT cells or the microbiome for cancer therapy.
Subject(s)
Antigens, Bacterial/immunology , Colorectal Neoplasms/immunology , Gastrointestinal Microbiome/immunology , Mucosal-Associated Invariant T Cells/immunology , Antigens, CD/immunology , Apyrase/immunology , CD4 Antigens/immunology , Cell Line, Tumor , Forkhead Transcription Factors/immunology , Humans , Lymphocyte Activation/immunology , Receptors, Antigen, T-Cell/immunologyABSTRACT
INTRODUCTION: Gastrointestinal (GI) dysfunction precedes the motor symptoms of Parkinson's disease (PD) by several years. PD patients have abnormal aggregation of intestinal α-synuclein, the accumulation of which may be promoted by inflammation. The relationship between intestinal α-synuclein aggregates and central nervous system neuropathology is unknown. Recently, we observed a possible inverse association between inflammatory bowel disease (IBD) and PD as part of a predictive model of PD. Therefore, the objective of this study was to examine the relationship between PD risk and IBD and IBD-associated conditions and treatment. METHODS: Using a case-control design, we identified 89,790 newly diagnosed PD cases and 118,095 population-based controls >65 years of age using comprehensive Medicare data from 2004-2009 including detailed claims data. We classified IBD using International Classification of Diseases version 9 (ICD-9) diagnosis codes. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between PD and IBD. Covariates included age, sex, race/ethnicity, smoking, Elixhauser comorbidities, and health care use. RESULTS: PD was inversely associated with IBD overall (ORâ¯=â¯0.85, 95% CI 0.80-0.91) and with both Crohn's disease (ORâ¯=â¯0.83, 95% CI 0.74-0.93) and ulcerative colitis (ORâ¯=â¯0.88, 95% CI 0.82-0.96). Among beneficiaries with ≥2 ICD-9 codes for IBD, there was an inverse dose-response association between number of IBD ICD-9 codes, as a potential proxy for IBD severity, and PD (p-for-trendâ¯=â¯0.006). CONCLUSION: IBD is associated with a lower risk of developing PD.