Gut Microbiota Density Influences Host Physiology and is Shaped By Host and Microbial Factors

Our understanding of the contributions of the gut microbiome to human health and disease has expanded dramatically with the development of high-throughput sequencing approaches for measuring microbial community structure. However, the wealth of data produced by these efforts has been limited by its compositional nature that neglects the possibility of changes in the overall size of the microbial community (microbiota density). Here, we present advances in the ability to measure microbiota density with greater throughput and as part of a standard microbiome analysis pipeline. We assayed gut microbiota density across mammals, disease, and therapeutic interventions. We identify microbiota density as an important feature of the microbiota that is shaped by physiologic features of the host (host carrying capacity) and the composition of the gut microbiota itself (gut microbiota fitness). Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn’s disease, ulcerative colitis, and ileal pouch-anal anastomosis compared to healthy individuals. The gutmicrobiota in recurrent Clostridium difficile infection also had lower density as a result of reduced microbiota fitness that was restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease through the conceptual framework of microbiota density, host carrying capacity, and microbiota fitness could provide biomarkers to identify candidates for microbiota therapeutics and monitor their responses

Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt+ Regulatory T Cells and Exacerbate Colitis in Mice

Microbiota are thought to influence the development and progression of inflammatory bowel disease (IBD), but determining generalizable effects of microbiota on IBD etiology requires larger-scale functional analyses. We colonized germ-free mice with intestinal microbiotas from 30 healthy and IBD donors and determined the homeostatic intestinal T cell response to each microbiota. Compared to microbiotas from healthy donors, transfer of IBD microbiotas into germ-free mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt+ Treg cells. Colonization with IBD microbiotas exacerbated disease in a model where colitis is induced upon transfer of naive T cells into Rag1-/- mice. The proportions of Th17 and RORγt+ Treg cells induced by each microbiota were predictive of human disease status and accounted for disease severity in the Rag1-/- colitis model. Thus, an impact on intestinal Th17 and RORγt+ Treg cell compartments emerges as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis

Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression

Inflammation in HIV infection is predictive of non-AIDSmorbidity and death1, higher set point plasma virus load2 and virus acquisition3; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection4–10, also provide target cells for the virus during acute infection, impairCD4T-cell recovery, and are associated with disease progression6,7,11–19.Herewe manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivointerventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-α2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-α2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution