Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort

Qin, Youwen; Havulinna, Aki S.; Liu, Yang; Jousilahti, Pekka; Ritchie, Scott C.; Tokolyi, Alex; Sanders, Jon G.; Valsta, Liisa; Brożyńska, Marta; Zhu, Qiyun; Tripathi, Anupriya; Vázquez-Baeza, Yoshiki; Loomba, Rohit; Cheng, Susan; Jain, Mohit; Niiranen, Teemu J.; Lahti, Leo; Knight, Rob; Salomaa, Veikko; Inouye, Michael; Méric, Guillaume

doi:10.1038/s41588-021-00991-z

Cited by 264 publications

(177 citation statements)

References 123 publications

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“…In humans, the ABO genotype affects susceptibility to various viral (including SARS-CoV-1 and 2), bacterial and protozoan pathogens 20 , 42 , 43 , and possibly the composition of the intestinal microbiota 21 – 23 . Invoked mechanisms are usually immune related, including pathogen adhesion, toxin binding, soluble decoys and natural antibodies 26 , 44 .…”

Section: Discussionmentioning

confidence: 99%

“…While this paper was in the last phase of the publication process two papers came out reporting an effect of ABO genotype on intestinal microbiota composition in human, albeit on distinct taxa 22 , 23 .…”

Section: Discussionmentioning

confidence: 99%

“…3b ). This is a strong candidate that modulates interactions with several pathogens 20 , and was recently suggested to affect the intestinal microbiota in healthy humans 21 – 23 . A 2.3 kb deletion encompassing the last exon has been reported in pigs 24 .…”

Section: A 35-million-year-old Deletion In the Pig Abo ...mentioning

confidence: 99%

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ABO genotype alters the gut microbiota by regulating GalNAc levels in pigs

Yang

Huang

et al. 2022

Nature

101

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The composition of the intestinal microbiome varies considerably between individuals and is correlated with health 1 . Understanding the extent to which, and how, host genetics contributes to this variation is essential yet has proved to be difficult, as few associations have been replicated, particularly in humans 2 . Here we study the effect of host genotype on the composition of the intestinal microbiota in a large mosaic pig population. We show that, under conditions of exacerbated genetic diversity and environmental uniformity, microbiota composition and the abundance of specific taxa are heritable. We map a quantitative trait locus affecting the abundance of Erysipelotrichaceae species and show that it is caused by a 2.3 kb deletion in the gene encoding N -acetyl-galactosaminyl-transferase that underpins the ABO blood group in humans. We show that this deletion is a ≥3.5-million-year-old trans-species polymorphism under balancing selection. We demonstrate that it decreases the concentrations of N -acetyl-galactosamine in the gut, and thereby reduces the abundance of Erysipelotrichaceae that can import and catabolize N -acetyl-galactosamine. Our results provide very strong evidence for an effect of the host genotype on the abundance of specific bacteria in the intestine combined with insights into the molecular mechanisms that underpin this association. Our data pave the way towards identifying the same effect in rural human populations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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ABO genotype alters the gut microbiota by regulating GalNAc levels in pigs

Yang

Huang

et al. 2022

Nature

101

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“…Network analysis built on LEfSe results indicated that the reduction of A. furcosa, P. cinnamivorans , and Defluviitalea saccarophila drove the loss of the microbiota structure in 6-OHDA+CFX mice, being responsible for the biodiversity decrease. Furthermore, P. cinnamivorans, A. furcosa, B. breve , and A. finegoldii were negatively correlated in the network analysis with R. lactaris , recently renamed Faecalicatena lactaris , a member of Clostridium cluster XIVa, a mucin-degrading commensal [ 39 ] that was strongly enriched in 6-OHDA+CFX mice. Although there is a lack of a well-defined role for R. lactaris , some studies associate its enrichment with both chronic gut inflammatory disease and neurodevelopmental disorders [ 40 , 41 , 42 ], suggesting a pro-inflammatory potential for this bacterial species.…”

Section: Discussionmentioning

confidence: 99%

Dual-Hit Model of Parkinson’s Disease: Impact of Dysbiosis on 6-Hydroxydopamine-Insulted Mice—Neuroprotective and Anti-Inflammatory Effects of Butyrate

Avagliano

Coretti

Lama

et al. 2022

IJMS

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Recent evidence highlights Parkinson’s disease (PD) initiation in the gut as the prodromal phase of neurodegeneration. Gut impairment due to microbial dysbiosis could affect PD pathogenesis and progression. Here, we propose a two-hit model of PD through ceftriaxone (CFX)-induced dysbiosis and gut inflammation before the 6-hydroxydopamine (6-OHDA) intrastriatal injection to mimic dysfunctional gut-associated mechanisms preceding PD onset. Therefore, we showed that dysbiosis and gut damage amplified PD progression, worsening motor deficits induced by 6-OHDA up to 14 days post intrastriatal injection. This effect was accompanied by a significant increase in neuronal dopaminergic loss (reduced tyrosine hydroxylase expression and increased Bcl-2/Bax ratio). Notably, CFX pretreatment also enhanced systemic and colon inflammation of dual-hit subjected mice. The exacerbated inflammatory response ran in tandem with a worsening of colonic architecture and gut microbiota perturbation. Finally, we demonstrated the beneficial effect of post-biotic sodium butyrate in limiting at once motor deficits, neuroinflammation, and colon damage and re-shaping microbiota composition in this novel dual-hit model of PD. Taken together, the bidirectional communication of the microbiota–gut–brain axis and the recapitulation of PD prodromal/pathogenic features make this new paradigm a useful tool for testing or repurposing new multi-target compounds in the treatment of PD.

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“…It is now well established that the microbiome can modulate host phenotype ( 2 , 3 ). The host immune system constantly interacts with the microbiome ( 4 , 5 ), and there is mounting evidence that the underlying host genotype can influence microbiome composition ( 6 , 7 ). Thus, emerging hologenomic theory posits that the genomes of the host and all its associated microorganisms are subject to coevolutionary forces and should be viewed as a “holobiont” rather than as independently evolving organisms ( 8 ).…”

Section: Introductionmentioning

confidence: 99%