The human gut is co-inhabited by trillions of microbes such as bacteria and fungi, which are known to play fundamental impact on human physiology. While gut dysbiosis is associated with a large number of diseases including the Alzheimer’s and diabetes, it is not yet clear how the microbes localized in the gut exert their impact on sterile extragastrointestinal organs such as the brain and pancreas. 

Searching and understanding of the microbiota-derived small molecules in host circulatory system may offer new insights. Our earlier study showed that soluble bacterial peptidoglycan (PGN) fragments are ubiquitously present in sera of human and many animals including bovine, horse, sheep, rabbit, and mice, but are undetectable in germ-free mice (Nat. Microbiol.2019). As PGN is an essential and unique feature of the bacteria that is absent in mammalian cells, our observations strongly support that host microbiota are the source of host circulating PGNs. To explore the physiological relevance of serum PGNs, we showed that modulating the PGN levels can affect autoimmune arthritis development in mice model, and interestingly, circulating PGNs are present at significantly higher levels in autoimmune disease patients such as RA and SLE. Thus we hypothesise that the circulating PGNs act as signalling molecules in the microbe-host crosstalk. 

Figure 1. Microbiota-derived peptidoglycan fragments in serum may act are signalling molecules in microbe-host interactions. There are many open questions in the emerging role of microbiota.

Our research group is interested in understanding the life cycle of these circulating PGNs including their origins, transportation, structures, distribution, and functions in the host. These questions are pertinent to the understanding of how our body tolerates the PGNs that are ubiquitously released by commensal strains, yet get activated by the PGN signals of pathogens in times of bacterial infections. Unbalanced and excessive triggers by such signals may lead to chronic inflammation and undesirable activation of the immune system resulting in autoimmune diseases. 

Figure 2. Three main sub-areas of the research program in Qiao lab toward understanding of gut microbiota-derived PGNs in hosts.

We take multidisciplinary approaches including organic synthesis, biochemistry, microbiology, cell culture studies etc. to elucidate the structures and functions of circulating PGNs in hosts. Our research program falls into three sub-areas: 1) PGN impact on host innate immunity; 2) PGN impact on human fungus; and 3) Developing toolkits to study gut microbiota-derived PGNs (Figure 2). 

The insights from our work will not only address fundamental biology questions, but also establish PGN as new effector molecules in the microbiota-host crosstalk, and lead to new therapeutic interventions against microbiome-associated diseases.