Linked read sequencing reveals the ecological resilience of a human gut microbial community during antibiotic treatment

Souradip Mallick, National Institute of Technology, Rourkela

The gastrointestinal metagenome is aggregation of all the genomes of gut microbiota. The gut flora is established after birth, by which time the intestinal epithelium and the intestinal mucosal barrier that it secretes developed its tolerance and also provides a barrier to pathogenic organisms. The relationship between gut flora and humans is not merely commensal but rather a mutualistic  relationship. Some human gut microorganisms benefit the host by fermenting  dietary fiber into short-chain fatty acids (SCFAs), such as acetic acid and butyric acid, which are then absorbed by the host. The response of these gut microbial communities to antibiotics plays a crucial role in their susceptibility to pathogens, the spread of antibiotic resistance genes, and their long-term stability. 

Linked read metagenomic sequencing was studied to identify the dynamics of single nucleotide variants within 36 different species and also to compare these dynamics with the broader ecological shifts at the species level. 

It was observed that antibiotic perturbations result in widespread shifts in the genetic composition of individual species at a higher overall rate than observed in healthy hosts. The genetic responses varied widely across species, with some resident populations acquiring thousands of consensus sequence differences, and others acquiring only a handful. Also some fluctuations were observed at both the species and SNV levels. Hence it was concluded that the response to doxycycline is not driven by discrete recolonization events, but rather, by the subtler processes of strain-level competition and evolution within the host.

At this population genetic level, observations suggested that the sweeping haplotypes may have been stably maintained in their respective populations over time, i.e. due to metabolic or spatial niches. This provides an explanation for the “oligo-colonization” structure which is observed in a variety of host microbial populations. 

There are some limitations in this study. As primary focus was on single nucleotide variants in well-behaved regions of reference genomes so many of the true targets of selection were missing, particularly in the case of antibiotic resistance. This creates difficulty to know what fraction of genetic changes are a direct response to antibiotics. It is even possible that nearly all of the mutations that were observed are simply passenger mutations that are hitchhiking alongside the true causative variants. These can be overcome by combining a read mapping approach with de novo genome assembly. The longer effective read lengths resolve genetic linkage in some species or genomic regions that contain high-levels of intra-host diversity. Thus alternative approaches like chromatin conformation capture (Hi-C) or linked-read sequencing of single cells offer advantages over traditional long-read sequencing .

In summary, these results provide new insights into the population genetic forces that shape individual microbiomes on therapeutically relevant timescales, with potential implications for personalized health and disease.

Also read: Variation of SARS-CoV-2 genomes in populations due to RNA editing enzymes

Source:- doi:https://doi.org/10.1101/2019.12.21.886093

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