Curtis Huttenhower

Curtis Huttenhower
Harvard University | Harvard · Department of Biostatistics

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731
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Publications

Publications (731)
Preprint
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Non-human-associated microbial communities play important biological roles, but they remain less understood than human-associated communities. Here, we assess the impact of key environmental sample properties on a variety of state-of-the-art metagenomic analysis methods. In simulated datasets, all methods performed similarly at high taxonomic ranks...
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The gut microbiome of companion animals is relatively underexplored, despite its relevance to animal health, pet owner health, and basic microbial community biology. Here, we provide the most comprehensive analysis of the canine and feline gut microbiomes to date, incorporating 2639 stool shotgun metagenomes (2272 dog and 367 cat) spanning 14 publi...
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Importance Understanding how attachment to pets can alleviate depression and anxiety offers valuable insights for developing preventive and therapeutic strategies, particularly for those with insecure attachment styles from childhood trauma. Objective To determine if a close bond with a pet is associated with reduced depression and anxiety, especi...
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Characterizing the dynamics of microbial community succession in the infant gut microbiome is crucial for understanding child health and development, but no normative model currently exists. Here, we estimate child age using gut microbial taxonomic relative abundances from metagenomes, with high temporal resolution (±3 months) for the first 1.5 yea...
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The association of gut microbial features with type 2 diabetes (T2D) has been inconsistent due in part to the complexity of this disease and variation in study design. Even in cases in which individual microbial species have been associated with T2D, mechanisms have been unable to be attributed to these associations based on specific microbial stra...
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A major task of microbiome epidemiology is association analysis, where the goal is to identify microbial features related to host health. This is commonly performed by differential abundance (DA) analysis, which, by design, examines each microbe as isolated from the rest of the microbiome. This does not properly account for the microbiome's composi...
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INTRODUCTION We conducted a study within the Hispanic Community Health Study/Study of Latinos- Investigation of Neurocognitive Aging (HCHS/SOL-INCA) cohort to examine the association between gut microbiome and cognitive function. METHODS We analyzed the fecal metagenomes of 2,471 HCHS/SOL-INCA participants to, cross-sectionally, identify microbial...
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Objective To test hypotheses that appendectomy history might lower long-term colorectal cancer risk and that the risk reduction might be strong for tumors enriched with Fusobacterium nucleatum , bacterial species implicated in colorectal carcinogenesis. Background The absence of the appendix, an immune system organ and a possible reservoir of cert...
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Axial Spondyloarthritis (axSpA) is characterized by type-17 immune-driven joint inflammation, and intestinal inflammation is present in around 70% of patients. In this study, we asked whether axSpA stool contained Th17-associated cytokines and whether this related to systemic Th17 activation. We measured stool cytokine and calprotectin levels by EL...
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The success of deep learning in various applications depends on task-specific architecture design choices, including the types, hyperparameters, and number of layers. In computational biology, there is no consensus on the optimal architecture design, and decisions are often made using insights from more well-established fields such as computer visi...
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The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large prospective cohort, we performed shotgun metagenomic sequencing and untargeted metabolomics profiling among 121 women diagnosed with diverticulitis requiring antibiotics or hospitalizations...
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The myriad microorganisms that live in close association with humans have diverse effects on physiology, yet the molecular bases for these impacts remain mostly unknown1–3. Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the ‘exoproteome’). Commensal mi...
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Microbial biochemistry is central to the pathophysiology of inflammatory bowel diseases (IBD). Improved knowledge of microbial metabolites and their immunomodulatory roles is thus necessary for diagnosis and management. Here, we systematically analyzed the chemical, ecological, and epidemiological properties of ~82k metabolic features in 546 Integr...
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Viruses are an abundant and crucial component of the human microbiome, but accurately discovering them via metagenomics is still challenging. Currently, the available viral reference genomes poorly represent the diversity in microbiome samples, and expanding such a set of viral references is difficult. As a result, many viruses are still undetectab...
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Background We examined associations between dog ownership, morning dog walking and its timing and duration, and depression risk in female nurses, exploring effect modification by chronotype. We hypothesized that dog ownership and morning walking with the dog are associated with lower odds of depression, and that the latter is particularly beneficia...
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Background Bowel movement frequency and the gut microbiome may be associated with the risk of dementia. Method We examined the association between bowel movement frequency and cognitive function in 112,753 women and men from Nurses’ Health Study (NHS), Nurses’ Health Study II (NHSII), and Health Professionals Follow‐Up Study (HPFS) and explored th...
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Emerging evidence implicates gut microbial metabolism in neurodevelopmental disorders, but its influence on typical neurodevelopment has not been explored in detail. We investigated the relationship between the microbiome and neuroanatomy and cognition of 381 healthy children, demonstrating that differences in microbial taxa and genes are associate...
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Microbiome data, metadata and analytical workflows have become 'big' in terms of volume and complexity. Although the infrastructure and technologies to share data have been established, the interdisciplinary and multi-omic nature of the field can make resources difficult to identify and use. Following best practices for data deposition requires sub...
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The role of diet and the gut microbiome in the etiopathogenesis of irritable bowel syndrome (IBS) is not fully understood. Therefore, we investigated the interplay between dietary risk factors and gut microbiota in IBS subtypes using a food frequency questionnaire and stool metagenome data from 969 participants aged 18–65 years in the ZOE PREDICT 1...
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Background and Objectives Little is known regarding the association between intestinal motility patterns and cognitive function in individuals who are baseline cognitively healthy. The gut microbiome may contribute to the association. We examined the association between bowel movement (BM) pattern and cognitive function and explored the role of the...
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Objectives To identify indolepropionate (IPA)-predicting gut microbiota species, investigate potential diet–microbiota interactions, and examine the prospective associations of circulating IPA concentrations with type 2 diabetes (T2D) and coronary heart disease (CHD) risk in free-living individuals. Design We included 287 men from the Men’s Lifest...
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The gut microbiome affects the inflammatory environment through effects on T-cells, which influence the production of immune mediators and inflammatory cytokines that stimulate osteoclastogenesis and bone loss in mice. However, there are few large human studies of the gut microbiome and skeletal health. We investigated the association between the h...
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The growth of antimicrobial resistance (AMR) has highlighted an urgent need to identify bacterial pathogenic functions that may be targets for clinical intervention. Although severe bacterial infections profoundly alter host metabolism, prior studies have largely ignored alterations in microbial metabolism in this context. Performing metabolomics o...
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The literature of human and other host-associated microbiome studies is expanding rapidly, but systematic comparisons among published results of host-associated microbiome signatures of differential abundance remain difficult. We present BugSigDB, a community-editable database of manually curated microbial signatures from published differential abu...
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Lateral gene transfer (LGT) is an important mechanism for genome diversification in microbial populations, including the human microbiome. While prior work has surveyed LGT events in human-associated microbial isolate genomes, the scope and dynamics of novel LGT events arising in personal microbiomes are not well understood, as there are no widely...
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Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut...
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Background The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional alterations in severe COVID-19, defined as acute respiratory or other organ failure. Methods We profiled 127 hospitalized patients with COV...
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Objective: Prior studies on the gut microbiome in Parkinson's disease (PD) have yielded conflicting results, and few studies have focused on prodromal (premotor) PD or used shotgun metagenomic profiling to assess microbial functional potential. We conducted a nested case-control study within two large epidemiological cohorts to examine the role of...
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Background Characterization of microbial activity is essential to the understanding of the basic biology of microbial communities, as the function of a microbiome is defined by its biochemically active (“viable”) community members. Current sequence-based technologies can rarely differentiate microbial activity, due to their inability to distinguish...
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Obesity has been associated with increased risk of morbidity and mortality as well as decreased odds of healthy aging. Physical activity is often prescribed to reduce body weight by increasing energy use, but the amount of weight loss is highly variable. Our gut microbiome may play a role in this variability through its influence on energy balance...
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Bacteria can evolve to withstand a wide range of antibiotics (ABs) by using various resistance mechanisms. How ABs affect the ecology of the gut microbiome is still poorly understood. We investigated strain-specific responses and evolution during repeated AB perturbations by three clinically relevant ABs, using gnotobiotic mice colonized with a syn...
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Background The gut microbiome regulates host energy balance and adiposity-related metabolic consequences, but it remains unknown how the gut microbiome modulates body weight response to physical activity (PA). Methods Nested in the Health Professionals Follow-up Study, a subcohort of 307 healthy men (mean[SD] age, 70[4] years) provided stool and b...
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The microbial cells colonizing the human body form an ecosystem that is integral to the regulation and maintenance of human health. Elucidation of specific associations between the human microbiome and health outcomes is facilitating the development of microbiome-targeted recommendations and treatments (e.g., fecal microbiota transplant; pre-, pro-...
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Background: Indolepropionate (IPA), a tryptophan metabolite of human gut microbiota origin, is associated with lower risk of type 2 diabetes (T2D) in humans. The complex interplay among tryptophan intake, the gut microbiome, prebiotics, circulating IPA concentrations, and T2D risk has not been investigated. Objectives: We aimed to identify IPA-prod...
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Metagenomic assembly enables new organism discovery from microbial communities, but it can only capture few abundant organisms from most metagenomes. Here we present MetaPhlAn 4, which integrates information from metagenome assemblies and microbial isolate genomes for more comprehensive metagenomic taxonomic profiling. From a curated collection of...
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For decades, variability in clinical efficacy of the widely used inflammatory bowel disease (IBD) drug 5-aminosalicylic acid (5-ASA) has been attributed, in part, to its acetylation and inactivation by gut microbes. Identification of the responsible microbes and enzyme(s), however, has proved elusive. To uncover the source of this metabolism, we de...
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We describe deepG, a platform for the generation, interpretation, and application of deep learning models for sequence labeling, classification, and regression based on nucleotide sequences. Unlike other bioinformatic deep learning platforms that focus on training on the human genome, deepG can handle sets of (meta)genomes via a range of data augme...
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In computational biology, there is a lack of agreement on the optimal design of deep learning architectures, such as types and number of layers, often resulting in non-optimal design choices. We introduce GenomeNet-Architect , an architectural design framework that researchers can use to optimize deep learning models for genome sequence data. Relat...
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BACKGROUND Variation in clinical response to 5-aminosalicylic acid (5-ASA) has been attributed in part to its inactivation by gut microbes. Recently, in the Inflammatory Bowel Disease (IBD) Multi’omics Database (IBDMDB), a multicenter year-long cohort of 100+ participants with IBD, we identified 12 gut microbial enzymes from two protein families th...
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Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology,...
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The metabolome lies at the interface of host–microbiome crosstalk. Previous work has established links between chemically diverse microbial metabolites and a myriad of host physiological processes and diseases. Coupled with scalable and cost-effective technologies, metabolomics is thus gaining popularity as a tool for characterization of microbial...
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Background Only few longitudinal studies with high risk of bias have examined relationship between pets and adolescents' mental health. Methods Our prospective cohort study followed depression-free US adolescents aged 12–18, enrolled in the Growing Up Today Study from pet ownership assessment in 1999 to possible occurrence of high depressive sympt...
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Background: Evidence suggests that Fusobacterium nucleatum (F. nucleatum) plays a role in colorectal carcinogenesis by suppressing the host immune response to tumors. The appendix is an organ that may influence the intestinal microbiome. We hypothesized that appendectomy history might be associated with altered colorectal cancer incidence and that...
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Emerging experimental evidence indicates that toxicant-induced alterations in gut microbiota composition and activity may affect host homeostasis. However, data from human studies are scarce; to our knowledge, no previous studies have quantified the association of lifetime exposure to environmental chemicals, across multiple time points, with the c...
Preprint
Full-text available
The literature of human and other host-associated microbiome studies is expanding rapidly, but systematic comparisons among published results of host-associated microbiome signatures of differential abundance remain difficult. We present BugSigDB, a community-editable database of manually curated microbial signatures from published differential abu...
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Full-text available
Objective To assess whether maternal ultra-processed food intake during peripregnancy and during the child rearing period is associated with offspring risk of overweight or obesity during childhood and adolescence. Design Population based prospective cohort study. Setting The Nurses’ Health Study II (NHSII) and the Growing Up Today Study (GUTS I...
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Microbiome studies of inflammatory bowel diseases (IBD) have achieved a scale for meta-analysis of dysbioses among populations. To enable microbial community meta-analyses generally, we develop MMUPHin for normalization, statistical meta-analysis, and population structure discovery using microbial taxonomic and functional profiles. Applying it to t...
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Studies of the human microbiome share both technical and conceptual similarities with genome-wide association studies and genetic epidemiology. However, the microbiome has many features that differ from genomes, such as its temporal and spatial variability, highly distinct genetic architecture and person-to-person variation. Moreover, there are var...
Preprint
Full-text available
Metagenomic assembly enables novel organism discovery from microbial communities, but from most metagenomes it can only capture few abundant organisms. Here, we present a method - MetaPhlAn 4 - to integrate information from both metagenome assemblies and microbial isolate genomes for improved and more comprehensive metagenomic taxonomic profiling....
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Full-text available
Members of the human gut microbiome enzymatically process many bioactive molecules in the gastrointestinal tract. Most gut bacterial modifications characterized so far are hydrolytic or reductive in nature. Here we report that abundant human gut bacteria from the phylum Bacteroidetes perform conjugative modifications by selectively sulfonating ster...