The Multibiome: The Intestinal Ecosystem's Influence on Immune Homeostasis, Health, and Disease

Abstract

Mammalian evolution has occurred in the presence of mutualistic, commensal, and pathogenic micro- and macro-organisms for millennia. The presence of these organisms during mammalian evolution has allowed for intimate crosstalk between these colonizing species and the host immune system. In this review, we introduce the concept of the 'multibiome' to holistically refer to the biodiverse collection of bacteria, viruses, fungi and multicellular helminthic worms colonizing the mammalian intestine. Furthermore, we discuss new insights into multibiome-host interactions in the context of host-protective immunity and immune-mediated diseases, including inflammatory bowel disease and multiple sclerosis. Finally, we provide reasons to account for the multibiome in experimental design, analysis and in therapeutic applications.

Keywords: Autoimmune disease; Helminth immunotherapy; Inflammatory bowel disease; Microbiome; Mucosal immunology.

Fig. 1

The multibiome. Due to the shortcomings of the terms microbiome and trans-kingdom, we propose the introduction of the term multibiome. This all-encompassing term accounts for viruses (that are not part of any taxonomic kingdom) and for macrobionts such as helminth parasites. Each multibiome member (when present, in the case of helminths) and the mammalian host, together, contribute their genetic information to the holistic metagenome.

Fig. 2

The immune response associated with each constituent of the multibiome. Type 1 responses are initiated by detecting microbe-associated molecular patterns. Type 1 pro-inflammatory cytokines and cells target intracellular microbes, including bacterial pathogens, opportunistic commensal bacterial infection and viruses. The innate type 1 and 3 IFN pathways are critical components of the antiviral immune response. Type 1 responses are pro-inflammatory and can cause collateral damage to the host if the immune response is not balanced and regulated. Type 2 immune responses are triggered by helminth infections. A type 2 responses coordinates worm expulsion and rapid wound healing; however, it can lead to fibrosis if the immune response is not balanced and regulated. Regulatory responses are promoted by certain bacterial species (some Clostridia species, B. fragilis), and many helminth infections. Their broad immunosuppressive actions contribute to self-tolerance and commensal multibiome-tolerance. They are also initiated during the resolution phase of type 1, 2, and 3-promoting infections. Type 17 responses are triggered by extracellular bacterial pathogens, fungi and some epithelial cell binding commensal bacterial species. Type 17-associated cytokines promote mucosal barrier function, but are also widely implicated in autoimmune and CIDs.

Fig. 3

Multibiome-mediated regulation of immune polarization and homeostasis. This illustration simplifies the many interactions and pathways involved in multibiome-host cross-talk down to the core T helper (Th) cell subsets they promote. It also demonstrates how each Th subset is able to regulate, inhibit, or promote the activation or function of another subset. During a proper immune response, balancing these subsets is crucial to avoid pathology and generate a good memory response. Immune cross-regulation is mediated through a variety of mechanisms including cytokines, chemokines, receptor interactions, and transcription factor expression. Certain members of the multibiome promote the expansion of different subsets of Th cells, which in turn inhibit, promote, and/or balance the other subsets. T-bet expressing Th1 (activated in response to bacteria and viruses) and GATA3 expressing Th2 cells (helminth-induced), antagonize each other. Some bacterial species and helminths promote Foxp3-expressing Tregs, which in turn limit the activation of Th1, Th2 and Th17 cells.

Fig. 4

Interactions between multibiome members regulate the intestinal community. In addition to immune-mediated regulation, composition of the intestinal ecosystem is dynamically regulated by interactions across taxonomic boundaries. A) A diverse commensal bacterial community limits outgrowth of opportunistic or pathogenic bacteria and Candida albicans by niche competition for space and nutrients, production of metabolites and immune-mediated mechanisms. B) Bacteriophage diversity can dictate bacterial community composition and drive evolution, through a predator-prey relationship. Some enteric pathogens have evolved to take advantage of the ubiquitous presence of intestinal commensal bacteria. Bacteria expressing histo-blood group antigen (HBGA) promote human and murine Norovirus can promote infection of B cells. C) Helminths have evolved to utilize cues from commensals, to ensure the life cycle is completed in the appropriate location and host. Helminth-induced type 2 responses promote a thickening of the mucus layer, which can alter the colonizing microbiota species.

Fig. 5

The multibiome as a critical regulator of immune responses. Differences between industrialized and non-industrialized regions (infrastructure, sanitation, diet, medical interventions, and multibiome exposures) are factors associated with the disparity in the prevalence of CIDs and the efficacy of vaccines between different human populations. A) An intestinal ecosystem with limited diversity is associated with antibiotic usage, decreased exposures to the multibiome and/or a ‘Westernized’ diet (high fat and sugar, low fiber). In industrialized nations, this is associated with good vaccine efficacy and decreased childhood mortality to infectious disease, but increased rates of autoimmune and CIDs. B) An intestinal ecosystem rich in diversity may drive a balanced immune system. Non-industrialization is associated with endemic helminth infections, malnutrition, childhood morbidity and mortality, and diminished vaccine efficacy. Nevertheless, these regions have less autoimmune and CID incidence, indicating that factors that promote a complex multibiome might support a balanced immune system. Further research could help determine how to establish optimal multibiome diversity to limit CIDs without compromising host-protective immunity.