Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors
, including complex genetic elements
, patient exposures
and ...the gut microbiome
. Viral infections
and broader gut dysbioses
have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts
and a T1D mouse model
, these data support the protective effects of short-chain fatty acids in early-onset human T1D.
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KISLJ, NUK, SBMB, UL, UM, UPUK
The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later ...life diseases
such as persistent islet autoimmunity and type 1 diabetes
. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.
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Gut Microbiota and Lifestyle Interventions in NAFLD Houghton, David; Stewart, Christopher J; Day, Christopher P ...
International Journal of Molecular Sciences,
03/2016, Volume:
17, Issue:
4
Journal Article, Book Review
Peer reviewed
Open access
The human digestive system harbors a diverse and complex community of microorganisms that work in a symbiotic fashion with the host, contributing to metabolism, immune response and intestinal ...architecture. However, disruption of a stable and diverse community, termed "dysbiosis", has been shown to have a profound impact upon health and disease. Emerging data demonstrate dysbiosis of the gut microbiota to be linked with non-alcoholic fatty liver disease (NAFLD). Although the exact mechanism(s) remain unknown, inflammation, damage to the intestinal membrane, and translocation of bacteria have all been suggested. Lifestyle intervention is undoubtedly effective at improving NAFLD, however, not all patients respond to these in the same manner. Furthermore, studies investigating the effects of lifestyle interventions on the gut microbiota in NAFLD patients are lacking. A deeper understanding of how different aspects of lifestyle (diet/nutrition/exercise) affect the host-microbiome interaction may allow for a more tailored approach to lifestyle intervention. With gut microbiota representing a key element of personalized medicine and nutrition, we review the effects of lifestyle interventions (diet and physical activity/exercise) on gut microbiota and how this impacts upon NAFLD prognosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The last decade has witnessed a meteoric rise in research focused on characterizing the human microbiome and identifying associations with disease risk. The advent of sequencing technology has all ...but eradicated gel-based fingerprinting approaches for studying microbial ecology, while at the same time traditional microbiological culture is undergoing a renaissance. Although multiplexed high-throughput sequencing is relatively new, the discoveries leading to this are nearly 50 years old, coinciding with the inaugural Microbiology Society Fleming Prize lecture. It was an honour to give the 2022 Fleming Prize lecture and this review will cover the topics from that lecture. The focus will be on the bacterial community in early life, beginning with term infants before moving on to infants delivered prematurely. The review will discuss recent work showing how human milk oligosaccharides (HMOs), an abundant but non-nutritious component of breast milk, can modulate infant microbiome and promote the growth of
spp. This has important connotations for preterm infants at risk of necrotizing enterocolitis, a devastating intestinal disease representing the leading cause of death and long-term morbidity in this population. With appropriate mechanistic studies, it may be possible to harness the power of breast milk bioactive factors and infant gut microbiome to improve short- and long-term health in infants.
Sarcopenia and Mortality after Liver Transplantation Englesbe, Michael J., MD; Patel, Shaun P., BS; He, Kevin, MS ...
Journal of the American College of Surgeons,
08/2010, Volume:
211, Issue:
2
Journal Article
Peer reviewed
Open access
Background Surgeons frequently struggle to determine patient suitability for liver transplantation. Objective and comprehensive measures of overall burden of disease, such as sarcopenia, could inform ...clinicians and help avoid futile transplantations. Study Design The cross-sectional area of the psoas muscle was measured on CT scans of 163 liver transplant recipients. After controlling for donor and recipient characteristics using Cox regression models, we described the relationship between psoas area and post-transplantation mortality. Results Psoas area correlated poorly with Model for End-Stage Liver Disease score and serum albumin. Cox regression revealed a strong association between psoas area and post-transplantation mortality (hazard ratio = 3.7/1,000 mm2 decrease in psoas area; p < 0.0001). When stratified into quartiles based on psoas area (holding donor and recipient characteristics constant), 1-year survival ranged from 49.7% for the quartile with the smallest psoas area to 87.0% for the quartile with the largest. Survival at 3 years among these groups was 26.4% and 77.2%, respectively. The impact of psoas area on survival exceeded that of all other covariates in these models. Conclusions Central sarcopenia strongly correlates with mortality after liver transplantation. Such objective measures of patient frailty, such as sarcopenia, can inform clinical decision making and, potentially, allocation policy. Additional work is needed develop valid and clinically relevant measures of sarcopenia and frailty in liver transplantation.
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GEOZS, NUK, OILJ, SBJE, UL, UPUK
A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts ...A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens.
IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens.
These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply.
We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program.
Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Aim
This narrative review summarises the benefits of maternal breastmilk to both the infant and the mother, specifically the benefits that relate to modification of the infant microbiome, and how ...this might vary in the preterm infant.
Methods
We used PubMed to primarily identify papers, reviews, case series and editorials published in English until May 2020. Based on this, we report on the components of breastmilk, their associated hypothesised benefits and the implications for clinical practice.
Results
Breastmilk is recommended as the exclusive diet for newborn infants because it has numerous nutritional and immunological benefits. Additionally, exposure to the maternal breastmilk microbiome may confer a lasting effect on gut health. In the preterm infant, breastmilk is associated with a significant reduction in necrotising enterocolitis, an inflammatory gastrointestinal disease and reduction in other key morbidities, together with improved neurodevelopmental outcomes.
Conclusion
These impacts have long‐term benefits for the child (and the mother) even after weaning. This benefit is likely due, in part, to modification of the infant gut microbiome by breastmilk microbes and bioactive components, and provide potential areas for research and novel therapies in preterm and other high‐risk infants.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. ...Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.
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•2.1-, 2.1-, and 2.5-Å GLP-1R:Gs structures bound to GLP-1 and non-peptide agonists•Critical water networks stabilize peptide and small-molecule agonist binding•PF 06882961, but not CHU-128, closely mimics the GLP-1 signaling profile•Insight into how select non-peptide agonists mimic receptor activation by GLP-1
Zhang et al. show that the non-peptide GLP-1R agonist PF 06882961, but not CHU-128, was able to closely mimic the in vitro pharmacological fingerprint of GLP-1. These pharmacological activities could be rationalized from high-resolution structures that provide a novel template for the design of new agonists targeting the GLP-1R.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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