Effects of a gut pathobiont in a gnotobiotic mouse model of childhood undernutrition

Abstract

To model how interactions among enteropathogens and gut microbial community members contribute to undernutrition, we colonized gnotobiotic mice fed representative Bangladeshi diets with sequenced bacterial strains cultured from the fecal microbiota of two 24-month-old Bangladeshi children: one healthy, the other underweight. The undernourished donor’s bacterial collection contained an enterotoxigenic Bacteroides fragilis strain (ETBF), whereas the healthy donor’s bacterial collection contained two nontoxigenic strains of B. fragilis (NTBF). Analyses of mice harboring either the unmanipulated culture collections or systematically manipulated versions revealed that ETBF was causally related to weight loss in the context of its native community, but not when introduced into the healthy donor’s community. This phenotype was transmissible from the dams their offspring and was associated with derangements in host energy metabolism manifest by impaired tricarboxylic acid cycle activity and decreased acyl-CoA utilization. NTBF reduced ETBF’s expression of its enterotoxin and mitigated the effects of ETBF on the transcriptomes of other healthy donor community members. These results illustrate how intraspecific (ETBF-NTBF) and interspecific interactions impact the effects of harboring B. fragilis..

Deciphering interactions between the gut microbiota and the immune system via microbial cultivation and minimal microbiomes

“…Interestingly, non-toxigenic strains of B. fragilis may mitigate the pathogenic effects of toxigenic strains by competitive exclusion mediated via the Type VI secretion system (82) and/or by reducing toxin expression (83). Together, these reports highlight the profoundly different interactions that can occur between the immune system and B. fragilis depending on which strain(s) are present in the host.…”

A Two-Component System Regulates Bacteroides Fragilis Toxin to Maintain Intestinal Homeostasis and Prevent Lethal Disease

“…As up to 20% of human-associated strains of B. fragilis encode bft (Toprak et al, 2006;Zhang et al, 1999), significant disease pathogenesis is a rare outcome of colonization. Thus, the selective advantage of BFT expression and potentially lethal disruption of host homeostasis is unclear (Casterline et al, 2017;Wagner et al, 2016).…”

“…Subacute or self-resolving colitis may be advantageous for B. fragilis colonization, while severe disease is a stochastic consequence of ETBF exposure in the context of a heterogeneous host population (Casterline et al, 2017;Wagner et al, 2016; Figure S2F). Our findings suggest that the native RprXY TCS is encoded to ensure stability within WT hosts but is insufficiently regulated to maintain host-ETBF homeostasis in susceptible animals.…”

“…As up to 20% of human-associated strains of B. fragilis encode bft (Toprak et al, 2006;Zhang et al, 1999), significant disease pathogenesis is a rare outcome of colonization. Thus, the selective advantage of BFT expression and potentially lethal disruption of host homeostasis is unclear (Casterline et al, 2017;Wagner et al, 2016).Both host and bacterial factors are required to maintain stable, quiescent ETBF colonization. Mucus may physically entrap BFT and facilitate its expulsion (McLoughlin et al, 2016) or prevent ETBF colonization within sufficient distance of the epithelium to cause injury.…”

A Two-Component System Regulates Bacteroides fragilis Toxin to Maintain Intestinal Homeostasis and Prevent Lethal Disease

“…As up to 20% of human-associated strains of B. fragilis encode bft (Toprak et al, 2006; Zhang et al, 1999), significant disease pathogenesis is a rare outcome of colonization. Thus, the selective advantage of BFT expression and potentially lethal disruption of host homeostasis is unclear (Casterline et al, 2017; Wagner et al, 2016). …”