The compositional and functional diversity of the gut fungal microbiome
Authors: Fen Zhang, PhD, Dominik Aschenbrenner, PhD, Ji Youn Yoo, PhD, Prof Tao Zuo, PhD
The gut mycobiome (fungi) is a small but crucial component of the gut microbiome in humans. Intestinal fungi regulate host homoeostasis, pathophysiological and physiological processes, and the assembly of the co-residing gut bacterial microbiome. Over the past decade, accumulating studies have characterised the gut mycobiome in health and several pathological conditions. We review the compositional and functional diversity of the gut mycobiome in healthy populations from birth to adulthood. We describe factors influencing the gut mycobiome and the roles of intestinal fungi—especially Candida and Saccharomyces spp—in diseases and therapies with a particular focus on their synergism with the gut bacterial microbiome and host immunity. Finally, we discuss the underappreciated effects of gut fungi in clinical implications, and highlight future microbiome-based therapies that harness the tripartite relationship among the gut mycobiome, bacterial microbiome, and host immunity, aiming to restore a core gut mycobiome and microbiome and to improve clinical efficacy.
Beyond bacteria and viruses, the human gastrointestinal tract is also home to a large number of fungi—0·1% of the total gut microbes—which play crucial roles in human intestinal homoeostasis and disease pathogenesis. Thanks to the technological advances in deep sequencing and microbial cultivation seen over the past decade, a large diversity of fungi are increasingly being uncovered in the human gut, including keystone fungal species that are fundamental to human health or linked to disease onset or progression.
Dysbiosis (ie, an imbalance in the composition of the microbial community, which includes loss of symbionts, outgrowth of pathobionts or opportunists, and disturbed inter-microbial competition and microbial diversity) of the gut mycobiota has been implicated in a number of diseases, spanning autoimmune, metabolic, and neurological disorders, and cancers. Colonisation and growth of opportunistic fungal pathogens in the gut can induce dysregulated host immune responses thereby influencing the disease course.
In addition, gut fungi—particularly Candida spp—sophistically influence the assembly and function of the gut bacterial microbiome (another cardinal regulator of host physiology), through cellular contact, competition or collaboration for available nutrients, production of secondary metabolites and antimicrobial peptides, and physiochemical changes to the gut niche. Overall, these mechanisms, which interplay among gut fungi, bacteria, and host immunity, are the underpinnings of human immune homoeostasis, all contributing to health and disease.
Accumulating studies have provided insight into the landscape of gut mycobiome composition in humans, and have laid the foundation for exploring how the gut fungi are linked to—or even cause—different diseases and how to manipulate gut fungi to treat diseases. The time has come for us to explore and unveil the functions of gut fungi, as well as its trans-kingdom interactions with the gut bacterial microbiome for disease pathogenesis and therapeutics.
Importantly, gut fungi are still largely overlooked in the context of microbiota-based development of therapeutics, and available mycobiome findings are not fully harnessed in clinical practice. Hence, we review the latest progress in basic and translational research of the gut mycobiome, pinpoint the roles of pathobiontic, probiotic, and opportunistic fungi in diseases, and underscore the ecological effect of gut fungal–bacterial interactions in host physiology and pathophysiology. We also discuss the previously underappreciated effects of microbiome-based therapies on the gut mycobiome in clinical implications and highlight avenues to translate the gut mycobiome knowledge to clinical practice, particularly to therapies.
Current challenges and future perspectives
The field has made huge strides over the past decade thanks to the advances in metagenomics, and understanding of the gut mycobiome has advanced greatly as a result. However, understanding of gut fungi is still incomplete and there is no consensus in how much has been uncovered of the genetic and phenotypic diversity of the human gut mycobiome. Given the high inter-individual and intra-individual variability of the gut mycobiome, the largely under-sampled populations across continents and ethnicities, and the substantially heterogeneous configurations between individuals at the fungal strain level it is probable that there is much more to learn.
The causal or consequential relationship between gut mycobiome alterations and disease is largely unclear for different diseases, and remains to be established in future. Gut fungi might be both mechanistically and consequentially linked to a disease, playing either driver or passenger roles, or both, in a disease-dependent manner. For instance, C albicans was concordantly observed to be increased in patients with C difficile infection, inflammatory bowel disease, and COVID-19. This increase might partly be a consequence of antibiotic use or disruption in the gut microbiome equilibrium in these patients. Apart from that, variations in the strain-diversity and molecular diversity of a single fungal species across individuals could functionally evoke different phenotypic and therapeutic responses. Therefore, considering the many unknowns in the mechanisms of gut fungi linking to the pathogenesis and therapeutics of diseases, it warrants extensive investigation to translate the gut mycobiome research from bench to bedside.
The gut microbiome is an intricate inter-kingdom collection of diverse microbes (including bacteria, fungi, viruses, and archaea). Beyond the fungal–bacterial interactions in the gut, the enteric viral and phage–bacterial and archaeal–bacterial interactions also underline the health and wellbeing of humans. Overall, the gut bacteriome and virome are more taxonomically diverse and heterogeneous between individuals than the gut mycobiome; geography-related, ethnicity-related, and diet-related host factors could explain 30·8%, 15·6%, and 9·8% of the respective microbiome variations across healthy individuals, whereas many unexplored host factors and environmental factors could account for the remaining variations. Interplay between all the constituent microbial components in the gut are poorly defined to date. Equally important, the interaction between the gut microbes and the host (such as immunity, transcriptome, epigenome, metabolome, and nutrition) is a more sophisticated layer of functional pathways yet to be investigated in human health.
Research over the past decade supports a crucial role for the gut mycobiome in human health and various diseases in association with the gut bacterial microbiome assembly. The intricate, reciprocal relationships among gut fungi, bacteria, and host immunity underpin the homoeostasis of host physiology as well as the pathogenesis, progression, and even therapeutic outcome of diseases. The large diversity of gut fungi plays disparate roles in a disease-dependent and context-dependent manner, which is influenced by environmental and host factors including the non-fungal microbiome, diet, urbanisation, medication, age, genetics, and the immune system. Using the gut mycobiome for disease diagnosis, prognosis, and therapeutic intervention as part of precision medicine approaches is possible in the future. Building upon the basic, translational, and clinical knowledge of the gut mycobiome and microbiome and human pathophysiology, future microbiome-targeting or microbiome-inspired therapeutic avenues should be revolutionised and tailored to synergistically modulate gut fungi and bacteria to improve clinical efficacy.