The human gut microbiota produces dozens of metabolites that accumulate in the bloodstream1,2, where they can have systemic effects on the host. Although these small molecules commonly reach concentrations similar to those achieved by pharmaceutical agents, remarkably little is known about the microbial metabolic pathways that produce them. Here we use a combination of genetics and metabolic profiling to characterize a pathway from the gut symbiont Clostridium sporogenes that generates aromatic amino acid metabolites. Our results reveal that this pathway produces twelve compounds, nine of which are known to accumulate in host serum. All three aromatic amino acids (tryptophan, phenylalanine and tyrosine) serve as substrates for the pathway, and it involves branching and alternative reductases for specific intermediates. By genetically manipulating C. sporogenes, we modulate serum levels of these metabolites in gnotobiotic mice, and show that in turn this affects intestinal permeability and systemic immunity. This work has the potential to provide the basis of a systematic effort to engineer the molecular output of the gut bacterial community.

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Osmotic diarrhea is a prevalent condition in humans caused by food intolerance, malabsorption, and widespread laxative use. Here, we assess the resilience of the gut ecosystem to osmotic perturbation at multiple length and timescales using mice as model hosts. Osmotic stress caused reproducible extinction of highly abundant taxa and expansion of less prevalent members in human and mouse microbiotas. Quantitative imaging revealed decimation of the mucus barrier during osmotic perturbation, followed by recovery. The immune system exhibited temporary changes in cytokine levels and a lasting IgG response against commensal bacteria. Increased osmolality prevented growth of commensal strains in vitro, revealing one mechanism contributing to extinction. Environmental availability of microbiota members mitigated extinction events, demonstrating how species reintroduction can affect community resilience. Our findings (1) demonstrate that even mild osmotic diarrhea can cause lasting changes to the microbiota and host and (2) lay the foundation for interventions that increase system-wide resilience.

A variety of cell surface structures dictate interactions between bacteria and their environment, including their viruses (bacteriophages). Members of the human gut Bacteroidetes characteristically produce several phase-variable capsular polysaccharides (CPS), but their contributions to bacteriophage interactions are unknown. To begin to understand how CPS impact Bacteroides -phage interactions, we isolated 71 B. thetaiotaomicron -infecting bacteriophages from two locations in the United States. Using B. thetaiotaomicron strains that express defined subsets of CPS, we show that CPS dictates host tropism for these phages and that expression of non-permissive CPS variants are selected under phage predation, enabling survival. In the absence of CPS, B. thetaiotaomicron escapes bacteriophage predation by altering expression of 8 distinct phase-variable lipoproteins. When constitutively expressed, one of these lipoproteins promotes resistance to multiple bacteriophages. Our results reveal important roles for Bacteroides CPS and other cell surface structures that allow these bacteria to persist under bacteriophage predation and hold important implications for using bacteriophages therapeutically to target gut symbionts.

Highlights d Human microbiotas were resilient and recovered rapidly during antibiotic administration d A low-fiber diet aggravated microbiota collapse and delayed recovery from ciprofloxacin d Microbiota reprogramming and transmission conferred resilience to repeated treatment d Single housing disrupted recovery, highlighting roles of reservoirs and sanitation