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Bacterial PGNs and Why They Matter

Fairfax, VA

Living inside of your gut at this very moment is a diverse array of microorganisms, composed of a variety of bacteria, archaea, and viruses, first introduced during birth and later influenced throughout life by genetics and the environment. Aa research takes a closer look at the interaction within the gut microbiota, the current focus of research lies on the bacteria and analyzing the impact of their diversity on the human body or health conditions/diseases upon bacterial microbiota diversity. In looking at the bacterial microbiome, the far-reaching impact of the bacterial gut microbiome on one’s health, from inflammation to the immune system, is better understood and could potentially lead to treatments targeting the gut microbiome to improve a particular condition. For the gut microbiome to have such a broad impact, it interacts with specific regions or organs of your body (e.g. the brain) through pathways. Some of these pathways are more well-known than others. In particular, the gut-brain axis, a pathway between the central nervous system and the gut, is one that the gut microbiome acts like a third player in. Some other pathways are the vagus nerve, gut metabolite production, and tryptophan metabolism. However, though these pathways are known, the specific molecular mechanisms that underlie the interactions between the brain and the gut microbes are unclear. Nevertheless, it is clear that these pathways have a significant impact mainly on the brain and necessitate further research. 

gut microbiome human health medicine bacteria microbiota GI
Human gut microbiome

To add one more pathway to the list, recent research has led to the proposal that the interactions between bacteria-derived products such as peptidoglycan (PGN) and pattern-recognition receptors (PRRs) of the innate immune system may be a new way for the gut microbiome to influence brain development. To get a better understanding of this pathway, the role of PGNs in bacteria and PRRs in humans must be clarified. PGN is a major component in bacterial cell wall envelopes, both protecting the bacteria from environmental stressors and preserving the shape of the bacteria throughout their cell cycle. It is through PGNs that we can distinguish Gram-positive and Gram-negative bacteria, with the former having a thick lysine-type peptidoglycan wall and the latter a thinner diaminopimelic acid-type wall. As both kinds of bacteria go through the phases of their cell cycle, they shed PGN and other structural molecules from their cell walls. It is exactly these shed motifs that PRRs can use to identify microbes or pathogens. As such PGN motifs are highly conserved because of their importance for bacteria, their presence isn’t restricted to pathogenic bacteria and can also be found in the friendly bacteria of your gut microbiome--almost all of which use PGN in their cell walls. In this way, one’s own gut microbiome’s PGN motifs can interact with PRRs. 

So why exactly is it important that this new pathway was proposed? This pathway between gut microbiome motifs and PRRs has been found to influence three main things: 1) the promotion of developmental processes, 2) the maintenance of host homeostasis, and 3) systematic priming of the innate immune system. For example, the exposure of intestinal epithelial cells to PGN motifs from Gram-negative bacteria in the gut microbiota led to the maturation of particular gut-associated lymphoid tissues (e.g. singular lymphoid follicles). PGN motifs could also play a role in maternal-fetal level interactions between the host and microbiome. Two ways for PGNs to reach systemic circulation--whereupon it can impact the fetus--are normal physiological conditions and bacterial infections. Research has shown that bacterial structural components can cross the placental barrier, with a notable example being the PGN–teichoic acid complex of the pathogenic Streptococcus pneumoniae. After getting past the barrier, this complex harmed the developing mouse fetal brain, causing abnormally increased neuronal density (50+%) on the cortical plate. While more neurons may sound like a good thing, this overproduction is more likely to cause atypical brain functions. PGNs, then, are influential to human health both during time as a fetus and development afterward. 

Though the proposal of this pathway may have been recent, knowledge of PGNs and their influence on the human brain has been decades in the making. Indeed, scientists have been aware of two PGN-sensing molecules (PGLYRP2 and NOD1) that are highly expressed in neurons across several different brain regions. NOD1 in particular has been associated with peak expression during the period of peak synaptogenesis (the formation of synaptic connections) in rodent brains. Current research is building off of this knowledge and better understanding this potential new pathway between PGN motifs of commensal bacteria and the PRRs of our innate immune system could both build scientific understanding and open a door for treatments or causes for particular conditions of the human body.

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