Genotype influences the intestinal microbiotia composition
It is increasingly recognized that our health and well-being depend on the symbiotic relationship that we entertain with our multiple microflora (also known as microbiota), especially that of our intestines. Amongst others, our intestinal microflora predigests food, provides us with vitamins and protects us from harmful infections. The composition of the intestinal microbiota differs quite a bit between individuals. This is due to individual factors such as age, and to various behavioral and environmental factors including diet.
Aquestion that has intrigued scientists is to what extend the composition of the intestinal microbiota is determined by our genes, i.e. to what extend it is “heritable”. Could it be that our genes determine the composition of our microbiota which determines our health? In other words, how much of inherited predisposition to disease is mediated by our microbiota? Thus far, studies in humans have been rather confusing. Except for the effect of genetic variants that allow some human populations (including Europeans) to digest milk after weaning (intestinal lactase persistence) and decrease the abundance of Bifidobacterium, all other associations that have been reported have not been replicated. This is most likely due to the fact genetics plays a minor role in shaping the human microbiota, and… statistical shortcomings.
In 2019 Michel Georges and Carole Charlier were awarded a fellowship from the Chinese One Thousand Talents program. They were going to work for three years in collaboration with Prof. Lusheng Huang from Jiangxi Agricultural University in Nanchang. Over the last ten years, Lusheng Huang had assembled an amazing resource population comprising thousands of pigs that have been completely sequenced and characterized in utmost detail for hundreds of phenotypes including the composition of the intestinal microbiota.
Primarily working with one postdoctoral fellow (Hui Yang) and three PhD students (Jinyuan Wu, Yunyan Zhou and Yifeng Zhang) from Nanchang, Michel Georges, Congying Chen and Lusheng Huang embarked on studying the effect of host genetics on microbiota composition. The team first showed that – in this quite unique population (with more genetic variation than between modern human and Neanderthal, yet in which all animals have identical diet) – microbiota composition is indeed heritable. They were then able to map a locus in the genome that has a major effect on the abundance of a specific group of bacteria that are part of the family Erysipelotrichaceae. They demonstrated that the variant causing this effect is a deletion in the gene that in human underpins the ABO blood group. The deletion creates an allele that is equivalent to the human O blood type, while the other allele is equivalent to the human A type.
How does blood group affect microbiota composition? The A allele encodes a glycosyltransferase that adds an additional sugar, known as GalNAc, to various glycoproteins. The O allele has lost this activity. While the ABO gene is primarily known for its effect on red cells in the blood, one of its primary substrates is in fact the mucus that lines our intestinal tract. Thus, humans and pigs with A blood type have a more “sugary” mucus that those with O type. Indeed, the team showed by mass spectrometry that the concentration of GalNAc in the intestine of A-type pigs was double that in O-type pigs and – by using a special statistical approach – that this was causing the effect on the abundance of the sub-strain of Erysipelotrichaceae.
They reasoned that the bacteria that are affected by AO type of the pigs might be using GalNAc as carbon source. These bacteria would thus fare better in the guts of A-type than of O-type animals. Hui Yang and Jinyuan Wu cloned the corresponding bacteria and sequenced their entire genome as well as that of 3,000 other intestinal bacteria. It was immediately apparent that the AO-responsive Erysipelotrichaceae were quite unique in that their genome encoded all enzymes needed to fulfil the five key steps in GalNAc import and catabolism (otherwise only observed in 3% of bacterial genomes). To confirm this, they fed the bacteria with 13C-labelled GalNAc and indeed showed that 13C entered central metabolism.
Yet 3% of all intestinal bacteria is still quite a number. Why are these other species not AO-responsive? E. coli for instance is capable of utilizing GalNAc as well. A more detailed examination of the genomes revealed a hint. In E.coli the genes encoding the enzymes composing the GalNac import and catabolic pathway are clustered and on the same strand, forming a mono-cistronic transcriptional unit that is under tight control by a GalNAc repressor: E. coli will only activate this operon if GalNAc is present in the medium. In the AO-responsive Erysipelotrichaceae, on the contrary, the corresponding genes are spread over a 5-fold larger chromosome region, transcribed from both strands, and not controlled by a repressor. This suggests that this operon is not inducible and this was demonstrated experimentally. This led the authors to revise their hypothesis: it is more likely that the AO-responsive Erysipelotrichaceae are penalized in O-type animals because transcribing and translating useless genes.
We share the ABO blood group with pigs; why wasn’t this “microbiota QTL” previously found in humans? The reason is probably that thus far all studies conducted in humans used “city-dwellers”. The strains of Erysipelotrichaceae that were shown to be AO-responsive in pigs are virtually absent in the intestine of townspeople. However, they are found in the intestines of other subsistence groups, particularly pastoralists. The authors therefore predict that if looking at the right human populations the same effect will be found. It is noteworthy, that the human ABO polymorphism is more than 10 million years old, as the same alleles are shared between humans and Old-World monkeys. This balanced polymorphism is probably due to the role that the ABO blood group plays in resistance to infectious diseases (as confirmed recently for COVID). The authors showed that the same applies to Suidae. The pig O allele is at least 3.5 million years old, probably 10 million.
This study is probably the most convincing evidence thus far of a clear effect of host genotype on intestinal microbiota composition, all species confounded. Moreover, and quite uniquely, it comes with a detailed dissection of the molecular mechanisms that underpin the observed association.
Source
ABO genotype alters the gut microbiota by regulating GalNAc levels in pigs
Hui Yang, Jinyuan Wu, Xiaochang Huang, Yunyan Zhou, Yifeng Zhang, Min Liu, Qin Liu, Shanlin Ke, Maozhang He, Hao Fu, Shaoming Fang, Xinwei Xiong, Hui Jiang, Zhe Chen, Zhongzi Wu, Huanfa Gong, Xinkai Tong, Yizhong Huang, Junwu Ma, Jun Gao, Carole Charlier, Wouter Coppieters, Lev Shagam, Zhiyan Zhang, Huashui Ai, Bin Yang, Michel Georges, Congying Chen & Lusheng Huang
