The comings and goings of the healthy human gut microbiota
Authors: Ilana L. Brito
Journal: Cell Host & Microbe (2021)

SNP-level analysis of 5,000+ metagenomic samples enabled Hildebrand et al., 2021Hildebrand F. Gossmann T.I. Frioux C. Özkurt E. Myers P.N. Ferretti P. Kuhn M. Bahram M. Nielsen H.B. Bork P. Dispersal strategies shape persistence and evolution of human gut bacteria.Cell Host Microbe. 2021; 29 (S1931-3128(21)00236-5)https://doi.org/10.1016/j.chom.2021.05.008Abstract Full Text Full Text PDF Scopus (14) Google Scholar to identify human gut microbiota by their dispersal strategies in this issue of Cell Host & Microbe. This brings us a step closer in understanding how microbial communities are formed and maintained and also hints at ways in which microbiomes can be manipulated to improve human health. SNP-level analysis of 5,000+ metagenomic samples enabled Hildebrand et al., 2021Hildebrand F. Gossmann T.I. Frioux C. Özkurt E. Myers P.N. Ferretti P. Kuhn M. Bahram M. Nielsen H.B. Bork P. Dispersal strategies shape persistence and evolution of human gut bacteria.Cell Host Microbe. 2021; 29 (S1931-3128(21)00236-5)https://doi.org/10.1016/j.chom.2021.05.008Abstract Full Text Full Text PDF Scopus (14) Google Scholar to identify human gut microbiota by their dispersal strategies in this issue of Cell Host & Microbe. This brings us a step closer in understanding how microbial communities are formed and maintained and also hints at ways in which microbiomes can be manipulated to improve human health. A remarkable aspect of the gut microbiome of a healthy individual is just how stable it is. Despite daily changes in food sources, alcohol consumption, sleeping habits, and other behaviors shown to affect microbiome composition, barring major perturbations (e.g., antibiotics or infection), 90% of the gut strains persist over a year and roughly 60% persist over 5 years (Faith et al., 2013Faith J.J. Guruge J.L. Charbonneau M. Subramanian S. Seedorf H. Goodman A.L. Clemente J.C. Knight R. Heath A.C. Leibel R.L. et al.The long-term stability of the human gut microbiota.Science. 2013; 341: 1237439Crossref PubMed Scopus (1139) Google Scholar). Stability itself is thought to be an important characteristic feature of a healthy human gut, promoting both resistance to infection and long-term resilience. This finding is now quite robust with more extensive metagenomic sequencing efforts and recent advances in bioinformatics assembly and SNP-calling developments. This observation prompts a follow-up question—how is this stability maintained? Numerous host-derived factors contribute to stability, including host behaviors, genetics, and immune pressures. Yet, individual species may harbor specific traits that confer stability, via dispersal, colonization, and maintenance (Figure 1). Whereas stability is often assessed as a gross metric describing a microbial community over time, Hildebrand and colleagues, in this issue of Cell Host & Microbe, turned their attention toward classifying specific steadfast versus volatile microbiota (Hildebrand et al., 2021Hildebrand F. Gossmann T.I. Frioux C. Özkurt E. Myers P.N. Ferretti P. Kuhn M. Bahram M. Nielsen H.B. Bork P. Dispersal strategies shape persistence and evolution of human gut bacteria.Cell Host Microbe. 2021; 29 (S1931-3128(21)00236-5)https://doi.org/10.1016/j.chom.2021.05.008Abstract Full Text Full Text PDF Scopus (14) Google Scholar). By analyzing more than 5,000 metagenomes, they were able to identify organisms with high persistence (durable colonization), high resilience (repeated colonization), and lower persistence across individuals. In addition to accounting for these functional attributes, metagenomic assembled genomes has allowed for polymorphism-level examination of evolutionary evidence within genomes (i.e., rates of non-synonymous to synonymous mutation, effective population size, and bottlenecks) that can further disentangle the dispersal of individual strains. By accounting for these evolutionary signatures, as well as the geographic and familial distribution of individual strains, they were next able to label bacterial and archeael species as to whether they exploit vertical or horizontal modes of transmission. Dispersal strategies for specific clades of bacteria identified by Hildebrand and colleagues are consistent with those found in several previous studies. The archeae Methanobrevibacter, which they find has high heredipersistence, has been shown previously to circulate among twin siblings (Goodrich et al., 2014Goodrich J.K. Waters J.L. Poole A.C. Sutter J.L. Koren O. Blekhman R. Beaumont M. Van Treuren W. Knight R. Bell J.T. et al.Human genetics shape the gut microbiome.Cell. 2014; 159: 789-799Abstract Full Text Full Text PDF PubMed Scopus (1638) Google Scholar); and Bacteroides species, which they find to be "tenacious," a term they use to describe persistent organisms with high phylogeography and familial transmission, tend to be transmitted vertically even in wild mice species (Moeller et al., 2018Moeller A.H. Suzuki T.A. Phifer-Rixey M. Nachman M.W. Transmission modes of the mammalian gut microbiota.Science. 2018; 362: 453-457Crossref PubMed Scopus (105) Google Scholar). Hildebrand and colleagues extend these observations to more than 400 well-represented strains. The traits they highlighted—oxygen tolerance and sporulation—are thought to promote a persistence in the environment or among additional hosts and therefore greater dependence on horizontal transmission paths. A wider variety of traits are likely involved in other aspects of gut microbiota persistence. Some may favor a single transmission route, such as genes involved in pH or osmotic stress responses or attachment to a type of particle; host colonization may require certain adhesion factors; and maintenance within a host may involve genes involved in immune evasion, metabolism, or microbial antagonism, to suggest a few. Seminal studies addressing this question have applied powerful knock-in or knock-out approaches. For example, a metagenomic screening approach found that mucin and polysaccharide utilization, in addition to stress response pathways, promoted colonization of the murine host (Crook et al., 2019Crook N. Ferreiro A. Gasparrini A.J. Pesesky M.W. Gibson M.K. Wang B. Sun X. Condiotte Z. Dobrowolski S. Peterson D. Dantas G. Adaptive Strategies of the Candidate Probiotic E. coli Nissle in the Mammalian Gut.Cell Host Microbe. 2019; 25: 499-512.e8Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). This further suggests the causes for the tenacity of Bacteroides species, well known for their enrichment in carbohydrate utilization loci. Transposon mutagenesis of human microbes introduced into a mouse harboring a simplified human microbiome has revealed traits involved in nutrient competition as those most important for host colonization (Goodman et al., 2009Goodman A.L. McNulty N.P. Zhao Y. Leip D. Mitra R.D. Lozupone C.A. Knight R. Gordon J.I. Identifying genetic determinants needed to establish a human gut symbiont in its habitat.Cell Host Microbe. 2009; 6: 279-289Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar). Such experiments are bridging what we know about the genetic traits that bestow pathogens with enhanced transmission and colonization with those features exploited by commensals within the gut. Equipped with this characterization of bacteria, we can now ask about specifics regarding the stability and transmission of the gut microbiota. For example, what behaviors promote the inter-personal transmission of microbes? Daily sampling of the microbiota shows that punctuated events such as illness result in large numbers of replacement events, but large dietary shifts do not (David et al., 2014David L.A. Materna A.C. Friedman J. Campos-Baptista M.I. Blackburn M.C. Perrotta A. Erdman S.E. Alm E.J. Host lifestyle affects human microbiota on daily timescales.Genome Biol. 2014; 15: R89Crossref PubMed Scopus (485) Google Scholar). And do they tend to involve individual organisms or groups? Evidence from fecal microbiota transplantation suggests that closely related strains colonize together (Smillie et al., 2018Smillie C.S. Sauk J. Gevers D. Friedman J. Sung J. Youngster I. Hohmann E.L. Staley C. Khoruts A. Sadowsky M.J. et al.Strain Tracking Reveals the Determinants of Bacterial Engraftment in the Human Gut Following Fecal Microbiota Transplantation.Cell Host Microbe. 2018; 23: 229-240.e5Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Re-analysis of these findings in light of these newly defined categories may prompt greater investigation into mechanisms fostering persistence. For example, knowing which organisms follow heredipersistent versus spatiopersistent strategies may help explain and predict the large changes in the microbiome observed in first- or second-generation immigrants (Vangay et al., 2018Vangay P. Johnson A.J. Ward T.L. Al-Ghalith G.A. Shields-Cutler R.R. Hillmann B.M. Lucas S.K. Beura L.K. Thompson E.A. Till L.M. et al.US Immigration Westernizes the Human Gut Microbiome.Cell. 2018; 175: 962-972.e10Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). Likewise, it will be important to determine what role dispersal strategies play in the microbiomes of patients with various diseases. The authors show that children acquire an increasing number of persistent organisms in their gut microbiomes until around age 10, furthering the notion that these long-held organisms serve as a "second genome." But in light of this long-standing homeostasis, how can this framework for understanding dispersal strategies in the gut help explain compositional changes in the context of disease? The maintenance of Bacteroides species have been shown to be important for the aging gut (Wilmanski et al., 2021Wilmanski T. Diener C. Rappaport N. Patwardhan S. Wiedrick J. Lapidus J. Earls J.C. Zimmer A. Glusman G. Robinson M. et al.Gut microbiome pattern reflects healthy ageing and predicts survival in humans.Nat Metab. 2021; 3: 274-286Crossref PubMed Scopus (64) Google Scholar), but persistent bacteria within the inflamed gut may differ more widely than those in the healthy human gut and likely rely on an orthogonal set of colonization factors to be maintained. In addition to obtaining a better grasp on the evolution of host-microbiota interactions, these findings can be leveraged to improve human health interventions. Tenacious bacteria, which the authors define as those species with high levels of persistence and transmission across family and geography, are also those with higher population levels and have evolutionary patterns consistent with host adaptation. At the same time, these may be the most susceptible to antibiotic perturbations. These include the most abundant members of the gut microbiome, members of the genera Bacteroides and Prevotella. The authors postulate that these organisms may be easier to replace post-antibiotic exposure, suggesting that selected strains of Bacteroides or genetically modified Bacteroides may colonize more successfully than those implemented with other species, such as Lactobacilli, which exhibit lower persistence. Overall, a better grasp on the persistence and dispersal strategies of gut microbiota, both in terms of the taxa and ultimately the mechanisms at play, will inform our knowledge of the evolution and assembly of the gut microbiome and will aid in designing therapeutic manipulations of our gut communities. Dispersal strategies shape persistence and evolution of human gut bacteriaHildebrand et al.Cell Host & MicrobeJune 9, 2021In BriefHildebrand et al., investigated strategies of bacterial persistence using publicly available time series metagenomes from stool samples. They found that three major dispersal strategies underlie human gut bacterial persistence. These have distinct evolutionary patterns such as the accumulation of rare variation and differences in their strength of selection. Full-Text PDF Open Access