My publications summarized. What did I do and why.

Metagenomic estimation of dietary intake from human stool

2024-02-07 2m read

Dietary intake is tightly coupled to gut microbiota composition, human metabolism, and to the incidence of virtually all major chronic diseases. Dietary and nutrient intake are usually quantified using dietary questionnaires, which tend to focus on broad food categories, suffer from self-reporting biases, and require strong compliance from study participants. Here, we present MEDI (Metagenomic Estimation of Dietary Intake): a method for quantifying dietary intake using food-derived DNA in stool metagenomes.

Personalized Clostridioides difficile engraftment risk prediction and probiotic therapy assessment in the human gut

2024-01-31 2m read

Clostridioides difficile colonizes up to 30-40% of community-dwelling adults without causing disease. C. difficile infections (CDIs) are the leading cause of antibiotic-associated diarrhea in the U.S. and typically develop in individuals following disruption of the gut microbiota due to antibiotic or chemotherapy treatments. Further treatment of CDI with antibiotics is not always effective and can lead to antibiotic resistance and recurrent infections (rCDI). The most effective treatment for rCDI is the reestablishment of an intact microbiota via fecal microbiota transplants (FMTs).

Disease-specific loss of microbial cross-feeding interactions in the human gut

2023-10-20 1m read

Many gut microorganisms critical to human health rely on nutrients produced by each other for survival; however, these cross-feeding interactions are still challenging to quantify and remain poorly characterized. Here, we introduce a Metabolite Exchange Score (MES) to quantify those interactions. Using metabolic models of prokaryotic metagenome-assembled genomes from over 1600 individuals, MES allows us to identify and rank metabolic interactions that are significantly affected by a loss of cross-feeding partners in 10 out of 11 diseases.

Bifidobacterium infantis supplementation versus placebo in early life to improve immunity in infants exposed to HIV: a protocol for a randomized trial

2023-10-08 1m read

Infants who are born from mothers with HIV (infants who are HIV exposed but uninfected; iHEU) are at higher risk of morbidity and display multiple immune alterations compared to infants who are HIV-unexposed (iHU). Easily implementable strategies to improve immunity of iHEU, and possibly subsequent clinical health outcomes, are needed. iHEU have altered gut microbiome composition and bifidobacterial depletion, and relative abundance of Bifidobacterium infantis has been associated with immune ontogeny, including humoral and cellular vaccine responses.

Growth phase estimation for abundant bacterial populations sampled longitudinally from human stool metagenomes

2023-09-04 2m read

Longitudinal sampling of the stool has yielded important insights into the ecological dynamics of the human gut microbiome. However, human stool samples are available approximately once per day, while commensal population doubling times are likely on the order of minutes-to-hours. Despite this mismatch in timescales, much of the prior work on human gut microbiome time series modeling has assumed that day-to-day fluctuations in taxon abundances are related to population growth or death rates, which is likely not the case.

Island biogeography theory and the gut: why taller people tend to harbor more diverse gut microbiomes

2023-08-12 2m read

Prior work has shown a positive scaling relationship between vertebrate body size and gut microbiome alpha-diversity. This observation mirrors commonly observed species area relationships (SAR) in many other ecosystems. Here, we show a similar scaling relationship between human height and gut microbiome alpha-diversity across two large, independent cohorts, controlling for a wide range of relevant covariates, such as body mass index, age, sex, and bowel movement frequency. Island Biogeography Theory (IBT), which predicts that larger islands tend to harbor greater species diversity through neutral demographic processes, provides a simple mechanism for these positive SARs.

Coarse graining the human gut microbiome

2023-07-12 1m read

The composition of the human gut microbiome is heterogeneous across people. However, if you squint, co-abundant microbial genera emerge, accounting for much of this ecological variability. In this issue of Cell Host & Microbe, Frioux et al. provide a workflow for identifying these bacterial guilds, or “enterosignatures.”

More is Different: Metabolic Modeling of Diverse Microbial Communities

2023-03-21 2m read

Microbial consortia drive essential processes, ranging from nitrogen fixation in soils to providing metabolic breakdown products to animal hosts. However, it is challenging to translate the composition of microbial consortia into their emergent functional capacities. Community-scale metabolic models hold the potential to simulate the outputs of complex microbial communities in a given environmental context, but there is currently no consensus for what the fitness function of an entire community should look like in the presence of ecological interactions and whether community-wide growth operates close to a maximum.

Multiomic investigations of Body Mass Index reveal heterogeneous trajectories in response to a lifestyle intervention

2023-03-20 2m read

Multiomic profiling is useful in characterizing heterogeneity of both health and disease states. Obesity exerts profound metabolic perturbation in individuals and is a risk factor for multiple chronic diseases. Here, we report a global atlas of cross-sectional and longitudinal changes associated with Body Mass Index (BMI) across 1,100+ blood analytes, as well as their correspondence to host genome and fecal microbiome composition, from a cohort of 1,277 individuals enrolled in a wellness program.

Generally-healthy individuals with aberrant bowel movement frequencies show enrichment for microbially-derived blood metabolites associated with impaired kidney function

2023-03-04 2m read

Obiective Bowel movement frequency (BMF) variation has been linked to changes in the composition of the human gut microbiome and to many chronic conditions, like metabolic disorders, neurodegenerative diseases, chronic kidney disease (CKD), and other intestinal pathologies like irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Slow intestinal transit times (constipation) are thought to lead to compromised intestinal barrier integrity and a switch from saccharolytic to proteolytic fermentation within the microbiota, giving rise to microbially-derived toxins that may make their way into circulation and cause damage to organ systems.

Microbial community-scale metabolic modeling predicts personalized short-chain-fatty-acid production profiles in the human gut

2023-02-28 1m read

Microbially-derived short-chain fatty acids (SCFAs) in the human gut are tightly coupled to host metabolism, immune regulation, and integrity of the intestinal epithelium. However, the production of SCFAs can vary widely between individuals consuming the same diet, with lower levels often associated with disease. A mechanistic understanding of this heterogeneity is lacking. We present a microbial community-scale metabolic modeling (MCMM) approach to predict individual-specific SCFA production profiles. We assess the quantitative accuracy of our MCMMs using in vitro, ex vivo, and in vivo data.

Genome-microbiome interplay provides insight into the determinants of the human blood metabolome

2022-11-10 1m read

Variation in the blood metabolome is intimately related to human health. However, few details are known about the interplay between genetics and the microbiome in explaining this variation on a metabolite-by-metabolite level. Here, we perform analyses of variance for each of 930 blood metabolites robustly detected across a cohort of 1,569 individuals with paired genomic and microbiome data while controlling for a number of relevant covariates. We find that 595 (64%) of these blood metabolites are significantly associated with either host genetics or the gut microbiome, with 69% of these associations driven solely by the microbiome, 15% driven solely by genetics and 16% under hybrid genome–microbiome control.

Constraint-Based Reconstruction and Analyses of Metabolic Models: Open-Source Python Tools and Applications to Cancer

2022-07-07 2m read

The influence of metabolism on signaling, epigenetic markers, and transcription is highly complex yet important for understanding cancer physiology. Despite the development of high-resolution multi-omics technologies, it is difficult to infer metabolic activity from these indirect measurements. Fortunately, genome-scale metabolic models and constraint-based modeling provide a systems biology framework to investigate the metabolic states and define the genotype-phenotype associations by integrations of multi-omics data. Constraint-Based Reconstruction and Analysis (COBRA) methods are used to build and simulate metabolic networks using mathematical representations of biochemical reactions, gene-protein reaction associations, and physiological and biochemical constraints.

Heterogeneity in statin responses explained by variation in the human gut microbiome

2022-06-10 1m read

Despite the undeniable cholesterol lowering benefits of statin therapy, considerable heterogeneity exists in individual responses to the same treatment. Human gut bacteria are known to metabolize statins in vitro, but there is limited information on how microbiome composition may contribute to statin on-target and/or adverse effects. Here, the authors identify a novel blood-based biomarker for monitoring statin effects in two large, independent human cohorts. They identify gut microbiome features robustly associated with variable statin responses, both in terms of on-target (cholesterol lowering) and adverse (insulin resistance) effects.

From taxonomy to metabolic output: what factors define gut microbiome health?

2022-04-23 1m read

Many studies link the composition of the human gut microbiome to aberrant health states. However, our understanding of what constitutes a ‘healthy’ gut ecosystem, and how to effectively monitor and maintain it, are only now emerging. Here, we review current approaches to defining and monitoring gut microbiome health, and outline directions for developing targeted ecological therapeutics. We emphasize the importance of identifying which ecological features of the gut microbiome are most resonant with host molecular phenotypes, and highlight certain gut microbial metabolites as potential biomarkers of gut microbiome health.

Genomic and functional characterization of a mucosal symbiont involved in early-stage colorectal cancer

2021-10-13 1m read

Colorectal cancer is a major health concern worldwide. Growing evidence for the role of the gut microbiota in the initiation of CRC has sparked interest in approaches that target these microorganisms. However, little is known about the composition and role of the microbiota associated with precancerous polyps. Here, we found distinct microbial signatures between patients with and without polyps and between polyp subtypes using sequencing and culturing techniques. We found a correlation between Bacteroides fragilis recovered and the level of inflammatory cytokines in the mucosa adjacent to the polyp.

Lettuce (Lactuca sativa) productivity influenced by microbial inocula under nitrogen-limited conditions in aquaponics

2021-02-23 2m read

The demand for food will outpace productivity of conventional agriculture due to projected growth of the human population, concomitant with shrinkage of arable land, increasing scarcity of freshwater, and a rapidly changing climate. While aquaponics has potential to sustainably supplement food production with minimal environmental impact, there is a need to better characterize the complex interplay between the various components (fish, plant, microbiome) of these systems to optimize scale up and productivity.

Gut microbiome pattern reflects healthy ageing and predicts survival in humans

2021-02-18 1m read

The gut microbiome has important effects on human health, yet its importance in human ageing remains unclear. In the present study, we demonstrate that, starting in mid-to-late adulthood, gut microbiomes become increasingly unique to individuals with age. We leverage three independent cohorts comprising over 9,000 individuals and find that compositional uniqueness is strongly associated with microbially produced amino acid derivatives circulating in the bloodstream. In older age (over ~80 years), healthy individuals show continued microbial drift towards a unique compositional state, whereas this drift is absent in less healthy individuals.

Progressive shifts in the gut microbiome reflect prediabetes and diabetes development in a treatment-naive Mexican cohort

2021-01-08 2m read

Type 2 diabetes (T2D) is a global epidemic that affects more than 8% of the world’s population and is a leading cause of death in Mexico. Diet and lifestyle are known to contribute to the onset of T2D. However, the role of the gut microbiome in T2D progression remains uncertain. Associations between microbiome composition and diabetes are confounded by medication use, diet, and obesity. Here we present data on a treatment-naive cohort of 405 Mexican individuals across varying stages of T2D severity.

Baseline Gut Metagenomic Functional Gene Signature Associated with Variable Weight Loss Responses following a Healthy Lifestyle Intervention in Humans

2021-01-05 1m read

Recent human feeding studies have shown how the baseline taxonomic composition of the gut microbiome can determine responses to dietary interventions, but the exact functional determinants underlying this phenomenon remain unclear. In this study, we set out to better understand interactions between baseline BMI, metabolic health, diet, gut microbiome functional profiles, and subsequent weight changes in a human cohort that underwent a healthy lifestyle intervention. Overall, our results suggest that the microbiota may influence host weight loss responses through variable bacterial growth rates, dietary energy harvest efficiency, and immunomodulation.

Antimicrobial Peptide against Mycobacterium Tuberculosis That Activates Autophagy Is an Effective Treatment for Tuberculosis

2020-11-09 1m read

Mycobacterium tuberculosis (MTB) is the principal cause of human tuberculosis (TB), which is a serious health problem worldwide. The development of innovative therapeutic modalities to treat TB is mainly due to the emergence of multi drug resistant (MDR) TB. Autophagy is a cell-host defense process. Previous studies have reported that autophagy-activating agents eliminate intracellular MDR MTB. Thus, combining a direct antibiotic activity against circulating bacteria with autophagy activation to eliminate bacteria residing inside cells could treat MDR TB.

MEMOTE for standardized genome-scale metabolic model testing

2020-03-02 1m read

Reconstructing metabolic reaction networks enables the development of testable hypotheses of an organism’s metabolism under different conditions1. State-of-the-art genome-scale metabolic models (GEMs) can include thousands of metabolites and reactions that are assigned to subcellular locations. Gene–protein–reaction (GPR) rules and annotations using database information can add meta-information to GEMs. GEMs with metadata can be built using standard reconstruction protocols2, and guidelines have been put in place for tracking provenance and enabling interoperability, but a standardized means of quality control for GEMs is lacking3.

MICOM: metagenome-scale modeling to infer metabolic interactions in the microbiota

2020-01-21 2m read

Compositional changes in the gut microbiota have been associated with a variety of medical conditions such as obesity, Crohn’s disease, and diabetes. However, connecting microbial community composition to ecosystem function remains a challenge. Here, we introduce MICOM, a customizable metabolic model of the human gut microbiome. By using a heuristic optimization approach based on L2 regularization, we were able to obtain a unique set of realistic growth rates that corresponded well with observed replication rates.

Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2

2019-07-24 1m read

Rapid advances in DNA-sequencing and bioinformatics technologies in the past two decades have substantially improved understanding of the microbial world. This growing understanding relates to the vast diversity of microorganisms; how microbiota and microbiomes affect disease and medical treatment; how microorganisms affect the health of the planet; and the nascent exploration of the medical, forensic, environmental and agricultural applications of microbiome biotechnology. Much of this work has been driven by marker-gene surveys (for example, bacterial/archaeal 16S rRNA genes, fungal internal-transcribed-spacer regions and eukaryotic 18S rRNA genes), which profile microbiota with varying degrees of taxonomic specificity and phylogenetic information.

Use and abuse of correlation analyses in microbial ecology

2019-06-03 1m read

Correlation analyses are often included in bioinformatic pipelines as methods for inferring taxon–taxon interactions. In this perspective, we highlight the pitfalls of inferring interactions from covariance and suggest methods, study design considerations, and additional data types for improving high-throughput interaction inferences. We conclude that correlation, even when augmented by other data types, almost never provides reliable information on direct biotic interactions in real-world ecosystems. These bioinformatically inferred associations are useful for reducing the number of potential hypotheses that we might test, but will never preclude the necessity for experimental validation.

Non-responder phenotype reveals apparent microbiome-wide antibiotic tolerance in the murine gut

2019-04-06 2m read

Broad spectrum antibiotics cause both transient and lasting damage to the ecology of the gut microbiome. Antibiotic-induced loss of gut bacterial diversity has been linked to susceptibility to enteric infections. Prior work on subtherapeutic antibiotic treatment in humans and non-human animals has suggested that entire gut communities may exhibit tolerance phenotypes. In this study, we validate the existence of these community tolerance phenotypes in the murine gut and explore how antibiotic treatment duration or a diet enriched in antimicrobial phytochemicals might influence the frequency of this phenotype.

Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

2019-04-06 2m read

Background Links between colorectal cancer (CRC) and the gut microbiome have been established, but the specific microbial species and their role in carcinogenesis remain an active area of inquiry. Our understanding would be enhanced by better accounting for tumor subtype, microbial community interactions, metabolism, and ecology. Methods We collected paired colon tumor and normal-adjacent tissue and mucosa samples from 83 individuals who underwent partial or total colectomies for CRC. Mismatch repair (MMR) status was determined in each tumor sample and classified as either deficient MMR (dMMR) or proficient MMR (pMMR) tumor subtypes.

Synthesis of multi-omic data and community metabolic models reveals insights into the role of hydrogen sulfide in colon cancer

2019-04-06 1m read

Multi-omic data and genome-scale microbial metabolic models have allowed us to examine microbial communities, community function, and interactions in ways that were not available to us historically. Now, one of our biggest challenges is determining how to integrate data and maximize data potential. Our study demonstrates one way in which to test a hypothesis by combining multi-omic data and community metabolic models. Specifically, we assess hydrogen sulfide production in colorectal cancer based on stool, mucosa, and tissue samples collected on and off the tumor site within the same individuals.

Personalized Prediction of Proliferation Rates

2017-01-19 2m read

Cancer is a complex disease and manifests in many different forms. In fact, when speaking about cancer we are probably speaking about thousand different diseases and not one. The high level of heterogeneity between and across different cancer subtypes requires large amounts of data to study them. Luckily, we do have large data sets today. However, the kind of knowledge we can extract from those data sets depends a lot on where we got the data from.

Going from metabolites to affected enzymes in cancer

2016-06-21 2m read

When studying cancer or any disease one of the things we are interested in are the alterations that cause the disease. By now, we have quite some arsenal to study genomic aberrations, however assigning those to a specific phenotype is not trivial. This is particularly true for changes affecting metabolism, since there is a myriad of regulation events that take place after gene expression and which drive metabolism. The image above shows just an example of events that can happen between translation of an enzyme gene until it will finally catalyze a reaction.

Building multifunctional peptides by compatible function

2016-04-21 1m read

Artificially designed small peptides are currently quite interesting for medical research since they provide a way to target specific cellular activities. In many cases one wants to combine several functions into a single peptide that is as small as possible. This is problematic as the activity of the peptide is often lost when combining several functions. In our article we propose a design strategy based on “compatible function”, meaning functions that require similar physio-chemical properties of the peptide.

How yeast creates their own signaling landscape

2015-08-28 1m read

Signaling in yeast is often used as a blueprint for human signaling pathways since its general way of function is close to what we can observe in human. This is not only true for signaling pathways within a single yeast cell but also for the ways yeast cells communicate with each other. During the mating of yeast, individual cells communicate their position using distinct pheromones. However, at the same time they also secrete a protein that destroys those very pheromones and thos paradoxically counteracts this signaling.

CPPs and CAPs: Two sides of the same coin

2014-03-25 1m read

Cell penetrating peptides (CPP) and cationic antibacterial peptides (CAP) have similar physicochemical properties and yet it is not understood how such similar peptides display different activities. To address this question, we used Iztli peptide 1 (IP-1) because it has both CPP and CAP activities. Combining experimental and computational modeling of the internalization of IP-1, we show it is not internalized by receptor-mediated endocytosis, yet it permeates into many different cell types, including fungi and human cells.

Immunogenic variety and the Golden Agers

2012-11-30 2m read

The immune system protects us from foreign substances or pathogens by generating specific antibodies. The variety of immunoglobulin (Ig) paratopes for antigen recognition is a result of the V(D)J rearrangement mechanism, while a fast and efficient immune response is mediated by specific immunoglobulin isotypes obtained through class switch recombination (CSR). To get a better understanding on how antibody-based immune protection works and how it changes with age, the interdependency between these two parameters need to be addressed.

Ensuring low noise in the yeast cell cycle

2011-10-07 2m read

The budding yeast genome comprises roughly 6000 genes generating a number of about 10 000 mRNA copies, which gives a general estimation of 1-2 mRNA copies generated per gene. What does this observation implicate for cellular processes and their regulation? Whether the number of mRNA molecules produced is important for setting the amount of proteins implicated in a particular function is at present unknown. In this context, we studied cell cycle control as one of the highly fine tuned processes that guarantee the precise timing of events essential for cell growth.

What influences DNA replication rate in budding yeast?

2010-04-27 2m read

DNA replication begins at specific locations called replication origins, where helicase and polymerase act in concert to unwind and process the single DNA filaments. The sites of active DNA synthesis are called replication forks. The density of initiation events is low when replication forks travel fast, and is high when forks travel slowly. Despite the potential involvement of epigenetic factors, transcriptional regulation and nucleotide availability, the causes of differences in replication times during DNA synthesis have not been established satisfactorily, yet.