Metabolic independence drives gut microbial colonization and resilience in health and disease

Abstract

A detailed understanding of gut microbial ecology is essential to engineer effective microbial therapeutics and to model microbial community assembly and succession in health and disease. However, establishing generalizable insights into the functional determinants of microbial fitness in the human gut has been a formidable challenge. Here we employ fecal microbiota transplantation (FMT) as an in natura experimental model to identify determinants of microbial colonization and resilience. Our long-term sampling strategy and high-resolution multi-omics analyses of FMT donors and recipients reveal adaptive ecological processes as the main driver of microbial colonization outcomes after FMT. We also show that high-fitness donor microbial populations are significantly enriched in metabolic pathways that are responsible for the biosynthesis of nucleotides, essential amino acids, and micronutrients, independent of taxonomy. To determine whether such metabolic competence can explain the microbial ecology of human disease states, we analyzed genomes reconstructed from healthy humans and humans with inflammatory bowel disease (IBD). Our data reveal that such traits are also significantly enriched in microbial genomes recovered from IBD patients, linking presence of superior metabolic competence in bacteria to their expansion in IBD. Overall, these findings suggest that the transfer of gut microbes from a healthy donor to a disrupted recipient environment initiates an environmental filter that selects for populations that can self-sustain. Such ecological processes that select for self-sustenance under stress offer a model to explain why common yet typically rare members of healthy gut environments can become dominant in inflammatory conditions without any need for them to be causally associated with, or contribute to, such disease states.

Rare transmission of commensal and pathogenic bacteria in the gut microbiome of hospitalized adults

“…By contrast, adults have a microbiome that is relatively resistant to colonization with new organisms even after perturbation by antibiotics [19][20][21] . While adults living in the same household or in close-knit communities may have more similar microbes than those outside the group 22 , to our knowledge, direct transmission of gut microbes between adults has not been observed with high-resolution metagenomic methods, with the notable exception of fecal microbiota transplantation [23][24][25] , a drastic reshaping of the gut microbiota often used in response to Clostridiodes difficile infection. Transmission of gut microbiota is thought to occur by a fecal-oral route, which could happen in the hospital environment by exposure to contaminated surfaces or equipment, sharing a room or bathroom, contaminated hands of healthcare workers or other sources.…”

proovframe: frameshift-correction for long-read (meta)genomics

“…Genome W0 originated from the pre-FMT sample, whereas genomes W1 and W48 originated from 1-week and 48-weeks a ter FMT. e previous analysis of these data concluded that Akkermansia W0 is replaced by Akkermansia W1 a ter FMT and persisted in the recipient for at least 48 weeks 36 . Indeed, the genomes W1 and W48 resolved to Akkermansia muciniphila, and the pairwise genome-wide average nucleotide identity (gANI) between them was over 99.9%, confirming that these genomes likely represent the same population.…”

“…Akkermansia population W1 that replaces W0 is also reconstructed from Illumina short reads and named as DA_MAG_00110 in the original study 36 . We used Flye v2.6 -which includes one round of long-read consensus polishing -for long-read assembly 20 , Pilon v1.23 for short-read polishing 38 , and proovframe v0.9.6 for frame-shi t correction.…”

“…Since spurious amino acid sequences that emerge from frameshi t errors have a substantial impact on comparative genomics analyses, pangenomics o fers an ideal way to assess the e ficacy of any correction algorithm. We focused on three complete and circular genomes of the Verrucomicrobium Akkermansia, which we have assembled from the long-read sequencing of three fecal samples collected from a single individual who received Fecal Microbiota Transplantation (FMT) 36 .…”

Intraspecies strain exclusion, antibiotic pretreatment, and donor selection control microbiota engraftment after fecal transplantation

“…1A). Published across thirteen distinct studies, FMT was used to treat recurrent Clostridioides difficile infection (rCDI) (Watson et al 2021;Smillie et al 2018;Song et al 2013) (Podlesny et al, submitted), type 2 diabetes mellitus, obesity and metabolic syndrome (MetS) (Li et al 2016;Ng et al 2021;Wilson et al 2021), the inflammatory bowel diseases Crohn's disease and ulcerative colitis (IBD) (Kong et al 2020;Paramsothy et al 2019;Kump et al 2018), to eradicate multidrug-resistant Enterobacteriaceae carriage (MDR) (Bar-Yoseph et al 2020;Leo et al 2020), and to induce response to anti-PD-1 immunotherapy in immune checkpoint inhibitor therapy-refractory melanoma patients (ICI) (Davar et al 2021;Baruch et al 2021).…”