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Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome.
Rühlemann, MC, Hermes, BM, Bang, C, Doms, S, Moitinho-Silva, L, Thingholm, LB, Frost, F, Degenhardt, F, Wittig, M, Kässens, J, et al
Nature genetics. 2021;(2):147-155
Abstract
The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory1,2, neurologic3 and neoplastic diseases4. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain5-11. Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition11. In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a 'metaorganism' broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management.
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Reporting guidelines for human microbiome research: the STORMS checklist.
Mirzayi, C, Renson, A, , , , , Zohra, F, Elsafoury, S, Geistlinger, L, Kasselman, LJ, Eckenrode, K, van de Wijgert, J, et al
Nature medicine. 2021;(11):1885-1892
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Abstract
The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.
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Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.
Pryor, R, Norvaisas, P, Marinos, G, Best, L, Thingholm, LB, Quintaneiro, LM, De Haes, W, Esser, D, Waschina, S, Lujan, C, et al
Cell. 2019;178(6):1299-1312.e29
Abstract
Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.
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Application of the distance-based F test in an mGWAS investigating β diversity of intestinal microbiota identifies variants in SLC9A8 (NHE8) and 3 other loci.
Rühlemann, MC, Degenhardt, F, Thingholm, LB, Wang, J, Skiecevičienė, J, Rausch, P, Hov, JR, Lieb, W, Karlsen, TH, Laudes, M, et al
Gut microbes. 2018;(1):68-75
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Abstract
Factors shaping the human intestinal microbiota range from environmental influences, like smoking and exercise, over dietary patterns and disease to the host's genetic variation. Recently, we could show in a microbiome genome-wide association study (mGWAS) targeting genetic variation influencing the β diversity of gut microbial communities, that approximately 10% of the overall gut microbiome variation can be explained by host genetics. Here, we report on the application of a new method for genotype-β-diversity association testing, the distance-based F (DBF) test. With this we identified 4 loci with genome-wide significant associations, harboring the genes CBEP4, SLC9A8, TNFSF4, and SP140, respectively. Our findings highlight the utility of the high-performance DBF test in β diversity GWAS and emphasize the important role of host genetics and immunity in shaping the human intestinal microbiota.
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Henström, M, Diekmann, L, Bonfiglio, F, Hadizadeh, F, Kuech, EM, von Köckritz-Blickwede, M, Thingholm, LB, Zheng, T, Assadi, G, Dierks, C, et al
Gut. 2018;67(2):263-270
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Plain language summary
Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder which results in a lower ability to digest certain sugars, resulting in diarrhoea, abdominal pain and bloating, which are also common symptoms of Irritable Bowel Syndrome (IBS). The objective of this study was to test sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. The researchers looked at genetics in several populations with and without IBS. The researchers found that genetic mutations are associated with a 35% reduction in the activity of the SI enzymes. CSID mutations were almost twice as common in IBS patients than healthy controls. The genetic variant 15Phe was associated with diarrhoea, stool frequency and changes in the gut bacteria. The authors concluded that people with SI gene variants associated with reduced enzyme activity are more at risk of IBS. Genetic screening could help to identify individuals at increased risk of IBS, and may lead to more targeted treatment for some people with IBS.
Abstract
OBJECTIVE IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. DESIGN We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. RESULTS CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). CONCLUSIONS SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.