Alterations of oral microbiota and impact on the gut microbiome in type 1 diabetes mellitus revealed by integrated multi-omic analyses

in Microbiome (2022)

Background: Alterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure ... [more ▼]

Background: Alterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain‑resolved, integrated meta‑genomic, transcriptomic, and proteomic analyses of paired saliva and stool samples collected from 35 individuals from eight families with multiple cases of type 1 diabetes mellitus (T1DM). Results: We identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain‑variants from the oral cavity to the gut at the individual omic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract. Conclusions: Alterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of “mouth‑to‑gut” transfer of Streptococcus salivarius. Our results indicate that the observed oral‑cavity‑driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi‑omic analyses, we resolve strain‑variant “mouth‑to‑gut” transfer in a disease context. [less ▲]

Extensive transmission of microbes along the gastrointestinal tract

in eLife (2019)

The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary ... [more ▼]

The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more generally, for species described as opportunistic pathogens. This establishes the oral cavity as an endogenous reservoir for gut microbial strains, and oral-fecal transmission as an important process that shapes the gastrointestinal microbiome in health and disease. [less ▲]

Colonization and Succession within the Human Gut Microbiome by Archaea, Bacteria, and Microeukaryotes during the First Year of Life

in Frontiers in Microbiology (2017)

Perturbations to the colonization process of the human gastrointestinal tract have been suggested to result in adverse health effects later in life. Although much research has been performed on bacterial ... [more ▼]

Perturbations to the colonization process of the human gastrointestinal tract have been suggested to result in adverse health effects later in life. Although much research has been performed on bacterial colonization and succession, much less is known about the other two domains of life, archaea, and eukaryotes. Here we describe colonization and succession by bacteria, archaea and microeukaryotes during the first year of life (samples collected around days 1, 3, 5, 28, 150, and 365) within the gastrointestinal tract of infants delivered either vaginally or by cesarean section and using a combination of quantitative real-time PCR as well as 16S and 18S rRNA gene amplicon sequencing. Sequences from organisms belonging to all three domains of life were detectable in all of the collected meconium samples. The microeukaryotic community composition fluctuated strongly over time and early diversification was delayed in infants receiving formula milk. Cesarean section-delivered (CSD) infants experienced a delay in colonization and succession, which was observed for all three domains of life. Shifts in prokaryotic succession in CSD infants compared to vaginally delivered (VD) infants were apparent as early as days 3 and 5, which were characterized by increased relative abundances of the genera Streptococcus and Staphylococcus, and a decrease in relative abundance for the genera Bifidobacterium and Bacteroides. Generally, a depletion in Bacteroidetes was detected as early as day 5 postpartum in CSD infants, causing a significantly increased Firmicutes/Bacteroidetes ratio between days 5 and 150 when compared to VD infants. Although the delivery mode appeared to have the strongest influence on differences between the infants, other factors such as a younger gestational age or maternal antibiotics intake likely contributed to the observed patterns as well. Our findings complement previous observations of a delay in colonization and succession of CSD infants, which affects not only bacteria but also archaea and microeukaryotes. This further highlights the need for resolving bacterial, archaeal, and microeukaryotic dynamics in future longitudinal studies of microbial colonization and succession within the neonatal gastrointestinal tract. [less ▲]

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes.

in Nature Microbiology (2016), 2

The gastrointestinal microbiome is a complex ecosystem with functions that shape human health. Studying the relationship between taxonomic alterations and functional repercussions linked to disease ... [more ▼]

The gastrointestinal microbiome is a complex ecosystem with functions that shape human health. Studying the relationship between taxonomic alterations and functional repercussions linked to disease remains challenging. Here, we present an integrative approach to resolve the taxonomic and functional attributes of gastrointestinal microbiota at the metagenomic, metatranscriptomic and metaproteomic levels. We apply our methods to samples from four families with multiple cases of type 1 diabetes mellitus (T1DM). Analysis of intra- and inter-individual variation demonstrates that family membership has a pronounced effect on the structural and functional composition of the gastrointestinal microbiome. In the context of T1DM, consistent taxonomic differences were absent across families, but certain human exocrine pancreatic proteins were found at lower levels. The associated microbial functional signatures were linked to metabolic traits in distinct taxa. The methodologies and results provide a foundation for future large-scale integrated multi-omic analyses of the gastrointestinal microbiome in the context of host-microbe interactions in human health and disease. [less ▲]

Identification, recovery, and refinement of hitherto undescribed population-level genomes from the human gastrointestinal tract

in Frontiers in Microbiology (2016), 7(884),

Linking taxonomic identity and functional potential at the population-level is important for the study of mixed microbial communities and is greatly facilitated by the availability of microbial reference ... [more ▼]

Linking taxonomic identity and functional potential at the population-level is important for the study of mixed microbial communities and is greatly facilitated by the availability of microbial reference genomes. While the culture-independent recovery of population-level genomes from environmental samples using the binning of metagenomic data has expanded available reference genome catalogs, several microbial lineages remain underrepresented. Here, we present two reference-independent approaches for the identification, recovery, and refinement of hitherto undescribed population-level genomes. The first approach is aimed at genome recovery of varied taxa and involves multi-sample automated binning using CANOPY CLUSTERING complemented by visualization and human-augmented binning using VIZBINpost hoc. The second approach is particularly well-suited for the study of specific taxa and employs VIZBINde novo. Using these approaches, we reconstructed a total of six population-level genomes of distinct and divergent representatives of the Alphaproteobacteria class, the Mollicutes class, the Clostridiales order, and the Melainabacteria class from human gastrointestinal tract-derived metagenomic data. Our results demonstrate that, while automated binning approaches provide great potential for large-scale studies of mixed microbial communities, these approaches should be complemented with informative visualizations because expert-driven inspection and refinements are critical for the recovery of high-quality population-level genomes. [less ▲]

Adding anthropometric measures of regional adiposity to BMI improves prediction of cardiometabolic, inflammatory and adipokines profiles in youths: a cross-sectional study.

in BMC pediatrics (2015), 15

BACKGROUND: Paediatric research analysing the relationship between the easy-to-use anthropometric measures for adiposity and cardiometabolic risk factors remains highly controversial in youth. Several ... [more ▼]

BACKGROUND: Paediatric research analysing the relationship between the easy-to-use anthropometric measures for adiposity and cardiometabolic risk factors remains highly controversial in youth. Several studies suggest that only body mass index (BMI), a measure of relative weight, constitutes an accurate predictor, whereas others highlight the potential role of waist-to-hip ratio (WHR), waist circumference (Waist C), and waist-to-height ratio (WHtR). In this study, we examined the effectiveness of adding anthropometric measures of body fat distribution (Waist C Z Score, WHR Z Score and/or WHtR) to BMI Z Score to predict cardiometabolic risk factors in overweight and obese youth. We also examined the consistency of these associations with the "total fat mass + trunk/legs fat mass" and/or the "total fat mass + trunk fat mass" combinations, as assessed by dual energy X-ray absorptiometry (DXA), the gold standard measurement of body composition. METHODS: Anthropometric and DXA measurements of total and regional adiposity, as well as a comprehensive assessment of cardiometabolic, inflammatory and adipokines profiles were performed in 203 overweight and obese 7-17 year-old youths from the Paediatrics Clinic, Centre Hospitalier de Luxembourg. RESULTS: Adding only one anthropometric surrogate of regional fat to BMI Z Score improved the prediction of insulin resistance (WHR Z Score, R(2): 45.9%. Waist C Z Score, R(2): 45.5%), HDL-cholesterol (WHR Z Score, R(2): 9.6%. Waist C Z Score, R(2): 10.8%. WHtR, R(2): 6.5%), triglycerides (WHR Z Score, R(2): 11.7%. Waist C Z Score, R(2): 12.2%), adiponectin (WHR Z Score, R(2): 14.3%. Waist C Z Score, R(2): 17.7%), CRP (WHR Z Score, R(2): 18.2%. WHtR, R(2): 23.3%), systolic (WHtR, R(2): 22.4%), diastolic blood pressure (WHtR, R(2): 20%) and fibrinogen (WHtR, R(2): 21.8%). Moreover, WHR Z Score, Waist C Z Score and/or WHtR showed an independent significant contribution according to these models. These results were in line with the DXA findings. CONCLUSIONS: Adding anthropometric measures of regional adiposity to BMI Z Score improves the prediction of cardiometabolic, inflammatory and adipokines profiles in youth. [less ▲]

Early dynamics of the gastrointestinal microbiome in infants at risk of metabolic disease in adulthood.

Poster (2015, June)

Integrated omics analyses of the human gut microbiome in a multiplex family study of type 1 diabetes mellitus.

Poster (2015, March)

Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial

in JAMA: Journal of the American Medical Association (2014), 311(22), 2279-2287

Importance The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in ... [more ▼]

Importance The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. Objective To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. Design, Setting, and Participants A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows’ milk–based formula. The participants were observed to April 16, 2013. Interventions The participants received either a casein hydrolysate or a conventional cows’ milk formula supplemented with 20% of the casein hydrolysate. Main Outcomes and Measures Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated–2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). Results The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. Conclusions and Relevance Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. [less ▲]

Joining forces: a call for greater collaboration to study new medicines in children and adolescents with type 2 diabetes.

in Diabetes Care (2014), 37(10), 2665-2667