Gut colonisation in early life
Birth is a crucial moment in life. It’s not only a stage at which direct maternal support is lost, but also a period of drastic change in the gut. Even if the recent theories on the colonisation of the developing intestine in utero are plausible, birth and early-life remain a critical phase in the colonisation and development of the gut microbiota, as disturbances in the composition of the microbiota may lead to dysregulation in the functioning of the immune system and likelihood of developing metabolic diseases.
An important age-dependent factor that defines the colonisation of the gut is dietary intake. For instance, breast milk provides a high concentration of lactose which limits the carbon source to the gut microbes and it also provides antibacterial substances. However, assuming that the settlement of gut bacteria is driven merely by the exposure to the surrounding environment may be an incomplete picture of this intricate process. The genetic make-up and the physiological state of an individual are also contributing factors that shape this community. Interestingly, recent publications highlight both innate and adaptive immunity as key players for the distribution of a microbiota in the gut and suggest, at the same time, that gut colonisation follows a “first come, first served” pattern.
In their most recent publication, Fulde and colleagues suggested that a host-microbe regulatory circuit exists, acting as a gatekeeper influencing the establishment of bacteria in the intestine after birth. This checkpoint has to deal with the activation of a circuit regulated by epithelial toll-like receptor 5 (TLR5), myeloid differentiation primary response 88 (MYD88) and regenerating islet-derived protein 3 gamma (REG3γ). This was discovered after investigating the age-based expression of innate immune receptor molecules by intestinal epithelial cells in mice. The experiments showed TLR5 as the leading protein in the circuit whose presence led the establishment of a normal gut microbial composition by reducing the colonisation of flagellated bacteria - a configuration that was observed to persist life-long in the animals (at least 42 days).
The gene encoding TLR5 was seen to be highly expressed at an early stage. By series of (faecal) transplants, it was possible to find that the modulatory effects of TLR-5 were specific to the postnatal frame (around 21 days after birth, with a peak in the first two weeks of life). Pups or adult mice were unable to correct the altered microbiota even in presence of the TLR-5 gene. In addition, TLR5-deficient animals were found to have a phenotype characterised by a high food intake and body weight as well as differences in the pancreatic and liver tissue.
The findings indicate TLR5 as a key player in early colonisation. However, it is important to mention that a low expression of TLR5 during adulthood does not necessarily translate into the host being more vulnerable to pathogens. It may actually have a beneficial effect by avoiding an upregulated inflammatory state at this later stage of life which has direct consequences on the homeostasis of the gut microbiota.
Concerning the adaptive immune system, in experiments using a faecal suspension or bacterial cocktail transplants, Martinez and colleagues observed that mice without Rag1 (recombination activating gene 1) had significantly lower diversity when compared to wild type animals. Moreover, when host genetics and diet were standardised, the order of microbes arrival was seen to have a priority effect that defined the ecological success in the assembly of the microbiota. In this set of studies, different strains isolated from adult mice were used to colonise the gut of young mice. The first microbes introduced showed their dominance in the arising ecosystem. These results were also confirmed when using a defined cocktail of bacteria. When compared with the effects from adaptive immunity experiments, the order by which the microbes were inoculated was seen to have a stronger colonisation impact.
Early life is considered by many researchers as a window of opportunity to steer the gut community in order to support host’s health. The findings from Fulde et al. and Martinez et al. highlight the potential relevance of order and timing during microbial colonisation of the gut. Furthermore, the shifting responses on the activation of receptors from the innate and adaptive immune systems are suggested to perform in an age-dependent way.