Breakthrough research in the past decade has highlighted the importance of the gut to our overall wellness and health. Gut health covers multiple positive aspects of the gastrointestinal (GI) tract, such as the effective digestion and absorption of food, the absence of GI illness, normal and stable intestinal microbiota, effective immune status, balanced endocrine function and an overall state of well-being. There is a delicate interaction between the host and the microbiota, and the disruption of this balance can compromise the homeostasis and survival of the entire organism, affecting human health, disease, and ageing, even in organs that are distant from the gut.
It also opens opportunities for the development of novel and exciting therapeutic strategies. Contact us today to find out more.
The Human Gut Microbiome
The human body hosts trillions of bacteria with the majority residing in the gut. In the past, bacteria were mostly regarded as either pathogens or irrelevant to host’s function. However, the growing field of microbiome research has yielded new perspectives. Today, we know that our relationship with these microbes is symbiotic and that they play a key role in our overall physiology. This should not surprise us since around 65% of all the cells in our body are bacteria and their genetic information is at least 100-fold greater than our human genome. The gut microbiota contributes to energy homeostasis, prevents mucosal infections, modulates hormonal secretion and mitigates immune system hypersensitivity. Most importantly, it contributes to the maintenance of an intact GI barrier that is closely related to infectious, inflammatory and allergic diseases. Being adjacent to the mucosal immune system and within the area of constant sampling and communication between host and gut content, the gut microbiota appears to be the key to understanding the complex mechanisms that maintain gut and overall health.
Mucosal Immune System
The mucosal immune system comprises around 70% of our overall immune system and it is situated in the GI tract that presents a unique challenge to it. Dynamics and the diversity of GI components result in its constant need to monitor the vast surface for the presence of pathogens, while at the same time maintaining tolerance to beneficial or innocuous antigens. The impact of such interactions is not fully understood but the relationship is bidirectional. The mucosal immune system both controls the GI microbiota and it depends on it, because the continuous challenge of microbial antigens is required for its normal development and function. It contains specialised innate and adaptive immune cells capable of recognising microbial antigens by specific receptors. These form the basis of the communication between the gut microbiota and the mucosal immune system. Through this communication, dangers from pathogens can be quickly recognised and dealt with, while at the same time the friendly coexistence of microorganisms and host in the gut is maintained. Under normal conditions, those mechanisms allow regulation of inflammatory responses to harmless food or microbial antigens to achieve and maintain tolerance.
Host protection and maintenance of gut health is, thus, dependent on the ability of the mucosal immune system to sense the gut microbiota and to regulate the complex balance between the defence against it and the acceptance of it. Many advances in recent years have been made towards the understanding of these interactions and novel signalling molecules have been discovered that regulate host responses to microorganisms. It is now widely appreciated that these molecules interact in a concerted fashion to maintain a balance that governs an appropriate response to the microorganisms present. Researchers have focused on identifying gut microbiota members and/or metabolites that positively or negatively modulate the biologic response of immune cells and enhance the host’s ability to regulate mucosal homeostasis and achieve gut health. Some bacteria, such as the members belonging to the genus Bifidobacterium, are actively involved in the mutualistic dialog between the microbiota and mucosal immune system in order to maintain peaceful coexistence.
Bifidobacterium spp. are gut residents throughout our lifetime and their number is closely aligned with key stages of immune system maturation and function. They are the predominant commensal bacteria during infancy with an extensive role in training the mucosal immune system, and maintaining its appropriate function, but they significantly decline as we get older. Bifidobacteria have a complex strain-dependant role, regulating inflammation, promoting anti-pathogen immune responses, improving responses to immune-oncology therapies, and modulating immunity in the context of auto-immune or immune-mediated diseases, in both gut-associated and systemic conditions. They influence the critical homeostatic development and programming of the immune system through the release of specific metabolites that are recognised by mucosal immune cells, and impact signalling pathways associated with improved host well-being.
Although, the overall mechanisms of bifidobacterial-associated immune modulation aren’t fully understood, available data highlight immune receptor-ligand interactions and downstream signalling events linked to their specific molecules, whereby bifidobacteria induce/modulate T-cell responses through dendritic cells, via antigen presentation and stimulation of antigen-specific T cells.
Whereas previous microbiota-targeting strategies have focused on adding/subtracting certain microbes from the mix or altering the metabolic activity of specific bacteria, we are looking at the microbiome as a single human organ, a natural pool of antigens, that interacts with other parts of the body through the mucosal immune system.
With recent advances in the understanding of how immune cells communicate with each other to signal immune functions, and how the network of signalling molecules and cell surface receptors directs an appropriate host response to microorganisms, we aim to manipulate these signalling pathways in order to influence host responses. Our basic strategy underlying immunomodulation is to identify aspects of the mucosal immune system that can be enhanced or suppressed in such a way as to augment or complement a desired immune response, based on metabolites from Bifidobacterium species. Using Artificial Intelligence and synthetic biology, we optimise the naturally available molecules in a way that allows the host to better regulate the mucosal immune system allowing enhanced host-derived mechanisms to take part in the immune response without the need to use microbe-based or microbe-specific therapeutics.
We leverage the microbiome-host immune system pathways, at the point of interaction, for the development of therapeutics across many conditions including: chronic inflammation cardiometabolic, autoimmune, neurodevelopmental, neurodegenerative and immune-oncology. Contact us today to find out more.