Revealing the ecological principles that shape communities is a major challenge of the postgenomic era. To date, a systematic approach for describing inter-species interactions has been lacking. Here we independently predict the competitive and cooperative potential between 6,903 bacterial pairs derived from a collection of 118 species ' metabolic models. We chart an intricate association between competition and cooperation indicating that the cooperative potential is maximized at moderate levels of resource overlap. Utilizing ecological data from 2,801 samples, we explore the associations between bacterial interactions and coexistence patterns. The high level of competition observed between species with mutual-exclusive distribution patterns supports the role of competition in community assembly. Cooperative interactions are typically unidirectional with no obvious benefi t to the giver. However, within their natural communities, bacteria typically form close cooperative loops resulting in indirect benefi t to all species involved. These fi ndings are important for the future design of consortia optimized towards bioremediation and bio-production applications.

A leading hypothesis for the role of bacteria in inflammatory bowel diseases is that an imbalance in normal gut flora is a prerequisite for inflammation. Testing this hypothesis requires comparisons between the microbiota compositions of ulcerative colitis and Crohn's disease patients and those of healthy individuals. In this study, we obtained biopsy samples from patients with Crohn's disease and ulcerative colitis and from healthy controls. Bacterial DNA was extracted from the tissue samples, amplified using universal bacterial 16S rRNA gene primers, and cloned into a plasmid vector. Insert-containing colonies were picked for highthroughput sequencing, and sequence data were analyzed, yielding species-level phylogenetic data. The clone libraries yielded 3,305 sequenced clones, representing 151 operational taxonomical units. There was no significant difference between floras from inflamed and healthy tissues from within the same individual. Proteobacteria were significantly (P ‫؍‬ 0.0007) increased in Crohn's disease patients, as were Bacteroidetes (P < 0.0001), while Clostridia were decreased in that group (P < 0.0001) in comparison with the healthy and ulcerative colitis groups, which displayed no significant differences. Thus, the bacterial flora composition of Crohn's patients appears to be significantly altered from that of healthy controls, unlike that of ulcerative colitis patients. Imbalance in flora in Crohn's disease is probably not sufficient to cause inflammation, since microbiotas from inflamed and noninflamed tissues were of similar compositions within the same individual.

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Oscillospira is an under-studied anaerobic bacterial genus from Clostridial cluster IV that has resisted cultivation for over a century since the first time it was observed. In recent years its 16S rRNA gene was identified in several human gut microbiota studies where it was often associated with interesting traits, especially leanness. However, very little is known about its metabolism or physiology. Here we used nearly complete genomes derived from shot-gun metagenomic data from the human gut to analyze Oscillospira and related bacteria. We used sequence similarity, gene neighbourhood information and manual metabolic pathway curation to decipher key metabolic features of this intriguing bacterial genus. We infer that Oscillospira species are butyrate producers, and at least some of them have the ability to utilize glucuronate, a common animal-derived sugar that is both produced by the human host and consumed by that host in diets rich in animal products. These findings could help explain diet-related inter-individual variation in faecal Oscillospira levels as well as the observation that the presence of this genus is reduced in diseases that involve inflammation.

Deciphering the modular organization of metabolic networks and understanding how modularity evolves have attracted tremendous interest in recent years. Here, we present a comprehensive large scale characterization of modularity across the bacterial tree of life, systematically quantifying the modularity of the metabolic networks of >300 bacterial species. Three main determinants of metabolic network modularity are identified. First, network size is an important topological determinant of network modularity. Second, several environmental factors influence network modularity, with endosymbionts and mammal-specific pathogens having lower modularity scores than bacterial species that occupy a wider range of niches. Moreover, even among the pathogens, those that alternate between two distinct niches, such as insect and mammal, tend to have relatively high metabolic network modularity. Third, horizontal gene transfer is an important force that contributes significantly to metabolic modularity. We additionally reconstruct the metabolic network of ancestral bacterial species and examine the evolution of modularity across the tree of life. This reveals a trend of modularity decrease from ancestors to descendants that is likely the outcome of niche specialization and the incorporation of peripheral metabolic reactions.horizontal gene transfer ͉ lateral gene transfer ͉ systems biology ͉ bacterial evolution ͉ network modules M odularity is considered to be one of the main organizing principles of biological networks (1, 2). A biological network module consists of a set of elements (e.g., proteins/ reactions) that form a coherent structural subsystem and have a distinct function. Several studies have explored the role of modularity and network organization in various proteininteraction and regulatory cellular networks (3-10). Focusing specifically on modularity in metabolic networks (which is also the subject of this article), the metabolic networks of 43 distinct organisms were shown to be organized in many small, highly connected topologic modules that hierarchically combine into larger units (11). The functional and evolutionary modularity of the human metabolic network was also investigated from a topological perspective by using network decomposition (12). The network was shown to be organized in a highly modular way into basic core metabolism modules and peripheral modules that have specialized functions and evolve at a faster rate.Considering the evolution of modularity, two major hypotheses have been proposed: the ''evolution of evolvability'' and the congruence principle (13). The first posits that there is positive selection favoring modularity because it enhances evolvability by enabling evolutionary changes to take place in confined modules while preserving global cellular functions (14, 15). The second maintains that, although modularity is not directly selected for, there is nevertheless an evolutionary congruence between modularity and other directly selectable properties. Such properties may include accelerat...

In their natural environments, microorganisms form complex systems of interactions. Understating the structure and organization of bacterial communities is likely to have broad medical and ecological consequences, yet a comprehensive description of the network of environmental interactions is currently lacking. Here, we mine co-occurrences in the scientific literature to construct such a network and demonstrate an expected pattern of association between the species’ lifestyle and the recorded number of co-occurring partners. We further focus on the well-annotated gut community and show that most co-occurrence interactions of typical gut bacteria occur within this community. The network is then clustered into species-groups that significantly correspond with natural occurring communities. The relationships between resource competition, metabolic yield and growth rate within the clusters correspond with the r/K selection theory. Overall, these results support the constructed clusters as a first approximation of a bacterial ecosystem model. This comprehensive collection of predicted communities forms a new data resource for further systematic characterization of the ecological design principals shaping communities. Here, we demonstrate its utility for predicting cooperation and inhibition within communities.

Horizontal gene transfer (HGT) is a prevalent and a highly important phenomenon in microbial species evolution. One of the important challenges in HGT research is to better understand the factors that determine the tendency of genes to be successfully transferred and retained in evolution (i.e., transferability). It was previously observed that transferability of genes depends on the cellular process in which they are involved where genes involved in transcription or translation are less likely to be transferred than metabolic genes. It was further shown that gene connectivity in the protein-protein interaction network affects HGT. These two factors were shown to be correlated, and their influence on HGT is collectively termed the "Complexity Hypothesis". In this study, we used a stochastic mapping method utilizing advanced likelihood-based evolutionary models to quantify gene family acquisition events by HGT. We applied our methodology to an extensive across-species genome-wide dataset that enabled us to estimate the overall extent of transfer events in evolution and to study the trends and barriers to gene transferability. Focusing on the biological function and the connectivity of genes, we obtained novel insights regarding the "complexity hypothesis." Specifically, we aimed to disentangle the relationships between protein connectivity, cellular function, and transferability and to quantify the relative contribution of each of these factors in determining transferability. We show that the biological function of a gene family is an insignificant factor in the determination of transferability when proteins with similar levels of connectivity are compared. In contrast, we found that connectivity is an important and a statistically significant factor in determining transferability when proteins with a similar function are compared.

Curli fibers are adhesive surface fibers expressed by Escherichia coli and Salmonella enterica that bind several host extracellular matrix and contact phase proteins and were assumed to have a role in pathogenesis. The results presented here suggest that one such role is internalization into host cells. An E. coli K-12 strain transformed with a low-copy vector containing the gene cluster encoding curli fibers (csg operon) was internalized by several lines of eukaryotic cells. The internalization could be correlated with a high level of curli fiber expression and was abolished by disruption of the csg operon. The ability to be internalized by eukaryotic cells could be conferred even by the curli fiber gene cluster of a noninvasive K-12 strain, but the homologous csg cluster from a virulent septicemic E. coli isolate mediated a higher level of internalization. The finding that curli fibers promote bacterial internalization indicates a new role for curli fibers in pathogenesis.Curli fibers are thin aggregative surface fibers, connected with adhesion, which bind laminin (23), fibronectin (25), plasminogen (31), human contact phase proteins (4), and major histocompatibility complex (MHC) class I molecules (26). Curli fibers are coded for by the csg gene cluster, which is comprised of two divergently transcribed operons. One operon encodes the csgB, csgA, and csgC genes, while the other encodes csgD, csgE, csgF, and csgG. The assembly of the fibers is unique and involves extracellular self-assembly of the curlin subunit (CsgA), dependent on a specific nucleator protein (CsgB) (14). CsgD is a transcriptional activator essential for expression of the two curli fiber operons, and CsgG is an outer membrane lipoprotein involved in extracellular stabilization of CsgA and CsgB (20). The role of the other csg genes has yet to be elucidated.Curli fibers are expressed by many pathogenic isolates of Escherichia coli, as well as laboratory strains (25). Similar surface proteins were identified in both Salmonella enterica serovar Enteritidis (9) and S. enterica serovar Typhimurium (28). Curli fibers are also present in E. coli strains involved in avian colisepticemia (27)-a serious invasive disease of chickens and turkeys that is characterized by entry of the bacteria into the air sacs, bloodstream, and vital organs (36).Using PCR, we amplified the curli fiber-encoding (csg) gene cluster from a curli fiber-positive E. coli K-12 strain and cloned it in a low-copy-number vector. The resulting plasmid, when transformed to a noninvasive E. coli strain, conferred the ability to become internalized by eukaryotic cells. We have also cloned the homologous curli fiber-encoding cluster from a virulent isolate of avian E. coli O78 which could mediate a higher level of internalization. The results presented in this communication indicate that high levels of curli fiber expression can mediate entry of bacteria into eukaryotic cells and suggest that these fibers play a role in pathogenesis. MATERIALS AND METHODSBacterial strains and plasmids. T...