Prebiotics and Probiotics for the Elderly

Health benefits of FOS

Background Background With aging, multifaceted physiological changes (such as metabolic and immunological functions) occur in the human body (Kenyon, 2010). The overall bodily functions start to decline in their efficiency with aging. This may be a contributing factor to various chronic sicknesses like diabetes, obesity, cardiovascular disorders, infections, bowel diseases, cancers, low immunity associated diseases and nervous related diseases (Lopez-Otin et al. 2013). Intestinal health plays an important role in the occurrence of these health problems. Impairment in intestinal functions possibly reduces the nutrients’ supply for normal body function, leading to possibilities of altered digestive process, constipation, poor bacterial fermentation, altered metabolite production and reduced bacterial excretion (Biagi et al. 2012). Particularly, in immune compromised elderly condition, the negatively altered gut microbiome together increases the healt h risks (Maloy et al. 2008; Schiffrin et al. 2010). The gut microbiome plays key role in maintaining the health by supporting on energy supply, facilitating improved nutrients absorption rate (eg. minerals) and production of metabolites - short chain fatty acids (SCFA), directly or indirectly involves in the maintenance of immune and nervous functions and increases the defense mechanisms to protect the gut health from bad microbes. Also, the positive changes in the gut microbiome composition and it functions have shown positive health benefits not only in elderly but in all age groups (Biagi et al. 2012). Therefore the age related alterations in intestinal motility and functions and quality of diet will have a major influence on the gut microbial composition. Further, functions, elderly people need medications, maybe along with a modified dietary intake. Clinical evidences demonstrate association of dietary modifications and improvement of gut health in different age groups maintaining or improving the gut health. Prebiotics, probiotics and synbiotics are some of the alternate options for medications and their association on the improvement of gut microbiome are well established (Figure 1, Singh et al. 2017). What are Pr What are Prebiotics and Probiotics ebiotics and Probiotics? ? Figure 1: Impact of dietary intake on gut health. (Adopted from Singh et al. 2017) Prebiotics are defined as “a non-digestible food ingredient by the gastro intestinal tract but fermented in colon and beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria (particularly Lactobacilli Bifidobacteria spp.) in the colon (Singh et al. 2017), and thus improves host health” (Gibson and Roberfroid, 1995) by yielding beneficial metabolites such as Figure 1: Impact of dietary intake on gut health. (Adopted from Singh et al. 2017) 4 s hort chain fatty acids as end products. Fermentable carbohydrates derived from fructans such as fructooligosaccharide (FOS), short chain FOS (scFOS), inulin, galacto-oligosaccharides (GOS) and xylans are the most well documented prebiotic fibers. These reach the colon intact where they are fermented by the colon bacteria for metabolite production such as short chain fatty acids (SCFA). Probiotics are live microorganisms and adequate amounts intake leads to the beneficial health effects. The human gut consists of both good and bad. Highly recognized probiotic microorganisms are the to maintain the normal bodily Page 1 1 of 1 1

lactobacillus and Bifidobacterium and have well demonstrated their health benefits such as gut health and immunity. Table 1: Probiotics and prebiotics – Key differences (Adopted from Jockers 2019) Probiotics Probiotics Prebiotics Prebiotics Line Microorganisms Non-living (carbohydrate) by human digestive system non-digestible ingredient Bacteria or yeast Serve as food for friendly bacteria in the gut Available as food naturally occurring in certain foods, such as chicory artichoke,onion, leek, garlic, carrot and dandelion Prebiotics aid digestion and may support the treatment of several chronic digestive disorder or inflammatory bowel disease. Available as food supplements and in certain foods containing live cultures such as yoghurt, coconut water kefir, aged cheese, kombucha, pickles, kimchi sauerkaraut, or miso Probiotics may support the treatment of diarrhea, irritable bowel syndrome, certain intestinal infections, prevent or reduce the severity of colds and flu or aid digestion supplements and root, Jerusalem Ingested prebiotics not only helps in improving satiety, weight management and glycemic management, but also acts a fuel source for the colon probiotics. Since prebiotic and probiotics are essential for human health, balanced amount intake of these would be important. Key differences of pre and probiotics are listed in Table 1. The Elderly Gastrointestinal (GI) health The Elderly Gastrointestinal (GI) health Vital organs in the body and its physiological process are decline with ageing which leads to changes in the physiological processes that are dependent on the gastrointestinal (GI) tract. The intestinal functions are found to lower in elderly compared to the young adults (Ouwehand et al. 2008). An impaired GI health (Figure 2) would primarily cause poor digestion, altered or reduced nutrient absorption rate and thus end up with nutrient inadequacy for a normal and healthy body functioning. Unlike young adults, the gut health is weaker in its physiological functions, lower in gut microbial load (Ouwehand et al. 2008) and many times the older Figure 2: Leaky gut wall and its effects. Adopted from Jockers 2019 5 population is dependent on medications (majorly antibiotics), which may also affect internal organ functions such as gut and kidney. As a result of prolonged medications, it possibly slows down the gut transit time (Pimentel et al. 2006) and other functions. Page 2 2 of 2 2

In general, there are age related multiple difficulties are well recognized and presented in Table 2. (D’Souza, 2007) Table 2: Age related multiple gastro intestinal changes and difficultie SNo 1 2 GI tract Mouth Oesophagus Age related multiple difficulties Dysphagia (difficulty in initiating a swallow process), Odynophagia (painful swallowing due to decreased peristalsis, and uncoordinated contractions), Peptic ulcer, gastric atrophy, decreased gastric acid secretion, decreased mucus production and mucosal prostaglandin levels, reduced gastric emptying owing to slowing of transit time etc., Apparently does not change much but it has reduced physiological functions (nutrient malabsorption), however, with aging, it might worsen due to physiological changes in GI tract and other morbidity factors 3 Stomach 4 Small intestine Changes in gut microbiome and its metabolism in the elderly Changes in gut microbiome and its metabolism in the elderly The gut microbiome changes with aging, becoming less diverse compared to the younger populations (Ducan and Flint, 2013), suggesting a decline with aging. Beneficial bacteria such as bifidobacteria are found to be lower or altered in older age (Mitsuoka and Hayakawa, 1972, Hopkins and Macfarlane, 2001; He et al. 2003; Nagpal and Yamashiro, 2015) and also, might be altered by other factors such as changes in dietary intake patterns. Thus it is important to provide solutions that may support a good gut health for overall health maintenance. In elderly, primarily the GI tract and its functions (such as impaired digestion process, transit time) initiate to be weaker than younger adults. Also, the mortality due to GI infections is higher in the elderly compared to young adults. The changes in the gut related process and metabolites may s upport health maintenance and decrease morbidity in elderly (Figure 3; Nagpal et al. 2018; Duncan et al. 2009, Lopez-siles et al. 2012). SCFA, essential for various body functions, is the major metabolite produced in the gut. Butyric acid inhibits liver cholesterol synthesis and provides a source of energy for human colon epithelial cells. Propionic acid helps to inhibit the fatty acid synthesis in liver, thereby lowering the rates of triacylglycerol secretion. Acetate is involved in the control of hepatic cholesterol synthesis and it reduces the rate of cholesterol synthesis (Wong et al. 2006). Due to the SCFA production, there is reduction in the pH of colon, which indirectly influences on facilitating the mineral absorption and the potentially pathogenic microbes may reduce in acidic pH environment, thus supporting to the defense mechanism. To summarize, a leaky gut wall is more prevalent in elderly population and leads to impaired intestinal barrier function and thus reduced nutrient absorption, reduced immune functions, and an increased health risk (Figure 4; Nagpal et al. 2018). Page 3 3 of 3 3

Role of Prebiotics/Probiotics in Bowel Movements Role of Prebiotics/Probiotics in Bowel Movements Prebiotic fibers are hygroscopic in nature, which absorb water in intestine and increases the water retention rate, thereby changes in stool consistency, plasticity, adding bulk to stool. Thus ends with an improved intestinal transit time, improved stool frequency and reduced bowel related diseases such as constipation and diarrhea. Probiotics with bifidobacterium, lactobacillus spp. and yogurt supplementation would help to increase colonic transit, defecation frequency, and faeces stiffening process (Martínez-Martínez et al. 2017). L-rhamnosus supplementation in elderly had shown a 24% increase in defecation frequency (Ouwehand et al. 2002). Also, a synbiotic study with constipated women were supplemented FOS with Lactobacillus and Bifidobacterium strains (LACTOFOS) for 30 day and found that there was a significant improvement in stool consistency (Waitzberg et al. 2013). However, there are inconclusive data on the gut microbial composition changes associated improvement on constipation (Dimidi et al. 2014). Role of Prebio Role of Prebiotics/Probiotics in Immune Function tics/Probiotics in Immune Function The immune functions are adversely affected by the aging process (Goodwin 1995) and which leads to decreased diseased resistance and thus increased mortality rate in elderly (Wayne et al 1990). The most well-characterized age-related changes involve thymic (T) lymphocytes, including a decrease in the numbers of mature CD3+ T cells in peripheral circulation, a decrease in the pool of naïve (CD45RA+ ) T cells, a predisposition toward T helper 2 phenotype expression, and poor capacity of peripheral blood T cells to proliferate and secrete interleukin 2 or to contribute to effective delayed-type hypersensitivity responses in vivo (Lesourd 1995). Regardless, a decline in innate immune cell function is generally considered to be a contributing factor to decreased immunity in the elderly. Prebiotics and probiotics influence the microbial productions through the SCFA, which interact with immune cells and enterocytes and modify their activity (Vitali B et al. 2010). Balancing of T helper cells is critical to ensure an effective immune response to infection and human diseases based on the types of Page 4 4 of 4 4

cytokines secreted. Available evidences suggest that the supplementation of probiotics can increase the fecal bifidogenic bacterial load, immune markers (Bouhnik et al. 2007) and can regulate or support to balance the T helper cytokine functions (Katherine et al. 2014). In a study, 19 elderly nursing home patients were given 8 g FOS for 3 weeks (4g*2/day), there was an increase in the fecal bifidobacteria composition after FOS supplementation. Further, there was a decreased phagocytic activity of granulocytes and monocytes, as well as a decreased expression of interleukin-6 (IL-6) mRNA in peripheral blood monocytes. These results suggested a possible decrease in inflammatory process and increase in fecal bifidobacteria, total lymphocytes, CD4+ and CD8+ cells in elderly (Guigoz et al. 2002). Probiotic supplementation has been demonstrated to increase immune markers such as natural killer cells, serum albumin and intestinal immunoglobulin A (IgA) production and phagocytic activity (26-28- 29) (Patel et al. 2014), a-interferon, total lymphocyte counts, circulating counts of CD4+ and CD25+ cells (Arunachalam et al. 2000; Gill et al. 2001; Sheih et al. 2001) in elderly. In a study, gastrointestinal and respiratory infections were reduced in elderly after supplementation of a probiotics -Lactobacillus spp (Gill et al. 2001). In general, older people are immune compromised (Aspinall and Andrew, 2000) and many clinical evidences are suggesting that probiotic can support to improve the immune functions (Meydani and Ha WK, 2000; Turchet et al. 2003). Thus, interventions that might be an alternate method to restore the immune function in elderly are highly desirable. Role of Prebiotics/Probiotics in Bone health Role of Prebiotics/Probiotics in Bone health It has been estimated that more than 200 million people are suffering from osteoporosis. According to recent statistics from the International Osteoporosis Foundation, worldwide, 1 in 3 women over the age of 50 years and 1 in 5 men will experience osteoporotic fractures in their lifetime Sozen and Ozisik, 2017). The Metabolite Production and pH Reduction Theory: The Metabolite Production and pH Reduction Theory: Majorly, the acceptable theory between prebiotics and mineral absorption is with respect to the production of short-chain fatty acids (SCFAs) in the lower gut (e.g. Prebiotics and calcium absorption mechanism; Figure 5). Page 5 5 of 5 5

Studies documented that that in the presence of SCFAs in the large intestine, there is a rise in cecal blood flow, (Kvietys et al. 1981) that have trophic effects epithelial proliferation, decrease the cecal pH (Younes et al. 1996, Le Blay et al. 1999), and increase the trans-cellular passage of minerals (Trinidad et al. 1996; Trinidad 1999). It is known that mineral absorption calcium) occurs in the large have on cell (e.g. majorly F Figure 5 igure 5: : intestine in a lowered pH condition (acidic environment). This lowered (acidic) cecal pH leads to greater solubilization of minerals (e.g magnesium) so that the biologically available mineral concentration is increased (Lutz et al. 1991; Rémésy et al. 1992). For example, it has been suggested that in the case of calcium, a reduced pH in the colon prevents calcium to form complexes with negatively charged metabolites (as phytates and oxalates). Production of SCFAs improves mineral (calcium) absorption through an exchange of intracellular H+ for Ca2+ in the distal colon (Younes et al. 1996, Demigne et al. 1999, Whisner and Castillo, 2018). Thus, there may be an increase in the mineral availability for absorption and subsequent improvement in bone health, supporting the concept of improved mineral status with the intake of prebiotic fibers. Animal studies have shown a possible relation between mineral absorption (particularly calcium and magnesium) and oligosaccharides, including FOS (Ohta et al. 1994; Ohta et al. 1995; Delzenne et al. 1995). The Gut Bone Axis Theory: The Gut Bone Axis Theory: Another theory is the Gut-Bone Axis theory. Dietary consumption of prebiotics (as FOS) stimulates the microbes in the gut and mediates the intestinal environment. These changes promote the production of signaling molecules, immune cells, and metabolites, which in turn are thought to influence bone mineral uptake through the mechanistic action of SCFAs. Microbial signaling molecules may trigger systemic neuro-inflammatory responses that ultimately stimulate the release of hematopoietic and immune system cells from the bone marrow which feed back to the intestinal tissue to influence intestinal Page 6 6 of 6 6

microbial communities and tissue inflammation (Whisner and Castillo, 2018; Figure 6). 9 In a clinical study, a daily intake of 3.6g short chain fructo-oligosaccharide for 24 months in a randomized double blind cross over study did not show any improvement in the bone mineral density among post-menopausal women, however, the study reported a slowdown in the total body and spinal bone loss indicating improvement in calcium status in long term (Slevin et al 2014). Role of Prebiotics/Probiotics in Cancer Role of Prebiotics/Probiotics in Cancer The other major health problem in elderly isx cancer and as the population ages, cancer also predominantly affect older individuals and advancing age is a high risk factor for cancer, with persons over 65 accounting for 60% of newly diagnosed malignancies and 70% of all cancer deaths. The age adjusted cancer incidence rate is 2151/100,000 population for those over 65 compared to 208/100,000 for those under 65 (Ries et al. 1998 and Yancik and Holmes,2002). A pH below 6 or 6.5 in the colon has been reported to inhibit colonic bacteri al enzyme 7α-dehydroxylase (responsible for degradation of primary bile acids to secondary bile acids; Thornton, 1981). Thus potentially also reducing the tumor promoter activity of secondary bile acids (Grubben et al. 2001). In other words, a reduced colonic pH possibly helps to reduce in colonic cancer cell proliferation. Role of Prebiotics/Probiotics in Metabolic Health Role of Prebiotics/Probiotics in Metabolic Health Diabetes mellitus (DM) is highly prevalent metabolic disease in age groups over 40y old. Particularly, adults aged from 20-70y are the highest diabetes prevalence among all ages and India (42.2 million) is home to the second largest number of adults living with diabetes worldwide, after China (61.3 million) (IDF report, 2017). Prebiotics fiber such as scFOS, FOS, inulin or any other dietary fiber is well known for its low glycemic effects since they are non-digestible carbohydrates, low in energy, and low in glycemic index scores (Vandenplas et al. 2015; Slavin, 2013). These properties suggest that this type of molecule may play a crucial role in management of hyper-glycaemia and energy intake management (Alexandra et al. 2010). Studies have demonstrated effect of scFOS on glycemic response. Studies on scFOS for their glycemic response have shown positive effects on improvement in glycaemia (Yamashita et al 1984; Respondek et al. 2014; Lecerf et al. 2015; Sheth et al. 2015). Intestinal microbiota composition is highly associated with the Type 2 Diabetes Mellitus (T2DM; Jun-Ling et al. 2014; Larsen et al. 2010; Hulston et al. 2015) and supplementation of probiotics and synbiotics were significantly associated with positive improvement on blood glucose and lipid profile (Sáez-Lara et al. 2016; Nikbakht et al. 2016), on reducing HbA1c (Kasińska et al. 2015) in T2DM. Probiotics specifically Bifidobacterium and lactobasilus spp were mostly studied and also which had shown the improvement on HDL, insulin sensitivity, high sensitivity c-reactive protein (hsCRP) and also showed increase in good Page 7 7 of 7 7

bacteria and reduction in gram negative bacteria (Rajkumar et al. 2014). Further, L.acidophilus La-5 and B.animalis subsp. lactis BB-12 supplementation in T2DM showed significant changes in the hemoglobin A1c(HbA1c), Total Cholesterol and Low density lipoprotein C (LDL-C) levels, decrease in the LDL-C/ High Density Lipoprotein (HDL-C) ratio and fasting blood glucose (Tonucci et al. 2015; Mohamadshahi et al. 2014; Ejtahed et al. 2011 and 2012). , 10 Synbiotic (probiotics containing FOS) based supplementation studies have shown the positive improved in fasting blood glucose and insulin resistance, , decrease in serum hs-CRP (Asemi et al. 2013) and increase in HDL in T2DM and overweight patients (Moroti et al. 2012). Therefore, prebiotics and probiotics supplementation could help management of blood glucose levels in T2DM, including the elderly patients. Summary Summary In elderly, the GI track functions start declines and end with impaired gut barrier functions such as leaky gut wall (Singh et al. 2017). Over all these leads to reduced immune functions, nutrient absorption and poor gut health. However, it can be controlled or improved by appropriate pre and probiotics (Hamilton- Miller, 2014; Blottiere et al 2003; Dong et al 2012; Ahmed et al 2007). Therefore modified dietary intake with prebiotic and probiotics would enhance the total gut health by reflecting on improvement in transit time, increased SCFA production, and reduction in pH, reduction in pathogenic bacterial load, and increase in beneficial bacterial load and improvement in mineral absorption. Hence a positive change in the gut microbial load in elderly is vital and more may enhance the health or disease recovery for the older population not only who are depends on medications but also for the apparently healthy older. Typically the prebiotic and probiotic supplementation helps to balance gut microbial composition would lead to improved gut wall barrier functions, increased metabolites productions such as SCFA, improved immune functions, increased mineral absorption and also improved defense mechanisms. Therefore pre and probiotic effect can be consider for its health benefits for elderly population, at the same time several other factors that may also contributes to health decline and composition of the gut microbiota in elderly is unavoidable. References References 1. Ahmed M, Prasad J, Gill H, Stevenson L, Gopal P. Impact of consumption of different levels of Bifidobacterium lactis HN019 on the intestinal microflora of elderly human subjects. J Nutr Health Aging 2007;11:26e31. 2. Arunachalam K, Gill HS, Chadra RK. Enhancement of natural immune function by dietary consumption of Bifidobacterium lactis (HNO19). Eur J Clin Nutr 2000;54:1–5. 3. Asemi, Z.; Zohreh, Z.; Shakeri, H.; Sima-sadat Sabihi, S.S.; Esmaillzadeh, A. Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes. Ann. Nutr. Metab. 2013, 63, 1–9. 4. Aspinall R, Andrew D. Immunosenescence: potential causes and strategies for reversal. Biochem Soc Trans 2000; 28:250–4. 5. Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P. Ageing of the human metaorganism: the microbial counterpart. Age 2012;34:247–67. 6. Blottiere HM, Buecher B, Galmiche JP, Cherbut C. Molecular analysis of the effect of short -chain fatty acids on intestinal cell proliferation. P Nutr Soc 2003; 62:101e6. Page 8 8 of 8 8

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