Apr 30

Apr 30 An Ageing Immunity and Gut Microbiota Disruption Lead to an Increase in Neurological and Psychiatric Disorders.

Search strategy

Through Scopus and PubMed, the search included keywords with “ageing” AND “immunity”, “nutrition”, “psychiatry” and “neurodegenerative”. The scientific papers in English were the only one considered. The abstracts were reviewed, and the full article was obtained through the right channels. Within the materials, the cited references were also explored. The area researched was to find out how does immunological and inflammatory changes affect the gut as the ageing process occurs, if these changes disrupt the nutrition of a person and the production of neurotransmitters such as serotonin in the gut, and if these could lead to chronic ailment and/or psychiatric/neurodegenerative disorders. The most recent data and advancement in knowledge were looked at.

Summary

Frailty is multifactorial, and ageing is a complex biological process that results in the degeneration of functional and physiological processes. Senescence affects and dysregulates the gut microbiota, the immune system and the delicate balance of the inflammatory state.
Resistance to diseases and the ability to recover declines as ageing progresses. Immunosenescence demonstrates a decrease production and maturity of white blood cells resulting in a decrease in immune responsiveness and an increase in the risk of infections and cancer; hence an increase in mortality in the elderly is noted.
Nutrition intake is affected due to structural and functional changes of the gastrointestinal tract such as delayed gastric emptying, changes in gut motility, decrease in the efficiency of the protective immune system and an increase inflammatory state. Behavioural and psychological changes push the elderly nutritional status to an energy-dense processed and unhealthy food. The result causes a deficiency in vitamins and minerals that are critical for the immune system as well for the function of the gut microbiota.
Gastrointestinal tract disease, gut microbiota dysregulation as well as senoinflammation along with an impaired inflammatory and immune system, are linked to neurological and psychiatric disorders. Neurodegenerative diseases, such as Alzheimer’s Disease, may start from a dysregulated gut microbiota, which is strongly connected with the immune system. Targeting the dysregulation of the microbiota may be a novel therapy for certain autoimmune diseases, depression and anxiety, and certain neurodegenerative diseases.

Introduction

Ageing is an inevitable biological process. Balanced and appropriate nutrition can influence and keep in check some of the most notable chronic diseases such as osteoporosis, cancers and diseases involved around the cardiovascular system (1). Nutrition throughout a person’s life plays a critical role in preventing diseases where otherwise serious and life-threatening illnesses develop as the body ages. In the diet/disease debate, micronutrients have been identified as a pivotal role in prevention and maintaining health (1). However, due to decrease in the nutrition and food intake, and food variety and preferences, the elderly lack micronutrients (1). Nutrition is nonetheless a major modifiable decisive factor and influence an individual’s likelihood of developing diseases and may prevent or at best delay age-related health disorders and cognitive decline (1).

The causes of a depressed immune response are multifactorial as a person is ageing (2). It is well documented that there is a decrease in the B and T cells production from the thymus (exemplified by involution) and bone marrow, and within secondary lymphoid tissues, a decrease in quality and mature lymphocytes (2,3). Over time, the thymic epithelial cells declines which impairs the proliferation as they are not replaced (2).

Inflammatory mediators increase in production with age and may be cytotoxic to the thymus (4,5). An ageing immunity does not imply an immunodeficient immunity, but the response time to either a novel or previously encountered antigens is significantly decreased and not as efficient (2). The outcome of an ageing immunity is an increase in cancers and infections and has been noted to a decrease in immune responsiveness and surveillance; resulting in an increase in mortality of the elderly (2). By 2022 the Australian population is projected to have four million people aged between 65-84 years with a rapid acceleration of certain age groups (65 and 85+ years) (6). Around the world, it is expected by 2050 to have almost 2.1 billion elderly above the age of 60 (7).

As ageing progresses, the overall immune system and the resistance to diseases declines (1-3,5). It is important to note that the gastrointestinal tract (GIT) diseases prevalence is common and that there is an increase in neurological and psychiatric disorders due to GIT structural and functional changes (1,2). During the ageing process, the nutrient intake is affected by structural and psychological factors (1). The result leads to nutritional deficiencies and have been found and condensed to:

Lack of exercise reduced basal metabolic rate, and lack of appetite leads to disinterest in eating nutritious food and replacing it with energy-dense processed and unhealthy nutrition food. Resulting in deficiency of various vitamins and minerals (1).
Loss of teeth and taste buds atrophy pushes the elderly to eat sweet and salted mash food, increasing the risk of cardiovascular diseases and endocrine disorders (8).
Delay gastric emptying along reduced gastric volume leads to avoiding particular food and altered food intake (1,8).
Mucosal defence defects, from structural and functional changes, is due to a decrease in the efficiency of the protective immune system and an increase in inflammation and oxidative stress state (8).
Reduced intestinal motility due to atrophy of the gastrointestinal tract musculature is the cause of various types of gastrointestinal disorders (1,8).

Substantial evidence demonstrates that minimal inflammation, regardless of its location or its extent, has apparent effects on the gastrointestinal function and structure (4). The net result is a change in digestion and absorption, affecting the nutritional status (4). Not surprisingly, ageing is associated with inflammaging, which is the condition of an accumulation of inflammatory mediators in tissues, and molecular inflammation (3-5). The increase in inflammatory mediators is varied between individuals. There is a shift from salutary to the inflammatory environment (5). These could be due to microenvironmental element age-related change, increase in naïve CD4+ T cells presenting activation defects and differentiate into Th17, and accumulation of CD8+ CD28– memory T cells (5).

It has been noted that the immune profile switches to Th17 dominance when changes in the gut microbiota composition have been seen (9). These changes result in a decreased immune function as ageing progresses. Overall, amongst the intricately connected pathways of senoinflammation, a novel term and definition of senescent inflammation, ageing is associated with the dysregulation of the immune response and the inflammatory response switch from beneficial to detrimental (5,10). Chung et al. (2019) describes the result of senoinflammation leads to a chronic systemic inflammatory state where the inflammation is unresolved and uncontrolled, which is characterised by multivariable low-grade, long duration, chronic and systemic responses (5). These traits exacerbate the ageing process, damages the immune system and increase age-related chronic diseases, as well as the reasons in the change in the gut microbiota composition that is commonly seen in the elderly.

There is growing evidence on the importance of keeping a healthy and balanced gut microbiota through nutritious and adequate foods, as it has a profound impact on the body (11). The gut microbiota regulates the metabolism of dietary components. It has a significant influence on the immune system response and brain development, which consequently strongly affects several brain processes impacting behaviour and mood (11,12). Several neuromodulators and neurotransmitters such as catecholamine, kynurenine, serotonin, amyloids, et cetera, are produced by the gut microbiota. This enables the gut microbiota to partake in a bidirectional communication system between the gut and the brain, where scientist have suggested its influence on the “second brain” and be responsible for neurodegenerative diseases such as Alzheimer’s Disease (AD) (10).

Disruption in the gut microbiota such as gut-triggered inflammation, which affects the tryptophan metabolism and disrupts the serotonergic signalling, affects the gut-associated neuroimmune mechanisms (12). These outcomes influence the behaviour and mood, leading to a greater risk of depression (12). Due to the disrupted serotonergic systems in the gut and the rest of the body, inflammation and depression are closely linked and connected, and has been well established (13-15). Latest research has suggested that dementia and AD may as well start from the dysregulation of the gut-brain communication and immune system, and the development of inflammation and dysbiosis (10,16,17). Pluta et al. (2020) mentions with high probability that a disruption in the intestine can cause autoimmune reactions and neuroinflammation, and that the microbiota disruption plays a considerable role in AD development.

The amino acid tryptophan has an essential role in the body and participates in the immune system homeostasis, synthesis of serotonin and inflammatory responses (12,18). Serotonin plays a key role in modulating pro-inflammatory cytokines and regulating the immune system. Within the gut is the kynurenine and serotonin pathways, where 90% of tryptophan is converted into kynurenine, and 3% is converted into serotonin. It is found that these two signalling molecules, kynurenine and serotonin, are vital in the immune response and gut-brain communication (12). In an inflammatory environment, more kynurenine is produced at the cost of serotonin (12). The gut microbiota moderates the function, formation and maturation of several immune cells (12,17,19). It is also involved with the adaptive and innate immune system to which has a robust immunomodulatory impact when gut inflammation is involved (12,17,19). Avoiding energy-dense processed food, unhealthy nutrition, stress and unnecessary antibiotics to prevent a change in the intestinal microbiota composition such as dysbiosis, which has a profound effect on serotonin biosynthesis, is recommended (20,21). Dysbiosis and viruses have been linked to autoimmune diseases and psychological or mental diseases (10,16,17). The prevention or therapy intervention for dysbiosis and the correct modulation of the gut microbiota could be the new therapeutic treatment of AD, and other neurodegenerative disorders (10,16,17). Studies have already demonstrated that restoring the gut microbiota with healthy nutrition could indirectly treat depression and anxiety, (12,20) and slow the neurodegeneration progression in AD (17). Waclawiková and Aidy (2018) mentions the gaps and the research development needed to understand further the complex interaction between the gut microbiota and the disruption in the immune system, products and diet metabolism, which are all linked to the brain and may change mood, behaviour and brain development.

Food Diary and Nutrition. — The importance of nutrition for an ageing immunity

In maintaining a healthy immune system and preventing frailty, a healthy nutritional status is required; however, there are gaps in the research of how specifically these nutrients interact with the immune system and needs further focus and discussion (22,23). It is well documented that protein deficiency in the elderly is one of the leading cause of a decrease in the immune system functionality. In contrast, vitamins A, B6, B12, C, D and E, β-carotene, monounsaturated fatty acids, iron, copper, zinc and selenium, probiotics and bioactive compounds have been linked to an improved immune response (22). An improve diet increases the resistance to infections, increase recovery time and reduces low-grade inflammation (22,23).

An example of the importance of micronutrients, vitamin D (VitD) shall be investigated. VitD and its benefits for bones and soft tissues are well understood (24). VitD is commonly seen deficient in the population, and it is adequately documented that VitD deficiency has been associated with poorer health (24). VitD plays several roles with the immune system by modulating the helper T cell response and increasing cathelecidin (IL-37) secretion (a protein that has viricidal and bactericidal characteristics) (24). Experimentally, calcitriol enhances macrophages to clear pathogens (24). Compared to VitD deficient population, the right amount of VitD has been shown beneficial in an extended inappropriate immune response and are likely involved with a reduction in mortality and critical illness (24). VitD has protective properties with autoimmune diseases such as Type 1 diabetes (T1DM) and thyroid-related autoimmune disorder (24,25). As ageing progresses, an increase in autoimmune thyroiditis incidence is noticed, resulting most of the time in permanent hypothyroidism. However, T1DM needs further follow up, and autoimmune thyroiditis data is limited. It is reported that low VitD is associated with cognitive disorders such as greater dementia risks and structural brain damage (24). A few randomized controlled trials (RCT) suggest the possibility to improve cognition with VitD supplementation and the increase in Parkinson’s disease risk if deficient (24,26). However, these RTCs need more investigations. There is no definitive link with VitD deficiency and depression as generally patients are already in a poor state of health, especially in the elderly where nutrition is poor, and inflammation is common (24). In AD, there isn’t sufficient certainty, but long-term deficiency of VitD may accentuate its risks and further development (24,26).

Tryptophan should not be forgotten as an essential nutritional component. As seen earlier, tryptophan has profound roles in the involvement of mood characteristics, immune system and as a crucial precursor for serotonin. Certain clinical conditions that involve cytokine therapy, principally interferon (IFN-α) and interleukin (IL)-2, and the chronic use of the immune system activation is seen with a much lower tryptophan level due to high catabolism (27). It is found that a nutrient-rich tryptophan foods such as nuts, seeds, soybeans and grains, along a diet including antioxidants can improve cognition, mood, and may be useful for patients with low-grade inflammation conditions (27). For an adult dose 5 mg/kg body weight per day of L-tryptophan is recommended (27). Tryptophan plays an essential role in the regulation of the immune system and the exhaustion and growth depletion of malignant cells and infectious agents. It is important to note that nutrition alone does not dictate the tryptophan availability, but the immune system status also influences its level (27). Studies have demonstrated that patients with Hepatitis C virus infection and malignant melanoma reports having an increase in indoleamine 2,3-dioxygenase (IDO), which converts tryptophan to kynurenine (28). This is a common outcome with patients that have different and various cancers, HIV-1 infected and pro-inflammatory cytokines treatment (29). As the ageing process continues, there is a general increase in an immune and inflammation state activation, which is associated with an increase in IDO activity leading to a further constant low level of tryptophan (27). Having a low tryptophan level is associated with neuropsychiatric abnormality changes leading to a higher risk of depression, poorer prognosis and shorten lifespan (27,30).

Conclusion

The elderly population is ever increasing. Ageing, inevitable and multifactorial, disrupts and dysregulates the gut microbiota, the immune system and the delicate balance of the inflammatory state. The immune system and resistance to diseases declines as ageing progresses. The elderly is increasingly prone to malnutrition due to loss of function and structure of organs, and changes in behaviour and psychological perception of food. As seen in vitamin D and tryptophan deficiency, poor nutrition as has a huge impact on the gut microbiota and the immune system response, which is closely related to psychological and neurological diseases. Further research should be made in targeting and preventing the dysregulation of the microbiota, which may be a novel treatment method for certain autoimmune diseases, depression and anxiety, and specific neurodegenerative diseases.

Published 30th April 2020. Last reviewed 1st December 2021.

Reference

1. Rath P. Nutrition for Elderly. In: Rath P. (eds). Models, Molecules and Mechanisms in Biogerontology. Singapore: Springer Nature Singapore; 2019:411-426. doi: 10.1007/978-981-13-3585-3_19.

2. Montecino-Rodriguez E, Berent-Maoz B, Dorshkind K. Causes, consequences, and reversal of immune system aging. J Clin Invest. 2013;123(3):958-965. doi: 10.1172/JCI64096.

3. Paudel S, Sharma P, Puri N. Immunosenescence, Inflammaging, and Their Implications for Cancer and Anemia. In: Rath P. (eds). Models, Molecules and Mechanisms in Biogerontology. Springer Nature Singapore; 2019:297-319. doi: 10.1007/978-981-13-3585-3_14.

4. Peuhkuri K, Vapaatalo H, Korpela R. Even low-grade inflammation impacts on small intestinal function. World J Gastroenterol. 2010;16(9):1057-1062. doi: 10.3748/wjg.v16.i9.1057.

5. Chung HY, Kim DH, Lee EK, et al. Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept. Aging Dis. 2019;10(2):367-382. doi: 10.14336/AD.2018.0324.

6. De Boer R. Challenges of an ageing population. Australian Parliament House website. https://www.aph.gov.au/About_Parliament/Parliamentary_Departments/Parliamentary_Library/pubs/BriefingBook43p/ageingpopulation. Reviewed October 12, 2010. Accessed April 8, 2020.

7. Department of Economic and Social Affairs. World Ageing Population. United Nations website. https://www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2017_Highlights.pdf. Published 2017. Accessed April 8, 2020.

8. Soenen S, Rayner CK, Jones KL, et al. The ageing gastrointestinal tract. Curr Opin Clin Nutr Metab Care. 2016;19(1):12-8. doi: 10.1097/MCO.0000000000000238.

9. Sochocka M, Donskow-Łysoniewska K, Diniz BS, et al. The Gut Microbiome Alterations and Inflammation-Driven Pathogenesis of Alzheimer's Disease-a Critical Review. Mol Neurobiol. 2019;56(3):1841-1851. doi: 10.1007/s12035-018-1188-4.

10. Sato K, Takahashi N, Kato T, et al. Aggravation of collagen-induced arthritis by orally administered Porphyromonas gingivalis through modulation of the gut microbiota and gut immune system. Sci Rep. 2017;7(1):6955. doi: 10.1038/s41598-017-07196-7.

11. Lassale C, Batty GD, Baghdadli A, et al. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Mol Psychiatry . 2019;24(7):965-986. doi: 10.1038/s41380-018-0237-8.

12. Waclawiková B, Aidy SE. Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression. Pharmaceuticals (Basel). 2018;11(3):63. doi: 10.3390/ph11030063.

13. Thomas J, Khanam R, Vohora D. Augmentation of Effect of Venlafaxine by Folic Acid in Behavioral Paradigms of Depression in Mice: Evidence of Serotonergic and pro-Inflammatory Cytokine Pathways. Pharmacol Rep. 2016;68:396-403. doi: 10.1016/j.pharep.2015.10.003.

14. Lebeña A, Vegas O, Gómez-Lázaro E, et al. Melanoma Tumors Alter Proinflammatory Cytokine Production and Monoamine Brain Function, and Induce Depressive-like Behavior in Male Mice. Behav Brain Res. 2014;272:83-92. doi: 10.1016/j.bbr.2014.06.045.

15. Wang J, Jia Y, Li G, et al. The Dopamine Receptor D3 Regulates Lipopolysaccharide-Induced Depressive-Like Behavior in Mice. Int J Neuropsychopharmacol. 2018;21:448-460. doi: 10.1093/ijnp/pyy005.

16. Garcez ML, Jacobs KR, Guillemin GJ. Microbiota Alterations in Alzheimer’s Disease: Involvement of the Kynurenine Pathway and Inflammation. Neurotox Res. 2019;36:424-436. doi: 10.1007/s12640-019-00057-3.

17. Pluta R, Ułamek-Kozioł M, Januszewski S. Gut microbiota and pro/prebiotics in Alzheimer's disease. Aging (Albany NY). 2020;12(6):5539-5550. doi:10.18632/aging.102930.

18. Gao K, Mu CL, Farzi A, et al. Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. Adv Nutr. 2019. doi: 10.1093/advances/nmz127.

19. Bruce-Keller AJ, Salbaum JM, Berthoud H-R. Harnessing Gut Microbes for Mental Health: Getting From Here to There. Biol Psychiatry. 2018;83:214-223. doi: 10.1016/j.biopsych.2017.08.014.

20. Evrensel A, Ünsalver BÖ, Ceylan ME. Immune-Kynurenine Pathways and the Gut Microbiota-Brain Axis in Anxiety Disorders. Adv Exp Med Biol. 2020;1191:155-167. doi: 10.1007/978-981-32-9705-0_10.

21. Galland L. The gut microbiome and the brain. J Med Food. 2014;17(12):1261-1272. doi:10.1089/jmf.2014.7000.

22. Maggini S, Pierre A, Calder PC. Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients. 2018;10(10):1531. doi: 10.3390/nu10101531.

23. Calder PC, Bosco N, Bourdet-Sicard R, et al. Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Res Rev. 2017;40:95-119. doi: 10.1016/j.arr.2017.09.001.

24. Boucher BJ. Vitamin D status and its management for achieving optimal health benefits in the elderly. Expert Rev Endocrinol Metab. 2018;13(6):279-293. doi: 10.1080/17446651.2018.1533401.

25. Yang CY, Leung PS, Adamopoulos IE, et al. The implication of vitamin D and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol. 2013;45:217-226.

26. Gold JJ, Shoaib A, Gorthy G, et al. The role of vitamin D in cognitive disorders in older adults. US Neurology.2018;14:41-46. doi:10.17925/usn.2018.14.1.41.

27. Strasser B, Gostner JM, Fuchs D. Mood, food, and cognition. Curr Opin Clin Nutr Metab Care. 2016;19(1):55-61. doi: 10.1097/MCO.0000000000000237.

28. Capuron L, Geisler S, Kurz K, et al. Activated immune system and inflammation in healthy ageing: relevance for tryptophan and neopterin metabolism. Curr Pharm Des. 2014;20:6048-6057.

29. Gostner JM, Becker K, Kurz K, et al. Disturbed amino acid metabolism in HIV: association with neuropsychiatric symptoms. Front Psychiatry. 2015;6:97.

30. Capuron L, Schroecksnadel S, Féart C, et al. Chronic low grade immune activation in the elderly is associated with increased tryptophan catabolism and altered phenylalanine turnover: role in neuropsychiatric symptomatology. Biol Psych. 2011;70:175-182.