Faculty Bibliography

The human gut harbors a large and complex community of beneficial microbes that remain stable over long periods. This stability is considered critical for good health but is poorly understood. Here we develop a body of ecological theory to help us understand microbiome stability. Although cooperating networks of microbes can be efficient, we find that they are often unstable. Counterintuitively, this finding indicates that hosts can benefit from microbial competition when this competition dampens cooperative networks and increases stability. More generally, stability is promoted by limiting positive feedbacks and weakening ecological interactions. We have analyzed host mechanisms for maintaining stability-including immune suppression, spatial structuring, and feeding of community members-and support our key predictions with recent data.

The human gut harbours a large and genetically diverse population of symbiotic microbes that both feed and protect the host. Evolutionary theory, however, predicts that such genetic diversity can destabilise mutualistic partnerships. How then can the mutualism of the human microbiota be explained? Here we develop an individual-based model of host-associated microbial communities. We first demonstrate the fundamental problem faced by a host: The presence of a genetically diverse microbiota leads to the dominance of the fastest growing microbes instead of the microbes that are most beneficial to the host. We next investigate the potential for host secretions to influence the microbiota. This reveals that the epithelium-microbiota interface acts as a selectivity amplifier: Modest amounts of moderately selective epithelial secretions cause a complete shift in the strains growing at the epithelial surface. This occurs because of the physical structure of the epithelium-microbiota interface: Epithelial secretions have effects that permeate upwards through the whole microbial community, while lumen compounds preferentially affect cells that are soon to slough off. Finally, our model predicts that while antimicrobial secretion can promote host epithelial selection, epithelial nutrient secretion will often be key to host selection. Our findings are consistent with a growing number of empirical papers that indicate an influence of host factors upon microbiota, including growth-promoting glycoconjugates. We argue that host selection is likely to be a key mechanism in the stabilisation of the mutualism between a host and its microbiota.

The human body carries vast communities of microbes that provide many benefits. Our microbiome is complex and challenging to understand, but evolutionary theory provides a universal framework with which to analyse its biology and health impacts. Here we argue that to understand a given microbiome feature, such as colonization resistance, host nutrition or immune development, we must consider how hosts and symbionts evolve. Symbionts commonly evolve to compete within the host ecosystem, while hosts evolve to keep the ecosystem on a leash. We suggest that the health benefits of the microbiome should be understood, and studied, as an interplay between microbial competition and host control.

Antibiotic treatment can deplete the commensal bacteria of a patient's gut microbiota and, paradoxically, increase their risk of subsequent infections. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), antibiotic administration is essential for optimal clinical outcomes but significantly disrupts intestinal microbiota diversity, leading to loss of many beneficial microbes. Although gut microbiota diversity loss during allo-HSCT is associated with increased mortality, approaches to reestablish depleted commensal bacteria have yet to be developed. We have initiated a randomized, controlled clinical trial of autologous fecal microbiota transplantation (auto-FMT) versus no intervention and have analyzed the intestinal microbiota profiles of 25 allo-HSCT patients (14 who received auto-FMT treatment and 11 control patients who did not). Changes in gut microbiota diversity and composition revealed that the auto-FMT intervention boosted microbial diversity and reestablished the intestinal microbiota composition that the patient had before antibiotic treatment and allo-HSCT. These results demonstrate the potential for fecal sample banking and posttreatment remediation of a patient's gut microbiota after microbiota-depleting antibiotic treatment during allo-HSCT.

Dramatic microbiota changes and loss of commensal anaerobic bacteria are associated with adverse outcomes in hematopoietic cell transplantation (HCT) recipients. In this study, we demonstrate these dynamic changes at high resolution through daily stool sampling and assess the impact of individual antibiotics on those changes. We collected 272 longitudinal stool samples (with mostly daily frequency) from 18 patients undergoing HCT and determined their composition by multiparallel 16S rRNA gene sequencing as well as the density of bacteria in stool by quantitative PCR (qPCR). We calculated microbiota volatility to quantify rapid shifts and developed a new dynamic systems inference method to assess the specific impact of antibiotics. The greatest shifts in microbiota composition occurred between stem cell infusion and reconstitution of healthy immune cells. Piperacillin-tazobactam caused the most severe declines among obligate anaerobes. Our approach of daily sampling, bacterial density determination, and dynamic systems modeling allowed us to infer the independent effects of specific antibiotics on the microbiota of HCT patients.

The host epithelium is the critical interface with microbial communities, but the mechanisms by which the host regulates these communities are poorly understood. Here we develop the hypothesis that hosts use differential adhesion to select for and against particular members of their microbiota. We use an established computational, individual-based model to study the impact of host factors that regulate adhesion at the epithelial surface. Our simulations predict that host-mediated adhesion can increase the competitive advantage of microbes and create ecological refugia for slow-growing species. We show how positive selection via adhesion can be transformed into negative selection if the host secretes large quantities of a matrix such as mucus. Our work predicts that adhesion is a powerful mechanism for both positive and negative selection within the microbiota. We discuss molecules-mucus glycans and IgA-that affect microbe adhesion and identify testable predictions of the adhesion-as-selection model.

The high-fat, high-calorie diets of westernized cultures contribute to the global obesity epidemic, and early life exposure to antibiotics may potentiate those dietary effects. Previous experiments with mice had shown that sub-therapeutic antibiotic treatment (STAT)-even restricted to early life-affected the gut microbiota, altered host metabolism, and increased adiposity throughout the lifetime of the animals. Here we carried out a large-scale cohousing experiment to investigate whether cohousing STAT and untreated (Control) mice would transfer the STAT-perturbed microbiota and transmit its impact on weight. We exposed pregnant dams and their young offspring to either low-dose penicillin (STAT) or water (Control) until weaning, and then followed the offspring as they grew and endured a switch from normal to high-fat diet at week 17 of life. Cohousing, which started at week 4, rapidly approximated the microbiota within cages, lowering the weight of STAT mice relative to non-cohoused mice. The effect, however, varied between cages, and was restricted to the first 16 weeks when diet consisted of normal chow. Once mice switched to high-fat diet, the microbiota α- and β-diversity expanded and the effect of cohousing faded: STAT mice, again, were heavier than control mice independently of cohousing. Metabolomics revealed serum metabolites associated with STAT exposure, but no significant differences were detected in glucose or insulin tolerance. Our results show that cohousing can partly ameliorate the impact of STAT on the gut microbiota but not prevent increased weight with high-fat diet. These observations have implications for microbiota therapies aimed to resolve the collateral damage of antibiotics and their load on human obesity.

Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have, thus far, largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFA) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication in the initial case-control cohort of transplant patients, and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed, however serum was available - rather than plasma - and the differences in SCFA observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort, and one of two cross-sectional cohorts explored, suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived short chain fatty acids.

Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.