Large-scale association analyses identify host factors influencing human gut microbiome composition

Kurilshikov, Alexander; Medina‐Gomez, Carolina; Bacigalupe, Rodrigo; Radjabzadeh, Djawad; Wang, Jun; Demirkan, Ayşe; Roy, Caroline; Garay, Juan A. Raygoza; Finnicum, Casey T.; Liu, Xingrong; Zhernakova, Daria V.; Bonder, Marc Jan; Hansen, Torben; Frost, Fabian; Rühlemann, Malte; Turpin, Williams; Moon, Jee-Young; Kim, Hanna; Lüll, Kreete; Barkan, Elad; Shah, Shiraz A.; Fornage, Myriam; Szopinska-Tokov, Joanna; Wallen, Zachary D.; Borisevich, Dmitrii; Agréus, Lars; Andréasson, Anna; Bang, Corinna; Bedrani, Larbi; Bell, Jordana T.; Bisgaard, Hans; Boehnke, Michael; Boomsma, Dorret I.; Burk, Robert D.; Claringbould, Annique; Croitoru, Kenneth; Davies, Gareth E.; Duijn, Cornelia M. van; Duijts, Liesbeth; Falony, Gwen; Fu, Jingyuan; Graaf, Adriaan van der; Homuth, Georg; Hughes, David A.; IJzerman, Richard G.; Jackson, Matthew A.; Jaddoe, Vincent W.V.; Joossens, Marie; Joergensen, Torben; Keszthelyi, Dániel; Knight, Rob; Laakso, Markku; Laudes, Matthias; Launer, Lenore J.; Lieb, Wolfgang; Lusis, Aldons J.; Masclee, Ad; Moll, Henriëtte A.; Mujagic, Zlatan; Qi, Qibin; Rothschild, Daphna; Shin, Hocheol; Sørensen, Søren J.; Steves, Claire J.; Thorsen, Jonathan; Timpson, Nicholas J.; Tito, Raúl Y.; Vieira-Silva, Sara; Voelker, Uve; Voelzke, Henry; Võsa, Urmo; Wade, Kaitlin H; Walter, Susanna; Watanabe, Kyoko; Weiß, Stefan; Weiß, Frank Ulrich; Weissbrod, Omer; Westra, Harm-Jan; Willemsen, Gonneke; Payami, Haydeh; Jonkers, Daisy; Vásquez, Alejandro Arias; Geus, E.J.C. de; Meyer, Katie A.; Stokholm, Jakob; Segal, Eran; Org, Elin; Wijmenga, Cisca; Kim, Hyung-Lae; Kaplan, Robert C.; Spector, Timothy D.; Uitterlinden, André G.; Rivadeneira, Fernando; Franke, André; Lerch, Markus M.; Franke, Lude; Sanna, Serena; D’Amato, Mauro; Pedersen, Oluf; Paterson, Andrew D.; Kraaij, Robert; Raes, Jeroen; Zhernakova, Alexandra

doi:10.1101/2020.06.26.173724

Cited by 22 publications

(39 citation statements)

References 90 publications

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“…These results recapitulate recent evidence for an mbQTL effect of this locus on the Collinsella genus and on other bacteria reported for a Finnish population cohort 18 . Associations of a functional variant in the FUT2 gene to other bacterial taxa were observed in a recent meta-analysis, but none of these bacterial taxa or pathways showed significant association for this locus in our cohort 13 .…”

Section: Introductionsupporting

confidence: 45%

“…However, reproducibility of these findings has been limited by differences in data processing methodologies, modest sample sizes and strong environmental effects, which, taken together, limit the detection of robust host genetic associations 12 . A recent large-scale genomewide meta-analysis of 24 cohorts replicated the association between Bifidobacterium abundance and the lactase (LCT) gene locus 13 , which had previously only been reported in single-cohort studies 6,14 . Other suggestive mbQTLs identified in this broad meta-analysis were proportional to heritability estimates from independent twin studies, indicating that additional loci found at lenient levels of significance are likely to be real but that larger sample sizes are needed to reach sufficient statistical power 13 .…”

Section: Introductionmentioning

confidence: 64%

“…We sought to replicate our genome-wide significant signals using summary statistics from other independent cohorts in which microbiome data was characterized using either 16S rRNA (MiBioGen study) 13 or metagenomic sequencing (LL-DEEP cohort) 17 . In the MiBioGen study, a meta-analysis of 24 cohorts comprising up to 18,340 individuals, 16S rRNA measurements do not allow for the evaluation of abundance of bacterial species and pathways and the X chromosome was not analyzed.…”

Section: Association Signals Reveal a Polygenic Architecture Of Micromentioning

confidence: 99%

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Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

Lopera-Maya

Kurilshikov

Graaf

et al. 2020

Preprint

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Host genetics are known to influence the gut microbiome, yet their role remains poorly understood. To robustly characterize these effects, we performed a genome-wide association study of 207 taxa and 205 pathways representing microbial composition and function within the Dutch Microbiome Project, a population cohort of 7,738 individuals from the northern Netherlands. Two robust, study-wide significant (p<1.89×10−10) signals near the LCT and ABO genes were found to affect multiple microbial taxa and pathways, and were replicated in two independent cohorts. The LCT locus associations were modulated by lactose intake, while those at ABO reflected participant secretor status determined by FUT2 genotype. Eighteen other loci showed suggestive evidence (p<5×10−8) of association with microbial taxa and pathways. At a more lenient threshold, the number of loci identified strongly correlated with trait heritability, suggesting that much larger sample sizes are needed to elucidate the remaining effects of host genetics on the gut microbiome.

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Section: Introductionsupporting

confidence: 45%

Section: Introductionmentioning

confidence: 64%

Section: Association Signals Reveal a Polygenic Architecture Of Micromentioning

confidence: 99%

See 1 more Smart Citation

Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

Lopera-Maya

Kurilshikov

Graaf

et al. 2020

Preprint

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“…While genus Methanobrevibacter has been consistently found to have a moderate heritability the TwinsUK (19,46,66) and other cohorts (48,67), it was not the case for members of Methanomassiliicoccales. Similar to humans, methane production (68) and abundance of Methanobrevibacter (69) are also heritable in bovine cattle, but not Methanomassiliicoccales taxa (69).…”

Section: Discussionmentioning

confidence: 89%

Genomic insights into adaptations of TMA-utilizing methanogens to diverse habitats including the human gut

Cuesta-Zuluaga

Spector

Youngblut

et al. 2020

Preprint

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Archaea of the order Methanomassiliicoccales use methylated-amines such as trimethylamine as a substrate for methane production. They form two large phylogenetic clades and reside in diverse environments, from soil to the human gut. Two genera, one from each clade, inhabit the human gut: Methanomassiliicoccus, which has one cultured representative, and “candidatus Methanomethylophilus”, which has none. Questions remain regarding their distribution across different biomes and human populations, their association with other taxa in the human gut, and whether host genetics correlate with their abundance. To gain insight into the Methanomassiliicoccales, and the human-associated members in particular, we performed a genomic comparison of 72 Methanomassiliicoccales genomes and assessed their presence in metagenomes derived from the human gut (n=4472 representing 25 populations), nonhuman animal gut (n=145) and nonhost environments (n=160). Our analyses showed that all taxa are generalists: they were detected in animal gut and environmental samples. We confirmed two large clades, one enriched in the gut, the other enriched in the environment, with notable exceptions. Genomic adaptations to the gut include genome reduction, a set of adhesion factors distinct from that of environmental taxa, and genes involved in the shikimate pathway and bile resistance. Genomic adaptations differed by clade, not habitat preference, indicating convergent evolution between the clades. In the human gut, the relative abundance of Methanomassiliicoccales correlated with trimethylamine-producing bacteria and was unrelated to host genotype. Our results shed light on the microbial ecology of this group may help guide Methanomassiliicoccales-based strategies for trimethylamine mitigation in cardiovascular disease.ImportanceMethanomassiliicoccales are a lesser known component of the human gut microbiota. This archaeal order is composed of methane producers that use methylated amines, such as trimethylamine, in methane production. This group has only one cultured representative; how they adapted to inhabit the mammalian gut and how they interact with other microbes is largely unknown. Using bioinformatics methods applied to DNA from a wide range of samples, we profiled the relative abundances of these archaea in environmental and host-associated microbial communities. We observed two groups of Methanomassiliicoccales, one largely host-associated and one largely found in environmental samples, with some exceptions. When host-associated, these archaea have a distinct set of genes related to adhesion and possess genes related to bile resistance. We did not detect Methanomassiliicoccales in all human populations tested but when present, they are correlated with Bacteria known to produce trimethylamine. Since trimethylamine is linked to cardiovascular disease risk, these intriguing Archaea may also be involved.

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Section: Discussionmentioning

confidence: 94%

AB0971 Combination of hyaluronate and sodium succinate in treatment of knee osteoarthritis

et al. 2018

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BackgroundAt present hyaluronic acid (HA) is rather widely used in treatment of patients with osteoarthritis (OA). HA normalises the properties of the synovial fluid; has a protective effects; promotes the cartilage nutrition and so improves the signs of OA and function of the joints. To the contrary the effects of sodium succinate (the salt of the succinic acid) are not investigated but can be promising in OA treatment due to its known anti hypoxic and energetic properties.ObjectivesTo investigate the clinical efficacy of combination of hyaluronate and sodium succinate in OA treatment in early stages.MethodsThe study included 126 patients with knee OA (stages I-II, Kelgren and Lawrence), mean age (54.3±2.7) years, among them – 75 women(60%) and 51 men(40%). All enrolled patients had OA exacerbation (without clinically evident synivitis) and received standard OA treatment (NSAIDs, exercises, orthopaedic devices) for 15 days; Gr.1 patients (58) also got 5 intra-articular injections of 1.1% hyaluronic acid, stabilised with sodium succinate (2 ml, once a week); patients of Gr.2 (68) in addition to standard treatment received 5 intra-articular injections of 1,1% solution of non-stabilised HA (2 ml, once a week). Clinical observation and evaluation of the results were performed at the beginning of the treatment, at 6th, 12th and 24th week after the study beginningResultsDuring the treatment period, patients in both groups showed the positive changes in clinical signs and symptoms of OA. The VAS score in both groups indicated a significant pain reduction, but the stability and duration of the clinical effect in the groups was different. In patients of Gr.1, the pain syndrome continued to decrease after 12 weeks till 24th week, whereas in Gr.2 after the treatment course there was no significant changes in further pain regression after 6th week point. The general WOMAC index was decreased from (78.3±4.1) in Gr. 1 and (75.4±3.8) in Gr. 2 at the beginning of the study to (27.9±2.6) and (29.8±1.9) accordingly at week 12, p<0,05. The changes in Lisholm score were also significantly better in Gr.1 than in Gr. 2 (before treatment (21.7±4.6) and (22.6±5.3), at week 6 – (86.4±5.7) and (71.3±4.8), at week 12 – (87.6±6.2) and (63.8±5.3), respectively, p<0,05.ConclusionsCombination of the hyaluronic acide and sodium succinate in early stages of knee OA (as intra-articular injections) allows to increase the treatment efficacy. Add of sodium succinate to hyaluronic acide achieve better pain control and longer remission.Disclosure of InterestNone declared

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Large-scale association analyses identify host factors influencing human gut microbiome composition

Cited by 22 publications

References 90 publications

Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

Genomic insights into adaptations of TMA-utilizing methanogens to diverse habitats including the human gut

AB0971 Combination of hyaluronate and sodium succinate in treatment of knee osteoarthritis

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