Our understanding of microbial evolution and diversification has been enriched by experimental studies of bacterial isolates in the laboratory, but it remains a challenge to study evolution in the context of more complex communities (Lenski, 2017). Ongoing advances in culture-independent technologies have allowed us to study bacteria in the complex and dense communities in which they naturally occur (Garud and Pollard, 2020). Within a community, individual players engage in many negative and positive ecological interactions. Negative interactions can originate from competition for resources and biomolecular warfare (Hibbing et al., 2010; Mitri and Foster, 2013), while positive interactions can stem from secreted metabolites that are used by other members of the community (cross-feeding) (Venturelli et al., 2018). These ecological interactions can create new niches and selective pressures, leading to eco-evolutionary feedbacks whose nature are yet to be fully understood.

Ecological interactions can yield positive or negative effects on the diversification of a focal species. Under the ‘diversity begets diversity’ (DBD) hypothesis, higher levels of community diversity increase the rate of speciation (or diversification, more generally) due to positive feedback mechanisms such as niche construction (Calcagno et al., 2017; Schluter and Pennell, 2017). Competition for limited niche space could also drive DBD if species diversify into new niches to avoid competition (Meyer and Kassen, 2007; Mitri and Foster, 2013; Schluter, 2000). By contrast, the ‘ecological controls’ (EC) hypothesis posits that competition for a limited number of niches at high levels of community diversity results in a negative effect on further diversification. Metabolic models predict that DBD may initially spur diversification due to cross-feeding, but the diversification rate eventually slows and reaches a plateau as metabolic niches are filled (San Roman and Wagner, 2021). These theoretical predictions are largely supported by our previous study involving 16S rRNA gene amplicon sequencing data from the Earth Microbiome Project, in which we observed a generally positive relationship (which we call the diversity slope; Figure 1) between community diversity and focal-taxon diversity at most taxonomic levels, reaching a plateau at the highest levels of diversity (Madi et al., 2020).

Figure 1

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In this previous study, we found stronger support for DBD in the animal gut relative to more diverse microbiomes such as soils and sediments, which were closer to a plateau of diversity (Madi et al., 2020). While diversity slopes were generally positive at taxonomic levels as fine as amplicon sequence variants (akin to species or strains) within a genus, they were most positive at higher levels such as classes or phyla. A recent experiment on soil bacteria also found evidence of DBD at the family level, likely driven by niche construction and metabolic cross-feeding (Estrela et al., 2022). It therefore remains unclear if the predictions of DBD hold primarily at these higher taxonomic levels, involving the ecological process of community assembly, or if they also apply at the finer intra-species level. Within-host intra-species diversity can arise by co-colonization of a host by genetically distinct strains belonging to the same species or evolutionary diversification of a lineage via de novo mutation and gene gain/loss events within a host.

Such fine-scale strain-level variation has important functional and ecological consequences; among other things, strains are known to engage in interactions that cannot be predicted from their species identity alone (Goyal et al., 2022). Although closely-related bacteria are expected to have broadly similar niche preferences, finer-scale niches may differ below the species level (Martiny et al., 2015). For example, the acquisition of a carbohydrate-active enzyme by Bacteroides plebeius allows it to exploit a new dietary niche in the guts of people consuming nori (seaweed) (Hehemann et al., 2010), and single nucleotide adaptations permit Enterococcus gallinarum translocation across the intestinal barrier resulting in inflammation (Yang et al., 2022). Despite their potential phenotypic effects, it is unknown if such fine-scale genetic changes are favored by higher community diversity (due, for example, to niche construction, as predicted by DBD) or suppressed (due to competition for limited niche space, as predicted by EC). Competition could also lead to DBD if focal species evolve new niche preferences to avoid extinction (Mitri and Foster, 2013; Schluter, 2000) – an idea with some support in experimental microcosms (Meyer and Kassen, 2007) but largely unexplored in natural communities.

Here, we investigate the relationship between intra-species genetic diversity and community diversity in the human gut microbiome, a well-studied system in which we previously found support for DBD at higher taxonomic levels. We use static and temporal shotgun metagenomic data from a large panel of healthy adult hosts from the Human Microbiome Project (HMP) (Lloyd-Price et al., 2017; Human Microbiome Project Consortium, 2012) as well as from four healthy individuals sampled almost daily over the course of 1 year (Poyet et al., 2019). Using metagenomic data allows us to track change in single nucleotide variation, strain diversity, and gene gain or loss events within relatively abundant species in the microbiome, and to study how these measures of intra-species diversity are associated with community diversity. Although such analyses of natural diversity cannot fully control for unmeasured confounding environmental factors, they are an important complement to controlled experimental and theoretical studies which lack real-world complexity.

We investigated the relationship between community diversity and within-species genetic diversity in human gut microbiota using two shotgun metagenomic datasets. First, we analyzed data from a panel of 249 healthy hosts (Lloyd-Price et al., 2017; Human Microbiome Project Consortium, 2012), in which stool samples were collected one to three times from each host at approximately 6-month intervals. Second, we analyzed data from four individuals sampled more densely over the course of ~18 months (Poyet et al., 2019). In both cases, we only consider intra-species diversity of relatively abundant species that are well sampled in these metagenomic datasets (Methods).

We examined several metrics of community diversity and intra-species diversity and calculated the slope of their relationship, defined as the diversity slope (Figure 1). We note that intra-species diversity can arise within hosts via de novo point mutation, gene gain or loss, or the coexistence of genetically distinct strains that diverged before colonizing the host. To quantify community diversity, we calculated Shannon diversity and richness at the species level. Shannon diversity is relatively insensitive to sampling effort (Madi et al., 2020; Walters and Martiny, 2020) but richness can be underestimated in low sample sizes. We therefore computed richness on data rarefied to an equal number of reads per sample, yielding generally similar results to unrarefied data (described below). In all cases, we included the number of reads per sample (coverage) as a covariate in our models, as this could affect estimates of both community diversity and intra-species diversity. To quantify intra-species diversity, we used a reference genome-based approach to call single nucleotide variants (SNVs) and gene copy number variants (CNVs) within each focal species and computed polymorphism rates, measured as the fraction of synonymous nucleotide sites in a species’ core genome with intermediate allele frequencies (between 0.2 and 0.8) within a host (Methods). We also repeated the analysis on nonsynonymous sites, as these are subject to stronger selective constraints. As an additional metric of intra-species diversity, we inferred the number of strains within each species using StrainFinder applied to all polymorphic sites (including those outside the 0.2–0.8 frequency range) (Smillie et al., 2018).

Community diversity is positively associated with intra-species polymorphism in the human gut microbiome

As an exploratory visualization, we began by plotting the relationship between community diversity and intra-species polymorphism rate calculated at synonymous sites in cross-sectional HMP metagenomes for the nine most prevalent species (Figure 2A and B). The slope of this relationship (the diversity slope; Figure 1) provides an indicator of the evidence for DBD (positive slope) or EC (flat or negative slope). The relationship between polymorphism rate and community diversity was mostly positive in the top nine most prevalent species in HMP hosts (Figure 2A and B). These nine species are used as a simple illustration of the diversity slope, not as a formal hypothesis-testing framework.

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To generalize across species and to formally test the predictions of DBD, we fit generalized additive models (GAMs) to the HMP data. Using GAMs, we are able to model non-linear relationships and account for random variation in the strength of the diversity slope across bacterial species, the uneven number of samples per host, and the non-independence of samples from the same host (Methods; see Supplementary file 1a and Supplementary file 2 section 1 for additional model details). These GAMs included 69 focal species with sufficient coverage to quantify within-species polymorphism (Methods); the results therefore apply to relatively abundant species in the human gut microbiome. GAMs showed an overall positive association between within-species polymorphism and Shannon diversity (Figure 2C, GAM, p=0.031, Chi-square test) as well as between within-species polymorphism and community richness after controlling for coverage as a covariate (Figure 2D, GAM, p=0.017, Chi-square test) or rarefying samples to an equal number of reads (Figure 2E, GAM, p=2.63e-04, Chi-square test). The random effect of species identity is highly significant in all models, indicating that each bacterial species has its own characteristic diversity slope (Supplementary file 1a). It appears that synonymous polymorphism reaches a plateau at high levels of community richness, which is particularly evident when using rarefied data (Figure 2E). Using the same GAMs applied to nonsynonymous polymorphism, we found no significant associations between diversity and within-species polymorphism rate (GAM, p>0.05, Chi-square test) (Supplementary file 1b, Supplementary file 2 section 4). This could be due to lower statistical power, since there are fewer nonsynonymous than synonymous sites, or it could reflect a true difference in the diversity slope between these site categories.

These generally positive correlations between focal species polymorphism and species-level measures of community diversity also hold when community diversity is measured at higher taxonomic levels; specifically, synonymous polymorphism rate was significantly positively associated with Shannon diversity calculated at the genus and family levels (GAMs, p<0.05, Chi-square test) (Figure 2—figure supplement 1, Supplementary file 1c). However, synonymous polymorphism rate was not significantly associated with Shannon diversity calculated at the highest taxonomic levels (order, class, and phylum, GAMs, p>0.05, Chi-square test). The positive correlation between polymorphism rate and richness held at all taxonomic levels (GAMs, p<0.05, Chi-square test) (Figure 2—figure supplement 1, Supplementary file 1c, Supplementary file 2 sections 2 and 3). When estimated at nonsynonymous sites, polymorphism rate was not significantly correlated with Shannon diversity at any taxonomic level (GAMs, p>0.05, Chi-square test), but was positively correlated with richness at the highest levels (phyla, class, and order, p=3e-04, p=0.017, and p=6.11e-04, respectively, Chi-square test from GAMs) (Figure 2—figure supplement 2, Supplementary file 1d, Supplementary file 2 sections 5 and 6). Even when not statistically significant, the diversity slopes were generally positive at all taxonomic levels for both synonymous and nonsynonymous polymorphism (Figure 2—figure supplements 1 and 2). Overall, these results are consistent with the predictions of DBD at most taxonomic levels. However, slightly different relationships are observed when considering different measures of community diversity (Shannon or richness) and different components of within-species diversity (nonsynonymous or synonymous).

Different measures of community diversity have contrasting associations with intra-species strain diversity

Within host polymorphism rates span several orders of magnitude (10^–5/bp to 10^–2/bp), largely due to the fact that strain content is variable across hosts. As previously argued (Garud et al., 2019), with conservatively high estimates for mutation rate (μ~10⁻⁹) (Sung et al., 2012), generation times (~10/day) (Poulsen et al., 1995), and time since colonization (<100 years), polymorphism rates of ~10^–2/bp or more are inconsistent with within-host diversification of a single colonizing lineage. Therefore, hosts with relatively high intra-host polymorphism rates are likely colonized by mixtures of multiple strains that diverged long before colonizing a host. Moreover, recent work suggests that the numbers and genetic composition of strains colonizing a host can vary from host to host (Garud et al., 2019; Olm et al., 2017; Russell and Cavanaugh, 2017; Truong et al., 2017; Verster et al., 2017). The associations between polymorphism and community diversity (Figure 2) are likely driven by a combination of de novo mutation and co-colonization by multiple strains.

To separate these two sources of diversity and to explicitly account for the strain structure within hosts, we inferred the number of strains per focal species with StrainFinder (Smillie et al., 2018) (Methods) and used strain number as another quantifier of intra-species diversity. The relationship between community diversity and strain number varied depending on the focal species and the measure of community diversity. For example, the inferred number of Bacteroides vulgatus strains increased with community diversity, while Bacteroides uniformis strain count decreased or remained flat (Figure 3A and B). Expanding upon these examples, we used generalized linear mixed models (GLMMs) to investigate the relationship between the number of strains per focal species and community diversity, while taking into account coverage per sample as a covariate and variation between species, hosts and samples as random effects (Methods). GLMMs are a special case of GAMs that can handle overdispersed, zero-truncated count data such as strain counts. The number of strains per focal species was positively correlated with community Shannon diversity (GLMM, p=3.58e-07, likelihood ratio test [LRT]) (Figure 3C, Supplementary file 1e, Supplementary file 2 section 7.1). This suggests that the positive correlation between polymorphism rate and Shannon diversity (Figure 2) is due at least in part to strain diversity.

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By contrast, species richness was negatively correlated with strain number (GLMM, p=1.67e-06, LRT) (Figure 3D, Supplementary file 1e, Supplementary file 2 section 7.2). The negative relationship with richness was unlikely to be confounded by sequencing depth, since the same result was obtained using rarefied data (Figure 3E, Supplementary file 1e, Supplementary file 2 section 7.3). The negative strain number-richness relationship also held at all other taxonomic ranks (GLMM, p<0.05, LRT), while the strain number-Shannon diversity relationship was generally positive (Figure 3—figure supplement 1, Supplementary file 1f, Supplementary file 2 sections 8 and 9). These effects also appear to be species-specific: for example, the number of B. vulgatus strains per host is positively correlated with both Shannon diversity and richness (consistent with DBD predictions) whereas Bacteroides ovatus has no relationship with Shannon diversity but a negative correlation with richness (consistent with EC; Figure 2A and B). Together, these results reveal that different components of community diversity can have contrasting effects on the diversity slope.

Community Shannon diversity is a predictor of intra-species polymorphism and gene loss in time series data

Our analyses thus far have considered only individual time points, which represent static snapshots of the dynamic processes of community assembly and evolution in the microbiome. To interrogate these phenomena over time, we analyzed 160 HMP subjects who were sampled two to three times ~6 months apart. Under a DBD model, we expect community diversity at an earlier time point to result in higher within-species polymorphism at a future time point. To test this expectation, we defined ‘polymorphism change’ as the difference between polymorphism rates at the two time points (Methods). We also investigated the effects of community diversity on gene loss and gain events within a focal species, as such changes in gene content are known to occur frequently within host gut microbiomes (Garud et al., 2019; Groussin et al., 2021; Yaffe and Relman, 2020; Zhao et al., 2019). Here, a gene was considered absent if its copy number (c) was <0.05 and present if 0.6 ≤c ≤ 1.2. As in the cross-sectional analyses above, we also controlled for sequencing depth of the sample and excluded genes with aberrant coverage or presence in multiple species (Methods).

In HMP samples, polymorphism change showed no significant relationships with community diversity at the earlier time point, whether it was estimated with Shannon index or species richness (GAM, p>0.05) (Supplementary file 2 section 10.1). These results suggest that DBD is negligible or undetectable over ~6 month time lags in the human gut. By contrast, we found that gene loss in a focal species between two consecutive time points was positively correlated with community diversity at the earlier time point (Figure 4; GLMM, p=0.028, p=0.034, and p=0.049, LRT for Shannon, richness and rarefied richness, respectively) (Supplementary file 1g, Supplementary file 2 section 10.3). Gene gains did not show any significant relationships with community diversity (GLMM, p>0.05). Selection for gene loss in more diverse communities is a prediction of the Black Queen hypothesis (BQH), provided that higher community diversity results in more redundant gene functions that compensate for losses in a focal species (Morris et al., 2012). Most species in HMP samples lost fewer than 10 genes over ~6 months – consistent with de novo deletion events of a few genes – but occasionally hundreds of genes were lost from a host, suggesting that strains with smaller genomes were selected in more diverse communities (Figure 4A and B).

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To study these dynamics at higher temporal resolution, we analyzed shotgun metagenomic data from four more frequently sampled healthy individuals from a previous study (Poyet et al., 2019). Stool from donor am was sequenced over 18 months with a median of 1 day between samples; an over 12 months (median 2 days between samples); ao over 5 months (median 1 day between samples); and ae over 7 months (median 2 days between samples). In this data, we tracked both polymorphism change and gene gains and losses between two successive time points in 15 species with a minimal marker gene coverage of 10 in at least 10 samples. These include seven species of Bacteroides, two Eubacterium, two Faecalibacterium, two Ruminococcus, as well as Alistipes putredinis and Parabacteroides merdae.

Using the Poyet dataset, we asked whether community diversity in the gut microbiome at one time point could predict polymorphism change at a future time point by fitting GAMs with the change in polymorphism rate as a function of the interaction between community diversity at the first time point and the number of days between the two time points. Shannon diversity at the earlier time point was correlated with increases in polymorphism (consistent with DBD) up to ~150 days (~4.5 months) into the future (Figure 5—figure supplement 1), but this relationship became weaker and then inverted (consistent with EC) at longer time lags (Figure 5A, Supplementary file 1h, GAM, p=0.023, Chi-square test). The diversity slope is approximately flat for time lags between 4 and 6 months, which could explain why no significant relationship was found in HMP, where samples were collected every ~6 months. No relationship was observed between community richness and changes in polymorphism (Supplementary file 1h, GAM, p>0.05).

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We next asked if community diversity at one time point could predict gene gains or losses at future time points by fitting GLMMs (analogous to the GAMs above, but more appropriate for gain/loss count data). Our method does not explicitly distinguish between gene gain/loss arising from recombination or deletion versus replacement of strains with different gene content. We found that community Shannon diversity predicted future gene loss in a focal species, and this effect became stronger with longer time lags (Figure 5B, Supplementary file 1i, GLMM, p=0.006, LRT for the effect of the interaction between the initial Shannon diversity and time lag on the number of genes lost). The model predicts that increasing Shannon diversity from its minimum to its maximum would result in the loss of 0.075 genes from a focal species after 250 days. In other words, about one of the 15 focal species considered would be expected to lose a gene in this time frame.

Higher Shannon diversity was also associated with fewer gene gains, and this relationship also became stronger over time (Figure 5C, Supplementary file 1i, GLMM, p=1.11e-09, LRT). We found a similar relationship between community species richness and gene gains, although the relationship was slightly positive at shorter time lags (Figure 5D, Supplementary file 1i, GLMM, p=3.41e-04, LRT). No significant relationship was observed between richness and gene loss (Supplementary file 1i, GLMM, p>0.05). Taken together with the HMP results (Figure 4), these longer time series reveal how the sign of the diversity slope can vary over time and how community diversity is generally predictive of reduced focal species gene content.

How eco-evolutionary feedbacks shape biological communities is an open question that, to date, has received substantial experimental and theoretical attention but is challenging to address in nature. In our previous study using 16S rRNA amplicon sequences from the Earth Microbiome Project, we found generally positive diversity slopes that eventually flattened at high levels of community diversity (Madi et al., 2020). This pattern is generally consistent with the predictions of DBD during the early stages of community assembly, but at later stages becomes more consistent with EC as niches become filled. Based on the time series metagenomic data analyzed here, the predictions of DBD also tend to hold over short time scales but fail over longer time scales of several months. Whether this leads to a terminal plateau of diversity, or whether ecological disturbances lead to cycles of DBD and EC, deserves further study.

In our previous study, the animal gut microbiome had one of the highest positive diversity slopes, making it an ideal candidate for investigating eco-evolutionary interactions at greater intra-species resolution using metagenomic data. In this follow-up study, we investigate the same phenomenon at a subspecies level, with results that are broadly consistent with the predictions of DBD giving way to EC over long time scales. We note that experiments supporting DBD have generally been conducted over short time scales ranging from 2 to 20 days (Estrela et al., 2022; Jousset et al., 2016), consistent with the importance of DBD early in community assembly. We also identify several nuances and caveats to this general conclusion, which are discussed below in detail.

Another recent study also found evidence for eco-evolutionary feedbacks in the HMP, in the form of a positive relationship between evolutionary modifications or strain replacements in a focal species and community diversity (Good and Rosenfeld, 2022). Using a model, they further showed that these eco-evolutionary dynamics could be explained by resource competition and did not require the cross-feeding interactions previously invoked (Estrela et al., 2022; San Roman and Wagner, 2021; San Roman and Wagner, 2018) to explain DBD at higher taxonomic levels. This could be because cross-feeding operates at the family or genus level and is less relevant at finer evolutionary scales.

There are several noteworthy caveats to our study. First, using metagenomic data from human microbiomes allowed us to study genetic diversity, but limited us to considering only relatively abundant species with genomes that were well covered by short sequence reads. Deeper or more targeted sequencing may permit us to determine whether the same patterns hold for rarer members of the microbiome. However, it is notable that the majority of the dozens of species across the two datasets analyzed support DBD, suggesting that the phenomenon may generalize.

Second, we cannot establish causal relationships without controlled experiments. We are therefore careful to conclude that positive diversity slopes are consistent with the predictions of DBD, and negative slopes with EC, but unmeasured environmental drivers could be at play. For example, increased dietary diversity could simultaneously select for higher community diversity and also higher intra-species diversity. In our previous study, we found that positive diversity slopes persisted even after controlling for potential abiotic drivers such as pH and temperature (Madi et al., 2020), but a similar analysis was not possible here due to a lack of metadata. Neutral processes can account for several ecological patterns such as species-area relationships (Hubbell, 2001), and must be rejected in favor of niche-centric models like DBD or EC. Using neutral models without DBD or EC, we found generally flat or negative diversity slopes due to sampling processes alone and that positive slopes were hard to explain with a neutral model (Madi et al., 2020). These models were intended mainly for 16S rRNA gene sequence data, but we expect the general conclusions to extend to metagenomic data. Nevertheless, further modeling and experimental work will be required to fully exclude a neutral explanation for the diversity slopes we report in the human gut microbiome.

Based on controlled experiments (Estrela et al., 2022) and modeling studies (San Roman and Wagner, 2021), DBD is a plausible causal explanation for positive diversity slopes in the gut microbiome. Although they also note that causality is difficult to establish, Good and Rosenfeld, 2022 suggest the importance of focal species evolution as a driver of changes in community structure, as shown in an experimental study of Pseudomonas in compost communities (Padfield et al., 2020). Clearly, further work is needed to establish the extent and relative rates of eco-evolutionary feedback in both directions. How these feedbacks among bacteria are influenced by abiotic factors and by interactions with fungi, archaea, and phages also deserves further study.

Third, the diversity slope changes depending on which component of within-species diversity or community diversity is considered. Notably, the number of strains within a focal species is positively correlated with Shannon diversity, but inversely correlated with species richness, suggesting that the ability of strains to colonize a host may be associated with higher community evenness rather than total species count. Higher evenness might maximize the chance of inter-species interactions, whereas higher richness might be driven by rare species that are less likely to interact. Although Shannon diversity is considered to be more robust and informative than richness in estimating bacterial diversity (He et al., 2013; Reese and Dunn, 2018), we observe the same contrasting results between Shannon diversity and richness when community diversity is calculated at higher taxonomic levels, suggesting that this pattern is not due to artifacts such as sequencing effort.

Our measures of intra-species diversity included both synonymous and nonsynonymous SNVs, inferred strain richness, and gene content. Synonymous nucleotide variation was consistently and positively associated with both community richness and Shannon diversity at all taxonomic levels (although not always with statistical significance). Nonsynonymous variation also tended to track positively with both measures of community diversity but was only statistically significantly associated with phylum and class richness. This suggests that evolutionarily older, less selectively constrained synonymous mutations and more recent nonsynonymous mutations that affect protein structure both track similarly with measures of community diversity. Nonetheless, a parsimonious explanation for possible differences between the two classes is that while they are affected similarly, we have more statistical power to identify correlations in the more numerous synonymous mutations. This merits further investigation.

Metagenomes from the same individual sampled over time allowed us to detect gene gain and loss events. In both HMP and Poyet et al. time series, community diversity was predictive of future gene loss in a focal species. This phenomenon is not explicitly predicted by either DBD or EC but it is compatible with aspects of the BQH, with some caveats. BQH predicts that a focal species will be less likely to encode genes with functions provided by other members of the surrounding community if such functions are ‘leaky’ and available as diffusible public goods (Morris et al., 2012). The BQH could also act as a driver of polymorphism within a species (Morris et al., 2014). Gene loss may be adaptive, provided that there is a cost to encoding and expressing the relevant genes (Albalat and Cañestro, 2016; Koskiniemi et al., 2012; Simonsen, 2022). The tendency for reductive genome evolution in bacteria is well established (Albalat and Cañestro, 2016; Koskiniemi et al., 2012; Puigbò et al., 2014). Genome reduction is a particular hallmark of endosymbiotic bacteria, which depend on their hosts for many metabolic gene products (McCutcheon and Moran, 2011; Nikoh et al., 2011). It has been shown that uncultivated bacteria from the gut have undergone considerable genome reduction, which may be an adaptive process that results from reliance on public goods (Nayfach et al., 2019). In the gut microbiome, the BQH has been invoked to explain the distribution of genes involved in vitamin B metabolism (Sharma et al., 2019) and iron acquisition (Vatanen et al., 2019).

Our findings in human gut metagenomes are compatible with the BQH under the assumption that increasing community diversity also increases the availability of leaky gene products – which may not be the case if genomes in the gut microbiome are functionally redundant, as inferred in a recent study (Tian et al., 2020). This study found that species in the gut microbiome were highly redundant at the level of annotated metabolic pathways (KEGG orthologs) and that more functionally redundant microbiomes were more resistant to colonization by fecal transplants. Relatively low redundancy microbiomes could therefore be more easily colonized but might also require migrants to encode more gene functions in order to persist. Importantly, functional redundancy may be high at the level of well-annotated metabolic functions, but low at the finer level of individual gene families, as demonstrated in marine microbiomes (Galand et al., 2018) but not yet studied explicitly in the gut. Here, we report that genome reduction in the gut is higher in more diverse gut communities. This could be due to de novo gene loss, preferential establishment of migrant strains encoding fewer genes, or a combination of the two. The mechanisms underlying this correlation remain unclear and could be due to biotic interactions – including metabolic cross-feeding as posited by some models (Estrela et al., 2022; San Roman and Wagner, 2021; San Roman and Wagner, 2018) but not others (Good and Rosenfeld, 2022) – or due to unknown abiotic drivers of both community diversity and gene loss. Finally, we measured community diversity from the phylum to the species level, not below. We therefore did not investigate how the BQH could extend to maintain gene content variation within a species, as has been shown experimentally in Escherichia coli (Morris et al., 2014). This could be an avenue for future work.

In our previous analysis of lower-resolution 16S rRNA amplicon sequences, we reported a tendency for focal genera with larger genomes to have higher diversity slopes, perhaps because they experience stronger DBD (Madi et al., 2020). At face value, this tendency seems at odds with the BQH, which predicts genome reduction in more diverse communities. This apparent contradiction may be reconciled by considering eco-evolutionary dynamics on different time scales. A recent study used phylogenetic and metabolic reconstructions to show that gene gains often drive metabolic dependencies among bacteria (Goyal, 2021), potentially explaining why genera with larger maximum genome size could experience stronger DBD. Our earlier study only had the genetic resolution to consider focal taxa down to the genus level, and by using the maximum genome size observed in a public database we did not capture the dynamic process of gene gain and loss within a species, as was possible in the current metagenomic study. It is therefore possible that on longer (ecological) time scales, larger genomes have more metabolic interactions and thus experience stronger DBD, while genome reduction in more diverse communities occurs on shorter (evolutionary) time scales.

In summary, we demonstrate how metagenomic data can be used to test the predictions of eco-evolutionary theory, including DBD, EC, and the BQH. It remains to be seen whether the distinct eco-evolutionary processes proposed by DBD and the BQH operate orthogonally or whether they interact. If BQH leads to gene losses that remain polymorphic rather than being lost entirely from the species (Morris et al., 2014) – or invasions of strains with fewer genes that remain incomplete and do not replace the resident strain – this could be viewed as a form of diversification and perhaps a special case of DBD. Here, we considered gene loss as a directional process; we did not attempt to distinguish between directional changes in gene copy number and the complete extinction of a gene, which is difficult to show using metagenomic data. Future work could attempt to resolve this point and to potentially combine DBD and BQH into a unified theory.

The raw sequencing reads for the metagenomic samples used in this study were downloaded from Human Microbiome Project Consortium, 2012 and Lloyd-Price et al., 2017 (URL: https://aws.amazon.com/datasets/human-microbiome-project/); and Poyet et al., 2019 (NCBI accession number PRJNA544527). All computer code for this paper is available at https://github.com/Naima16/DBD_in_gut_microbiome, (copy archived at swh:1:rev:eef9dc1643f279e4bb2f6d7e19c4fd7d5acc384f; Madi et al., 2023).

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Author details

1. Naïma Madi

   Département de sciences biologiques, Université de Montréal, Montréal, Canada

   Contribution

   Conceptualization, Software, Formal analysis, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8793-7389

2. Daisy Chen

   1. Computational and Systems Biology, University of California, Los Angeles, Los Angeles, United States
   2. Bioinformatics and Systems Biology Program, University of California, San Diego, San Diego, United States

   Contribution

   Data curation, Formal analysis, Methodology, Writing – review and editing

   Contributed equally with

   Richard Wolff

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6516-7029

3. Richard Wolff

   Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Formal analysis, Investigation, Methodology, Writing – review and editing

   Contributed equally with

   Daisy Chen

   Competing interests

   No competing interests declared

4. B Jesse Shapiro

   1. Département de sciences biologiques, Université de Montréal, Montréal, Canada
   2. McGill Genome Centre, McGill University, Montreal, Canada
   3. Quebec Centre for Biodiversity Science, Montreal, Canada
   4. McGill Centre for Microbiome Research, Montreal, Canada
   5. Department of Microbiology and Immunology, McGill University, Montreal, Canada

   Contribution

   Conceptualization, Supervision, Funding acquisition, Investigation, Visualization, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   jesse.shapiro@mcgill.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6819-8699

5. Nandita R Garud

   1. Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, United States
   2. Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Conceptualization, Data curation, Supervision, Funding acquisition, Investigation, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   ngarud@ucla.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4217-4407

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