Gut Mycobiota in Immunity and Inflammatory Disease

Abstract

The mammalian intestine is colonized by a wealth of microorganisms-including bacteria, viruses, protozoa, and fungi-that are all integrated into a functional trans-kingdom community. Characterization of the composition of the fungal community-the mycobiota-has advanced further than the much-needed mechanistic studies. Recent findings have revealed roles for the gut mycobiota in the regulation of host immunity and in the development and progression of human diseases of inflammatory origin. We review these findings here while placing them in the context of the current understanding of the pathways and cellular networks that induce local and systemic immune responses to fungi in the gastrointestinal tract. We discuss gaps in knowledge and argue for the importance of considering bacteria-fungal interactions as we aim to define the roles of mycobiota in immune homeostasis and immune-associated pathologies.

Figure 1:. Cellular mechanisms of innate and adaptive immune responses to gut commensal fungi.

Gut resident CX3CR1⁺ MNPs sense and phagocytose intestinal fungi, and respond by producing cytokines that support antifungal Th17 responses in a Syk dependent manner. This process further recruits neutrophils to the intestine that together with CX3CR1⁺ MNPs prevent the expansion of opportunistic fungi. Fungal-specific Treg cells against gut commensal fungi, such as C. albicans, have been detected in humans), but not in mice and might be involved in the maintenance immune homeostasis. Intestinal disease results in bacterial and fungal dysbiosis, with changes in the abundance of various fungal species. Intestinal fungi such as C. albicans expand and directly interact with intestinal epithelial cells (IECs). In vitro studies suggest that hyphal form of C. albicans can induce lECs damage via the toxin candidalysin. C. albicans can induce the expansion of fungal antigen-specific Th17 cells that can cross-react to other fungi such as A. fumigatus and are enriched in several inflammatory diseases targeting the gut and the lung. Increase of anti-fungal antibodies is associated with intestinal inflammation and the induction of these antibodies is partially dependent on CX3CR1⁺ MNPs. * Phenomenon observed in human, but not in mouse studies.

Figure 2:. Gut mycobiota initiate trained immunity and adaptive immune responses to protect against systemic bacterial and fungal infections.

Members of the gut mycobiota, such as C. albicans and S. cerevisiae, are protective against systemic bacterial and fungal infections via trained immunity and/or activation of adaptive Th17 immunity. Fungal cell wall constituents such as b-glucan and chitin can enhance aerobic glycolysis in monocytes through the activation of dectin-1/ AKT/mTOR/HIF-1α pathway, leading to pro-inflammatory cytokines production, such as IL-6 and CSF1. In addition, S. cerevisiae derived mannans can initiate systemic protection against DSS induced intestinal inflammation in mice in the absence of commensal bacteria. Thus, mycobiota mediated trained immunity provides systemic immune-protection against systemic infection with bacterial and fungal pathogens. Gut commensal C. albicans also provides protection against systemic C. albicans, A. fumigatus and S. aureus by priming adaptive Th17 mediated-immune responses.

Figure 3:. Mechanisms of gut mycobiota mediated gut-to-systemic immune crosstalk.

A. Gut fungal dysbiosis characterized by the overgrowth of filamentous fungi or Candida species contributes to lung allergy via a gut-lung axis. C-type lectin receptor-Syk-dependent recognition of gut filamentous fungi by intestinal CX3CR1⁺ MNPs leads to the activation and increase of pro-allergenic Th2 cells in the lung. Gut-derived and Candida species-derived PGE2 exacerbates allergic airway inflammation during intestinal fungal colonization by promoting M2 macrophage polarization in the lung. Intestinal C. albicans over-colonization can increase the levels of systemic Th17 cells that might exacerbate airways inflammation. B. Fungal cell wall components, including β-glucan, translocate from the intestinal lumen to the liver. Binding of β-glucan to Dectin-1 on Kupffer cells and possibly other bone marrow–derived cells induces the secretion of IL-1β and promotes alcoholic liver disease by leading to steatosis and cell death of hepatocytes. T cells primed by fungal antigens in the intestinal mucosa might migrate to the liver and contribute to liver disease.