Human symbionts inject and neutralize antibacterial toxins to persist in the gut

Abstract

The human gut microbiome is a dynamic and densely populated microbial community that can provide important benefits to its host. Cooperation and competition for nutrients among its constituents only partially explain community composition and interpersonal variation. Notably, certain human-associated Bacteroidetes—one of two major phyla in the gut—also encode machinery for contact-dependent interbacterial antagonism, but its impact within gut microbial communities remains unknown. Here we report that prominent human gut symbionts persist in the gut through continuous attack on their immediate neighbors. Our analysis of just one of the hundreds of species in these communities reveals 12 candidate antibacterial effector loci that can exist in 32 combinations. Through the use of secretome studies, in vitro bacterial interaction assays and multiple mouse models, we uncover strain-specific effector/immunity repertoires that can predict interbacterial interactions in vitro and in vivo, and find that some of these strains avoid contact-dependent killing by accumulating immunity genes to effectors that they do not encode. Effector transmission rates in live animals can exceed 1 billion events per minute per gram of colonic contents, and multiphylum communities of human gut commensals can partially protect sensitive strains from these attacks. Together, these results suggest that gut microbes can determine their interactions through direct contact. An understanding of the strategies human gut symbionts have evolved to target other members of this community may provide new approaches for microbiome manipulation.

Diverse NADase effector families mediate interbacterial antagonism via the type VI secretion system

“…Through cycles of extension and contraction, this pathway delivers effector proteins from the cytoplasm of a donor bacterium directly into the periplasm or cytoplasm of a recipient bacterium (3,4). Used by both pathogenic and commensal bacteria of eukaryotes, the T6SS mediates a complex interplay of bacterial cell-cell interactions between beneficial and disease-causing bacteria (5)(6)(7)(8)(9).…”

Microbial Herd Protection Mediated by Antagonistic Interaction in Polymicrobial Communities

“…Each antibacterial effector can be neutralized by a genetically linked immunity protein that confers protection against effector delivery between sister cells (7,12,13). In addition, the T6SS has been shown to play an important role in vivo in multiple species, including human-symbiotic Bacteroidetes species (14)(15)(16). As a lethal weapon, the T6SS has been shown to mediate kin recognition in the multicellular bacterium Proteus mirabilis, which can develop elongated swarmer cells and form distinct boundaries (known as Dienes lines) between different P. mirabilis strains (17)(18)(19)(20).…”

Invasions of Host-Associated Microbiome Networks

“…For instance, Kerr et al (2002) showed that E. coli strains coexist when interactions are spatially explicit, thus echoing theoretical work on the coexistence of species in structured communities (Hofbauer and Schreiber 2010;Mouquet and Loreau 2002). Indeed, experiments (in vivo or in vitro) of microbiome invasions, particularly those that combine them with ecological mathematical modelling (e.g., Stein et al 2013;Marino et al 2014;Wexler et al 2016), could help further probe the properties of the WH networks that make competitive interactions either effective or ineffective at preventing invasions.…”

“…are usually attributed to (i) their lowering of environmental pH through lactic acid production, (ii) their production of bacteriocins and other bacteriocidal compounds such as biosurfactant or hydrogen peroxide (H 2 O 2 ), and (iii) their competitive exclusion of other bacterial species (Boskey et al 2001;Fayol-Messaoudi et al 2005;Kaewsrichan et al 2006;Ling et al 2013;Ravel et al 2011). Similarly, a study on the persistence of human-associated Bacteroidetes in the gut (discussed earlier in Section 2.3) showed that some bacterial species can exclude an invader by producing bactericidal effectors triggered by direct physical contact, and that this activity is mediated by resistance evolution and relative population densities between species (Wexler et al 2016). Finally, how our commensal or mutualist viruses interact with each other or the microbiome in order to prevent invasions is significantly less understood.…”

“…Importantly, resident bacterial species produce compounds (e.g., bacteriocins) to directly inhibit growth of invading bacteria thus using interference competition as a mechanism to prevent invasion (Dethlefsen et al 2007). In a recent study, a cell-to-cell contact-dependent antagonism (where strains of Bacteroidetes inject toxic effectors into their neighbours) was described in detail (Wexler et al 2016). This phylum is very common in the human microbiome and thus, by demonstrating that this antagonistic behaviour affects the overall community composition and dynamics, they suggest that this interaction could be significantly shaping human microbiome communities.…”