Hello everyone! Welcome to our Research Digest #13.
The paper that I wanted to share with you today was published on the Animal Nutrition journal back in 2017 and is titled "Weaning stress and gastrointestinal barrier development: Implications for lifelong gut health in pigs" --- a work from Dr. Adam Moeser’s team from the Vet school at Michigan State University.
This is a really nice review paper that discusses in depth on the importance of gut barrier and the short-term & long-time effects that weaning stress can have on its development.
Importance of Gut Barrier
First of all, what is gut barrier? When we talk about gut barrier, in a narrow sense, we are talking about the single-layer epithelial cells lining the GI tract. With increasing understanding of the gut functionality, today, in a broader sense, we refer to gut barrier more as this "multi-layer barrier" that consists of microbial barrier (commensal bacteria), chemical barrier (mucus layer), physical barrier (the epithelial layer), and immunological barrier.
The importance on gut barrier is not a stranger to many of us...As the largest interface between the animal host and the outside world, it plays 2 important yet divergent functions:
- "Defense" --- It is the defense barrier against any luminal pathogenic and antigenic components in order to protect the host.
- "Entrance" --- At the same time, it must efficiently transport luminal nutrients into the system for the animal's maintenance and growth.
In the meantime, gut barrier also has an important job in modulating the gut immune system by the participation of the immunological barrier and its interaction with other layers --- The gut is the largest immune organ in the body. It is tightly regulated (to avoid excessive immune response), yet it needs to respond rapidly to any breach in the barrier to prevent systemic spread of the infection. So a "delicate balance between control and reactiveness" of the GI immune system is critical.
Notably, in the gut, there is also an enteric nervous system consisting of 2 major neural ganglia. Although typically it is not considered as part of the gut barrier, it plays a key role in gut motility, secretion and absorption, and modulation of epithelial permeability through the release of a bunch of neurochemicals. It is also a major regulator of systemic and local GI immune responses.
What a busy guy the gut barrier is!! And such a complex and delicate job it needs to perform on a daily basis!
With this huge responsibility, the gut barrier has to be capable ---- How? It is equipped with several extrinsic and intrinsic sophisticated mechanisms of defense ---- one of the most critical mechanisms is the establishment of a permeability barrier that's regulated by the tight junctions, for example.
(This particular review focused more on the epithelial and immunological barrier as well as a touch on the enteric nervous system).
Postnatal Gut Barrier Development
The first 3 months of postnatal life of pigs represent the most important maturational period of gut development. While some of these changes are a result of intrinsic genetic programming, many are influenced by environmental cues and have a high degree of plasticity, therefore, "perturbations occurring in this critical window can largely shape the long-term phenotype and GI function".
- For the epithelial barrier --- Its development occurs within the first 2 to 3 weeks of postnatal life.
- For the immune barrier --- Its development is quite suppressed at first after birth by several mechanisms. For example, mothers milk will provide immunoglobulins and anti-inflammatory cytokines to suppress immune activation. Several weeks after birth, this immunosuppresive stage will then pass when lymphocytes start developing. For unweaned piglets, a stable number of lymphocytes is achieved at about 6 weeks of age, and after that, secondary lymphoid organs start to mature.
This immunosuppressive environment is important for optimal and long-term maturation of the immune system --- therefore, inappropriate immune stimulation during this period may potentially disrupt the development of gut immune system.
- For the enteric nervous system --- after birth, "major changes take place...including formation of functional neurocircuits, gangliogenesis, and changes in the neurochemical phenotype". Among them, cholinergic neurons (i.e. neurons expressing choline acetyltransferase (ChAT) represent a major neuronal system in the gut. ChAT is the major excitatory neurotransmitter in the GI tract.
Weaning Stress and Gut Barrier Development
As discussed above, this critical period of gut barrier development should remain protected and undisturbed for optimal long-term development. In nature, weaning in pigs is a gradual process that usually complete around 10-12 weeks of age, which "coincides with the near complete maturation of the GI barrier"; whereas in commercial pig production today, weaning is abrupt, occurring between 14-30 days of age.
So...unfortunately, this "vulnerable developmental period for the GI system coincides with the most stressful production practices including early weaning, vaccination, transport, diet change...mixing, fighting and establishment of a new social hierarchy, and more".
Although weaned pigs today are able to survive, we should recognize the potential disruption of normal gut barrier development from stressors associated with weaning.
- Immediate Impact of Weaning
- Breakdown of barrier function and increased permeability compared with age-matched, non-weaned littermate pigs --- this is most pronounced at 24 h post-weaning and then gradually declined over the first 2 weeks post-weaning.
- A robust activation of the GI immune system, as evidenced by an upregulation of proinflammatory cytokines.
- Activation of enteric nerves and therefore induced secretory activity.
- Early weaning --- Long-term Impact
- Increased permeability from early-weaning can persist until 9 weeks post-weaning and even till adult-hood.
- Impaired immune barrier function, compromised immune response, and therefore increased disease susceptibility ( e.g. to E. Coli challenge).
- A persistent upregulation of the enteric cholinergic system. "Given the role of cholinergic nervous system in modulating immune responses, secretory diarrhea and the epithelial barrier, there are potential implications for an upregulated cholinergic system in early weaned pigs as a pathogenic mechanism for increased disease susceptibility associated with early life stressors such as weaning."(To my understanding, "early weaning" refers to both "earlier than natural" as well as "18 vs. 28 day kind of early weaning" here)
Possible Mechanisms of Barrier Dysfunction?
The authors proposed the role of "CRF-Mast cell axis" in modulating barrier function in weaned pigs.
1. Weaning is stressful → Elevation of stress related mediators, such as corticotropin releasing factor (CRF). It was found that changes in GI barrier function post-weaning coincides with elevation of CRF & intestinal CRF receptor expression , but not with the other stress hormones like cortisol. Consistently, administration of CRF receptor antagonists to early weaned pigs reduced elevations in intestinal permeability. So CRF may play a role in modulating gut permeability in weaned pigs.
2. Mast cells, located in gut mucosa, serve as important immune modulators, and are required for host defense. Early weaning increases intestinal mast cell activity; similar with CRF, when the pigs are administered the mast cell stabilizer, intestinal permeability increase was prevented. So...mast cells may also play a central role in driving intestinal epithelial permeability disturbances in the early weaned pig.
Mechanisms of intestinal barrier dysfunction induced by production stressors in pigs: corticotropin releasing factor (CRF)-mast cell axis.
Gut barrier functions are extremely important...The first few weeks postnatal are the critical window for gut barrier development, yet weaning at the age commercial pigs wean today can "alter the developmental trajectory of gut barrier functions, leading to long-lasting deleterious consequences on gut health and disease susceptibility of the animal throughout the production lifespan".
So, anything we can do to help weaning piglets better their gut barrier development will have long-term benefit for their health.
Full article access👇
Moeser, A.J., Pohl, C.S. and Rajput, M., 2017. Weaning stress and gastrointestinal barrier development: Implications for lifelong gut health in pigs. Animal Nutrition, 3(4), pp.313-321.
Hooper, L. 2009. Do symbiotic bacteria subvert host immunity? Nat Rev Microbiol 7, 367–374.
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