When your second brain gets old and what to do about it: the ageing of the enteric nervous system

In this post, nutrition and health neuroscience researcher Miguel Toribio-Mateas shares his insights on the ageing of a complex network of nerves that connects the gut with the brain, known as the enteric nervous system.

What is the enteric nervous system (ENS) and why should we care about it?

The Enteric Nervous System or ENS for short is one of the main divisions of the autonomic nervous system (ANS), which innervates the gut via a mesh-like network of neurones connected with the vagus nerve and prevertebral ganglia. The ENS is deeply intertwined with both the sympathetic and parasympathetic nervous systems, although it can thought of as “having a mind of its own”, as it can work independently of both and is also capable of operating independently of the spinal cord and even from the brain itself1.

Ageing of the neurones in the ENS is important because these cells control the motor functions of the gut. A lot of the issues with bowel motility experienced as we age can be tracked back to malfunction or indeed dysfunction of these neurones, which communicate through many of the same neurotransmitters as the central nervous system (CNS), including acetylcholine, dopamine, and serotonin. Last but not least, ENS neurones are also in charge of the secretion of gastrointestinal enzymes. With this incredible range of activity, it is no wonder that the ENS has been dubbed “the second brain”.

How the ENS changes during ageing

The ENS changes during normal ageing and the enteric neurones are also affected by some conditions which are primarily diseases of other systems and that often show progressive change with increasing age. Examples are Parkinson’s disease2 and diabetic neuropathy3, in which enteric, as well as other autonomic neurones, are affected. Changes in the ENS during ageing in humans is also confounded by effects of other, non-gastrointestinal conditions such as cardiovascular disease (CVD)4, in particular by side effects of CVD medication on gastrointestinal physiology5,6.

These are the three key changes that the ENS goes through during ageing:

  • A reduction in the number of neurones. In contrast with other parts of the nervous system where neuronal numbers are known to be significantly reduced only during pathologicalageing, the number of neurones in the ENS does diminish markedly during normal ageing too7,8.
  • Studies seem to point to a reduction in total myenteric neurones. These are neurones located in the myenteric plexus which control gut motility. They originate in the medulla oblongata and host a collection of neurones from the ventral part of the brain stem. The vagus nerve then carries their axons to their destination in the gastrointestinal (GI) tract. It does appear that age-related neuron loss occurs exclusively in the cholinergic subpopulation of myenteric neurons, whereas nitrergic neurones tend to survive (see further explanation of these below)9. Literature suggests the reduction of myenteric neurones that occurs with ageing is associated with an impairment in intestinal function, particularly motility8. From a clinical perspective, it makes sense that constipation is widely reported as an issue in ageing individuals.

Nitrergic neurones make up nerve fibres that transmit signals based on nitric oxide and associated molecules. Such nerves are recognised to play major roles in the control of smooth muscle tone and motility and of fluid secretion in the GI tract. The relevance of this discussion around different types of neurones involved in gut function is that they may benefit from different nutritional substrates. For example, nitrergic neurones would benefit from amino acids like L-arginine as a precursor to nitric oxide. Nuts, seeds, pulses and seaweed are good sources of L-arginine, as well as meat. Cholinergic neurones convey signals via acetylcholine, which requires choline for its production. Good sources of choline are eggs, liver, and peanuts.

  • Loss of overall neuroplasticity. This is based on the loss of density of nerve fibres and the widespread occurrence of age-related nerve degeneration. Although most of the evidence is based on animal studies, there is some human evidence too on the loss of nerves that transmit signals based on choline10.

As discussed above, the GI tract is capable of functioning in the absence of extrinsic neuronal inputs. The stomach and oesophagus are much more dependent on neuronal inputs from the CNS, particularly from the parasympathetic and sympathetic branches of autonomic nervous system (ANS), the control system that acts largely unconsciously and regulates bodily functions such as the heart rate, digestion, respiratory rate, pupillary response, urination, and sexual arousal.

The sympathetic nervous system exerts a predominantly inhibitory effect upon GI muscle and provides a tonic inhibitory influence over mucosal secretion while, at the same time, regulating GI blood flow via constriction of the capillaries that supply blood to the gut. On the other hand, the parasympathetic nervous system, exerts both excitatory and inhibitory control over gastric and intestinal tone and motility. Although these gastrointestinal functions are controlled by the autonomic nervous system and take place, by and large, independently of conscious perception, it is clear that the higher CNS still has overall control of the equilibrium or homeostasis in the ENS as well as cognitive and behavioural functions.

Ageing of the gut as an ecosystem

Apart from the factors mentioned above affecting the ageing process of the ENS, there are changes affecting the homeostatic intestinal environment of the gut as an ecosystem, referred to as eubiosis. Perturbations in microbiota composition and abundance known as dysbiosis and decline in the integrity of the gut barrier also contribute to the development of age-related conditions. Under conditions of equilibrium, epithelial cells produce natural anti-microbial peptides, known as AMPs for short, in response to pro-inflammatory cytokines such as interleukins, e.g. IL-22. They also express proteins known as pattern recognition receptors or toll-like receptors (TLR) which play a key role in recognising microbes.

A wide array of microorganisms regulate the secretion of mucous as well as the production of AMPs. Additionally, microorganisms help protect the integrity of the gut barrier by means of the production of short-chain fatty acids (SCFAs).

In addition to the activity of epithelial cells, goblet cells produce mucus which carries immunoglobulins, e.g. secretory IgA (sIgA), an immunoglobulin that limits invasion by potential pathogenic and opportunistic bacteria, yeast or parasites. SIgA binds to commensal bacteria and soluble antigens, disabling their ability to stick to the epithelium and thereby diminishing the risk of leakage through the gut barrier.

Lymphoid cells (e.g. TH17 cells) also play a role as part of the gut’s immune system, helping defend the rest of the body by producing further pro-inflammatory interleukins.

Ageing of the gut ecosystem can resemble dysbiosis in that altered microbiota composition and weakened/perturbed gut permeability may lead to increased sticking and leakage of various microbes and their by-products through the gut barrier, which triggers an inflammatory response eventually increasing susceptibility to gut-related as well as systemic conditions via the gut-brain axis as well as the gut-liver axis.

Enteric nervous system highlights

  • The enteric nervous system (ENS) is by far the largest component of the autonomic nervous system and is uniquely equipped with a series of tiny circuits (actually called “microcircuits”) that enable it to coordinate gastrointestinal function independently of input from the central nervous system (CNS).
  • Most of the communication molecules, their pathways and anatomical properties of the CNS are also used by the ENS. This explains why pathophysiological processes that underlie conditions affecting the CNS often have ramifications that affect the ENS. Transmissible spongiform encephalopathies, autistic spectrum disorders, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and varicella zoster virus (VZV) infection are examples of disorders with both gastrointestinal and neurological consequences.
  • In fact, the nervous system and immune systems are so intertwined that they enable the spread of diseases acquired in the gut to the brain, particularly via the main “communication highway” that is the vagus nerve.

What can we do to support healthy ageing of the ENS?

The adult enteric nervous system is maintained by a dynamic balance between the death and rebirth of neurones. Regeneration of nerve fibres relies on a positive neuroplastic balance11. In plain English, it depends on nerve structures experiencing more “bushing out”, helped by the addition of newly born neurones, i.e. neurogenesis, as well as on the “branching out” or arborisation of these and existing neurones, a process known as neuroplasticity.

Based on what we know already about how to promote healthy neuroplasticity in the CNS, it is postulated that the same natural compounds could be used in order to promote healthy ageing of the ENS.  These are my three key actions for supporting this process:

Eat the rainbow: Promote a balanced gut ecosystem

Poor dietary fibre intake is a key factor associated with low microbial diversity which, in turn, has been linked with an increase in chronic inflammatory disorders. In addition, the progressive contamination of the environment we inhabit with countless toxic compounds, e.g. plasticisers and emulsifiers, contribute to gut dysbiosis and act as a trigger for deranged host immune responses and mucosal defences12. In order to promote balance, lower inflammation and provide nutrition for the diverse community of microbes that live in our gut, eating a diet rich in fresh produce, particularly brightly coloured fruit and vegetables, as well as a variety of pulses, nuts and seeds, is my top evidence-based recommendation. In a wonderfully comprehensive paper entitled “A Review of the Science of Colorful, Plant-Based Food and Practical Strategies for “Eating the Rainbow”, Dr Deanna Minich provides the scientific background as to why this simple approach is so powerful13. This is one of the “recommended reading” articles that I have chosen for you and that you’ll find at the bottom of this article.

When pondering what “eating the rainbow” might mean for you, please think for a moment how you have hundreds of potential tools at your disposal and do include herbs and spices as part of this “therapeutic portfolio”. Herbs and spices are rich in polyphenols; molecules that go by names such as phenolic acids, stilbenes, lignans, flavonols, flavanols and anthocyanidins and that comprise a class of approximately 8,000 compounds with antioxidant properties14. You’ll also find polyphenols in fruits, vegetables, tea, wine, and even in beer and cider.

Whereas polyphenols are not considered “essential nutrients,” there is enough scientific evidence to suggest that they are powerful supporters for neuroprotection and age-related cognitive decline as well as oxidative stress via mechanisms involving the maintenance of metabolic homeostasis and the promotion of synaptic plasticity. Curcumin, catechin polyphenols from tea as well as flavanols from cocoa have the best scientific backing for use to support healthy ageing of the CNS and would make a positive addition to a dietary regime that enables practitioners to support the healthy ageing of the ENS15.

Support your stress response

Several natural compounds present in plants that are either used as food or as food supplements have been found to support human resilience, defined as the ability to thrive in conditions of adversity. Additionally, some live beneficial microorganisms known for their probiotic properties also have growing evidence of their ability to support a healthy stress response. Some examples of these factors include:

  • Bifidobacterium longum, described by some authors as a psychobiotic, i.e. a live microorganism with a potential mental health benefit16.
  • Ginsenosides in ginseng and rosavins / salidrosides, natural compounds found in Rhodiola rosea are reported in literature as having adaptogenic properties17,18.
  • Additionally, scientists have found these compounds work similarly to some of the polyphenols in olive oil, which might also support neuroplasticity19,20.

Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathoadrenal system (SAS) caused by the cumulative burden of repetitive or chronic environmental stress challenges, referred to as high allostatic load23, contributes to the development of neurological / mental health conditions, and is also a high risk factor for illnesses including hypertension, atherosclerosis, and the insulin-resistance-dyslipidaemia syndrome, as well as certain disorders of immune function24. More contextually relevant to our discussion in this article is the fact that psychosocial stress is almost synonymous with oxidative stress, which is implicated in ageing of the central nervous system. Oxidative stress occurs upon excessive free radical production resulting from an insufficiency of the counteracting antioxidant response system. The brain, with its high oxygen consumption and lipid-rich content, is highly susceptible to oxidative stress. Therefore, oxidative stress–induced damage to the brain has a strong potential to negatively impact normal CNS functions25. Dysbiosis might increase brain inflammation and reactive oxygen species levels, as well as abnormal aggregation of proteins that might also affect nerve fibres in the ENS26.

Keep active, keep moving: The importance of physical activity as part of lifestyle medicine

Recent studies have continued to support the hypothesis that exercise can enhance the number of beneficial microbial species, enrich microflora diversity, and improve the development of commensal bacteria. All these effects are beneficial for the whole of the body, and not just the gut, as they help improve overall health status. In fact, evidence suggests that different metabolites and signalling molecules, such as SCFAs produced by gut bacteria, can activate vagal afferent receptors of the enteric nervous system21. These signals are amplified by the gut-brain axis and delivered to various regions in the brain, such as the limbic system, thereby helping with stable mood22. Therefore, it could be argued that this third recommendation is entwined with number two above in that physical activity might contribute to mental wellbeing by means of these afferent signals that enable limbic plasticity.

Therefore, if keeping active contributes to a more balanced gut ecosystem, this is another simple yet powerful strategy to keep our ENS healthy as we age.

Final thoughts

The science of how to keep a “young and vibrant” enteric nervous system is patchy and mostly based on knowledge researchers have acquired from experiments in animals. However, a lot of the interventions we already have substantial evidence for, as approaches for keeping the central nervous system healthy as humans age, also seem to make sense when dealing with the ENS.

I hope this article has provided some additional tools to add to the range of strategies you can use when dealing with gut health. My intention was to shed light on angles different to just “feeding your gut bugs” or “eating fibre”. Even if the interventions are similar, the rationale might be slightly different, and often one finds that subtle changes in how a case is approached can have a positive outcome.


CLINICAL OUTCOMES STUDY – Call for participants

Measuring outcomes in modalities such as Nutritional Therapy can be tricky. This is why I’ve invested the last 4 years of my life to developing non-invasive tools that enable practitioners to gather solid understanding of their clients’ health by using validated tools in the areas of gut health and mental wellbeing. I am extremely excited to announce that the British Association for Nutrition and Lifestyle Medicine has started to recruit practitioners for its first clinical outcomes research study on this particular are. If you are a member of BANT, are actively involved in clinical practice and support clients with gut health and mental wellbeing matters, please sign up for the study here: http://wecudos.com/futureleadersprogram/. It is an excellent opportunity to contribute to your own learning about this subject as well as to the development of the profession.


Miguel is a multifaceted professional whose expertise crosses the bridge between research and practice in the fields of nutrition, biotechnology, microbiology and neuroscience. As a Research Fellow at the School of Applied Sciences of London South Bank University, Miguel is working on clinical trials to learn about the relationship between food, gut bacteria and mental wellbeing, which is the subject of his talk. He is also the Lead Investigator in BANT’s first clinical outcomes study, which BANT members can contribute to by signing up here. As an international public speaker he is well known for his depth of knowledge, his engaging and unique style of presentation and his ability to reach a wide range of listeners.


With many thanks to Miguel for this blog; if you have any questions regarding the health topics that have been raised, please don’t hesitate to get in touch with Clare via phone; 01684 310099 or e-mail clare@cytoplan.co.uk


Essential Reading for Practitioners on the Enteric Nervous System

  • Rao, M. & Gershon, M. D. (2016). The bowel and beyond: the enteric nervous system in neurological disorders. Nature reviews. Gastroenterology & hepatology, 13, 517-528.DOI:10.1038/nrgastro.2016.107
  • Santos, S. F., De Oliveira, H. L., Yamada, E. S., Neves, B. C. & Pereira, A., Jr. (2019). The Gut and Parkinson’s Disease-A Bidirectional Pathway. Frontiers in neurology, 10, 574-574.DOI:10.3389/fneur.2019.00574
  • Nagpal, R., Mainali, R., Ahmadi, S., Wang, S., Singh, R., Kavanagh, K., Kitzman, D. W., Kushugulova, A., Marotta, F. & Yadav, H. (2018). Gut microbiome and aging: Physiological and mechanistic insights. Nutrition and healthy aging, 4, 267-285.DOI:10.3233/NHA-170030
  • Minich, D. M. (2019). A Review of the Science of Colorful, Plant-Based Food and Practical Strategies for “Eating the Rainbow&#x201d. Journal of Nutrition and Metabolism, 2019, 19.DOI:10.1155/2019/2125070

Relevant Cytoplan Products

Acidophilus Plus –  contains Lactobacillus acidophilus and a further 8 live native bacterial strains, plus a small amount of fructo-oligosaccharides (FOS).

Fos-A-Dophilus – contains 6 strains of live native bacteria, plus a small amount of prebiotic. It is designed to have activity throughout the whole GI tract.

CytoProtect GI Tract – a synergistic multi-nutrient, botanical and live native bacteria formula designed to support integrity and stability of the surface membranes (i.e. lining) of the entire GI (gastrointestinal) tract.

Saccharomyces Boulardii – a unique, natural and safe microorganism, with a wealth of research data, which has been used worldwide as a food supplement for more than half a century.

Siberian Ginseng – suitable for the whole family and are free from live yeast.

Rhodiola – Rhodiola rosea has a history of use in herbal medicine. This product comes at a potency of 250mg per capsule.

Organic Turmeric Plus – a herbal complex containing Turmeric (providing curcumin), Cat’s Claw and Gotu Kola.

Phytoshield – a very potent and powerful phyto-antioxidant nutrient formula containing high levels of flavonoids and carotenoids.

Aloe XL Inner Leaf Gel – a single concentrate containing only pure, unprocessed inner leaf gel.

Psyllium Husk – cleaned to 99.9% purity, dry processed and importantly, contains no solvents.

Omega Balance – Omega-3 and omega-6 are essential to maintain the normal function of the body – they are found in every cell in the body where they have both structural and functional roles.


References

  1. Saffrey, M.J. Ageing of the enteric nervous system. Mechanisms of Ageing and Development 2004, 125, 899-906.https://doi.org/10.1016/j.mad.2004.09.003
  2. Santos, S.F.; de Oliveira, H.L.; Yamada, E.S.; Neves, B.C.; Pereira, A., Jr. The gut and parkinson’s disease-a bidirectional pathway. Frontiers in neurology 2019, 10, 574-574.10.3389/fneur.2019.00574
  3. Bagyánszki, M.; Bódi, N. Diabetes-related alterations in the enteric nervous system and its microenvironment. World journal of diabetes 2012, 3, 80-93.10.4239/wjd.v3.i5.80
  4. La Rovere, M.T.; Christensen, J.H. The autonomic nervous system and cardiovascular disease: Role of n-3 pufas. Vascul Pharmacol 2015, 71, 1-10.10.1016/j.vph.2015.02.005
  5. Zhang, D.Y.; Anderson, A.S. The sympathetic nervous system and heart failure. Cardiology clinics 2014, 32, 33-vii.10.1016/j.ccl.2013.09.010
  6. Florea, V.G.; Cohn, J.N. The autonomic nervous system and heart failure. Circulation Research 2014, 114, 1815-1826.doi:10.1161/CIRCRESAHA.114.302589
  7. Giaroni, C.; De Ponti, F.; Cosentino, M.; Lecchini, S.; Frigo, G. Plasticity in the enteric nervous system. Gastroenterology 1999, 117, 1438-1458.10.1016/S0016-5085(99)70295-7
  8. Saffrey, M.J. Cellular changes in the enteric nervous system during ageing. Developmental Biology 2013, 382, 344-355.https://doi.org/10.1016/j.ydbio.2013.03.015
  9. Phillips, R.J.; Kieffer, E.J.; Powley, T.L. Aging of the myenteric plexus: Neuronal loss is specific to cholinergic neurons. Autonomic Neuroscience 2003, 106, 69-83.https://doi.org/10.1016/S1566-0702(03)00072-9
  10. Bernard, C.E.; Gibbons, S.J.; Gomez-Pinilla, P.J.; Lurken, M.S.; Schmalz, P.F.; Roeder, J.L.; Linden, D.; Cima, R.R.; Dozois, E.J.; Larson, D.W., et al. Effect of age on the enteric nervous system of the human colon. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society 2009, 21, 746-e746.10.1111/j.1365-2982.2008.01245.x
  11. Kulkarni, S.; Micci, M.-A.; Leser, J.; Shin, C.; Tang, S.-C.; Fu, Y.-Y.; Liu, L.; Li, Q.; Saha, M.; Li, C., et al. Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis. Proceedings of the National Academy of Sciences 2017, 114, E3709-E3718.10.1073/pnas.1619406114
  12. Chassaing, B.; Van de Wiele, T.; De Bodt, J.; Marzorati, M.; Gewirtz, A.T. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut 2017, 66, 1414-1427.10.1136/gutjnl-2016-313099
  13. Minich, D.M. A review of the science of colorful, plant-based food and practical strategies for “eating the rainbow&#x201d. Journal of Nutrition and Metabolism 2019, 2019, 19.10.1155/2019/2125070
  14. Phillips, C. Lifestyle modulators of neuroplasticity: How physical activity, mental engagement, and diet promote cognitive health during aging. Neural Plasticity 2017, 2017, 22.10.1155/2017/3589271
  15. Gomez-Pinilla, F.; Nguyen, T.T. Natural mood foods: The actions of polyphenols against psychiatric and cognitive disorders. Nutritional neuroscience 2012, 15, 127-133
  16. Allen, A.P.; Hutch, W.; Borre, Y.E.; Kennedy, P.J.; Temko, A.; Boylan, G.; Murphy, E.; Cryan, J.F.; Dinan, T.G.; Clarke, G. Bifidobacterium longum 1714 as a translational psychobiotic: Modulation of stress, electrophysiology and neurocognition in healthy volunteers. Translational psychiatry 2016, 6, e939-e939.10.1038/tp.2016.191
  17. Panossian, A.; Wikman, G. Effects of adaptogens on the central nervous system and the molecular mechanisms associated with their stress-protective activity. Pharmaceuticals (Basel, Switzerland) 2010, 3, 188-224.10.3390/ph3010188
  18. Zhuang, W.; Yue, L.; Dang, X.; Chen, F.; Gong, Y.; Lin, X.; Luo, Y. Rosenroot (rhodiola): Potential applications in aging-related diseases. Aging Dis 2019, 10, 134-146.10.14336/ad.2018.0511
  19. Concerto, C.; Infortuna, C.; Muscatello, M.R.A.; Bruno, A.; Zoccali, R.; Chusid, E.; Aguglia, E.; Battaglia, F. Exploring the effect of adaptogenic rhodiola rosea extract on neuroplasticity in humans. Complement Ther Med 2018, 41, 141-146.10.1016/j.ctim.2018.09.013
  20. Sangiovanni, E.; Brivio, P.; Dell’Agli, M.; Calabrese, F. Botanicals as modulators of neuroplasticity: Focus on bdnf. Neural plasticity 2017, 2017, 5965371-5965371.10.1155/2017/5965371
  21. Forsythe, P.; Bienenstock, J.; Kunze, W.A. Vagal pathways for microbiome-brain-gut axis communication. Adv Exp Med Biol 2014, 817, 115-133.10.1007/978-1-4939-0897-4_5
  22. Stilling, R.M.; Ryan, F.J.; Hoban, A.E.; Shanahan, F.; Clarke, G.; Claesson, M.J.; Dinan, T.G.; Cryan, J.F. Microbes & neurodevelopment–absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav Immun 2015, 50, 209-220.10.1016/j.bbi.2015.07.009
  23. Ullmann, E.; Perry, S.W.; Licinio, J.; Wong, M.-L.; Dremencov, E.; Zavjalov, E.L.; Shevelev, O.B.; Khotskin, N.V.; Koncevaya, G.V.; Khotshkina, A.S., et al. From allostatic load to allostatic state—an endogenous sympathetic strategy to deal with chronic anxiety and stress? Frontiers in Behavioral Neuroscience 2019, 13.10.3389/fnbeh.2019.00047
  24. Vanitallie, T.B. Stress: A risk factor for serious illness. Metabolism 2002, 51, 40-45.10.1053/meta.2002.33191
  25. Salim, S. Oxidative stress and the central nervous system. Journal of Pharmacology and Experimental Therapeutics 2017, 360, 201-205.10.1124/jpet.116.237503
  26. Rao, M.; Gershon, M.D. The bowel and beyond: The enteric nervous system in neurological disorders. Nature reviews. Gastroenterology & hepatology 2016, 13, 517-528.10.1038/nrgastro.2016.107

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2 thoughts on “When your second brain gets old and what to do about it: the ageing of the enteric nervous system

    1. Hi Mark – Thanks for your comment on our blog and request for more on preventative measures. The practical key takeaways are:

      – To eat a rainbow of food colours – so as well as including vegetables of all colours green, yellow, orange, red, purple and white, also consider what herbs and spices you can add to your diet. On another blog we discussed diet diversity in more detail and talked about the 50 food challenge. This is where over the period of a week you record each time you have eaten a particular type of food, you can only record a food once. The challenge is to eat 50 different types of food over the course of a week. Bread and pasta would count as one food (i.e. both are wheat based) but a white onion and red onion would count as two different types of food. You can download a template table for this challenge here.

      – If stress is an issue, then consider stress management techniques. There are also supplements that are used for stress support. In the blog Miguel mentions in particular live bacteria and some herbal adaptogens.

      – Physical activity and exercise can support the maintenance of the enteric nervous system and thus gut health

      If you would like any specific advice we do offer a free health questionnaire service. If you complete and return a health questionnaire to us we will send you some written diet and supplement recommendations. You can find the questionnaire here.

      Thanks,
      Clare

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