Studies on populations at different ages have shown that after birth, the gastrointestinal (GI) microbiota composition keeps evolving, and this seems to occur especially in old age. Significant changes in GI microbiota composition in older subjects have been reported in relation to diet, drug use and the settings where the older subjects are living, that is, in community nursing homes or in a hospital. Moreover, changes in microbiota composition in the old age have been related to immunosenescence and inflammatory processes that are pathophysiological mechanisms involved in the pathways of frailty. Frailty is an age-related condition of increased vulnerability to stresses due to the impairment in multiple inter-related physiologic systems that are associated with an increased risk of adverse outcomes, such as falls, delirium, institutionalization, hospitalization and death. Preliminary data suggest that changes in microbiota composition may contribute to the variations in the biological, clinical, functional and psycho-social domains that occur in the frail older subjects. Multidimensional evaluation tools based on a Comprehensive Geriatric Assessment (CGA) have demonstrated to be useful in identifying and measuring the severity of frailty in older subjects. Thus, a CGA approach should be used more widely in clinical practice to evaluate the multidimensional effects potentially related to GI microbiota composition of the older subjects. Probiotics have been shown to be effective in restoring the microbiota changes of older subjects, promoting different aspects of health in elderly people as improving immune function and reducing inflammation. Whether modulation of GI microbiota composition, with multi-targeted interventions, could have an effect on the prevention of frailty remains to be further investigated in the perspective of improving the health status of frail ‘high risk' older individuals.

Keywords:
Aging, Frailty, Microbiota, Multidimensional prognostic index, Probiotics
1.
Saffrey MJ: Aging of the mammalian gastrointestinal tract: a complex organ system. Age (Dordr) 2014;36:9603.
2.
Lovat LB: Age related changes in gut physiology and nutritional status. Gut 1996;38:306-309.
3.
Camilleri M, Lee JS, Viramontes B, Bharucha AE, Tangalos EG: Insights into the pathophysiology and mechanisms of constipation, irritable bowel syndrome, and diverticulosis in older people. J Am Geriatr Soc 2000;48:1142-1150.
4.
Neish AS: Microbes in gastrointestinal health and disease. Gastroenterology 2009;136:65-80.
5.
Woodmansey EJ: Intestinal bacteria and ageing. J Appl Microbiol 2007;102:1178-1186.
6.
Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, Nikkila J, Monti D, Satokari R, Franceschi C, Brigidi P, De Vos W: Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 2010;5:e10667.
7.
Claesson MJ, Cusack S, O'Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, Marchesi JR, Falush D, Dinan T, Fitzgerald G, Stanton C, van Sinderen D, O'Connor M, Harnedy N, O'Connor K, Henry C, O'Mahony D, Fitzgerald AP, Shanahan F, Twomey C, Hill C, Ross RP, O'Toole PW: Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A 2011;108:4586-4591.
8.
Mäkivuokko H, Tiihonen K, Tynkkynen S, Paulin L, Rautonen N: The effect of age and non-steroidal anti-inflammatory drugs on human intestinal microbiota composition. Br J Nutr 2010;103:227-234.
9.
Mueller S, Saunier K, Hanisch C, Norin E, Alm L, Midtvedt T, Cresci A, Silvi S, Orpianesi C, Verdenelli MC, Clavel T, Koebnick C, Zunft HJ, Doré J, Blaut M: Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study. Appl Environ Microbiol 2006;72:1027-1033.
10.
Duncan SH, Flint HJ: Probiotics and prebiotics and health in ageing populations. Maturitas 2013;75:44-50.
11.
Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O'Sullivan O, Fitzgerald GF, Deane J, O'Connor M, Harnedy N, O'Connor K, O'Mahony D, van Sinderen D, Wallace M, Brennan L, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O'Toole PW: Gut microbiota composition correlates with diet and health in the elderly. Nature 2012;488:178-184.
12.
Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P: Aging of the human metaorganism: the microbial counterpart. Age (Dordr) 2012;34:247-267.
13.
Bartosch S, Fite A, Macfarlane GT, McMurdo ME: Characterization of bacterial communities in feces from healthy elderly volunteers and hospitalized elderly patients by using real-time PCR and effects of antibiotic treatment on the fecal microbiota. Appl Environ Microbiol 2004;70:3575-3581.
14.
van Tongeren SP, Slaets JP, Harmsen HJ, Welling GW: Fecal microbiota composition and frailty. Appl Environ Microbiol 2005;71:6438-6442.
15.
Biagi E, Candela M, Turroni S, Garagnani P, Franceschi C, Brigidi P: Ageing and gut microbes: perspectives for health maintenance and longevity. Pharmacol Res 2013;69:11-20.
16.
Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S: Host-gut microbiota metabolic interactions. Science 2012;336:1262-1267.
17.
Jernberg C, Lofmark S, Edlund C, Jansson JK: Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology 2010;156(pt 11):3216-3223.
18.
Cotter PD, Stanton C, Ross RP, Hill C: The impact of antibiotics on the gut microbiota as revealed by high throughput DNA sequencing. Discov Med 2012;13:193-199.
19.
Salyers AA, Gupta A, Wang Y: Human intestinal bacteria as reservoirs for antibiotic resistance genes. Trends Microbiol 2004;12:412-416.
20.
Young VB, Schmidt TM: Antibiotic-associated diarrhea accompanied by large-scale alterations in the composition of the fecal microbiota. J Clin Microbiol 2004;42:1203-1206.
21.
Dethlefsen L, Relman DA: Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 2011;108(suppl 1):4554-4561.
22.
O'Sullivan O, Coakley M, Lakshminarayanan B, Conde S, Claesson MJ, Cusack S, Fitzgerald AP, O'Toole PW, Stanton C, Ross RP; ELDERMET Consortium: Alterations in intestinal microbiota of elderly Irish subjects post-antibiotic therapy. J Antimicrob Chemother 2013;68:214-221.
23.
Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G: Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244-254.
24.
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S: Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007;128:92-105.
25.
Guigoz Y, Doré J, Schiffrin EJ: The inflammatory status of old age can be nurtured from the intestinal environment. Curr Opin Clin Nutr Metab Care 2008;11:13-20.
26.
Rampelli S, Candela M, Turroni S, Biagi E, Collino S, Franceschi C, O'Toole PW, Brigidi P: Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging (Albany N Y) 2013;5:902-912.
27.
Burcelin R, Serino M, Chabo C, Blasco-Baque V, Amar J: Gut microbiota and diabetes: from pathogenesis to therapeutic perspective. Acta Diabetol 2011;48:257-273.
28.
Collins SM, Surette M, Bercik P: The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 2012;10:735-742.
29.
Wang Y, Kasper LH: The role of microbiome in central nervous system disorders. Brain Behav Immun 2014;38:1-12.
30.
Luna RA, Foster JA: Gut brain axis: diet microbiota interactions and implications for modulation of anxiety and depression. Curr Opin Biotechnol 2015;32:35-41.
31.
Stilling RM, Dinan TG, Cryan JF: Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis. Genes Brain Behav 2014;13:69-86.
32.
Zapata HJ, Quagliarello VJ: The microbiota and microbiome in aging: potential implications in health and age-related diseases. J Am Geriatr Soc 2015;63:776-781.
33.
Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K: Frailty in elderly people. Lancet 2013;381:752-762.
34.
Ferrucci L, Giallauria F, Schlessinger D: Mapping the road to resilience: novel math for the study of frailty. Mech Ageing Dev 2008;129:677-679.
35.
Kirkwood TB: Understanding the odd science of aging. Cell 2005;120:437-447.
36.
Kahn A, Fraga MF: Epigenetics and aging: status, challenges, and needs for the future. J Gerontol A Biol Sci Med Sci 2009;64:195-198.
37.
Pilotto A, Ferrucci L, Franceschi M, D'Ambrosio LP, Scarcelli C, Cascavilla L, Paris F, Placentino G, Seripa D, Dallapiccola B, Leandro G: Development and validation of a multidimensional prognostic index for one-year mortality from comprehensive geriatric assessment in hospitalized older patients. Rejuvenation Res 2008;11:151-161.
38.
Pilotto A, Gallina P, Fontana A, Sancarlo D, Bazzano S, Copetti M, Maggi S, Paroni G, Marcato F, Pellegrini F, Donato D, Ferrucci L: Development and validation of a multidimensional prognostic index for mortality based on a standardized multidimensional assessment schedule (MPI-SVaMA) in community-dwelling older subjects. J Am Med Dir Assoc 2013;14:287-292.
39.
Pilotto A, Rengo F, Marchionni N, Sancarlo D, Fontana A, Panza F, Ferrucci L; FIRI-SIGG Study Group: Comparing the prognostic accuracy for all-cause mortality of frailty instruments: a multicentre 1-year follow-up in hospitalized older patients. PLoS One 2012;7:e29090.
40.
Fontana L, Addante F, Copetti M, Paroni G, Fontana A, Sancarlo D, Pellegrini F, Ferrucci L, Pilotto A: Identification of a metabolic signature for multidimensional impairment and mortality risk in hospitalized older patients. Aging Cell 2013;12:459-466.
41.
Tiihonen K, Ouwehand AC, Rautonen N: Human intestinal microbiota and healthy ageing. Ageing Res Rev 2010;9:107-116.
42.
Toward R, Montandon S, Walton G, Gibson GR: Effect of prebiotics on the human gut microbiota of elderly persons. Gut Microbes 2012;3:57-60.
43.
Russell WR, et al: The gut microbial metabolome: modulation of cancer risk in obese individuals. Proc Nutr Soc 2013;72:178-188.
44.
Pfister G, Savino W: Can the immune system still be efficient in the elderly? An immunological and immunoendocrine therapeutic perspective. Neuroimmunomodulation 2008;15:351-364.
45.
Sharma R, Kapila R, Kapasiya M, Saliganti V, Dass G, Kapila S: Dietary supplementation of milk fermented with probiotic Lactobacillus fermentum enhances systemic immune response and antioxidant capacity in aging mice. Nutr Res 2014;34:968-981.
46.
Ouwehand AC, Bergsma N, Parhiala R, Lahtinen S, Gueimonde M, Finne-Soveri H, Strandberg T, Pitkälä K, Salminen S: Bifidobacterium microbiota and parameters of immune function in elderly subjects. FEMS Immunol Med Microbiol 2008;53:18-25.
47.
Turchet P, Laurenzano M, Auboiron S, Antoine JM: Effect of fermented milk containing the probiotic Lactobacillus casei DN-114001 on winter infections in free-living elderly subjects: a randomised, controlled pilot study. J Nutr Health Aging 2003;7:75-77.
48.
Sheih YH, Chiang BL, Wang LH, Liao CK, Gill HS: Systemic immunity-enhancing effects in healthy subjects following dietary consumption of the lactic acid bacterium Lactobacillus rhamnosus HN001. J Am Coll Nutr 2001;20:149-156.
49.
Gill HS, Rutherfurd KJ, Cross ML, Gopal PK: Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am J Clin Nutr 2001;74:833-839.
50.
Bosch M, Méndez M, Pérez M, Farran A, Fuentes MC, Cuñé J: Lactobacillus plantarum CECT7315 and CECT7316 stimulate immunoglobulin production after influenza vaccination in elderly. Nutr Hosp 2012;27:504-509.
51.
Namba K, Hatano M, Yaeshima T, Takase M, Suzuki K: Effects of Bifidobacterium longum BB536 administration on influenza infection, influenza vaccine antibody titer, and cell-mediated immunity in the elderly. Biosci Biotechnol Biochem 2010;74:939-945.
52.
Van Puyenbroeck K, Hens N, Coenen S, Michiels B, Beunckens C, Molenberghs G, Van Royen P, Verhoeven V: Efficacy of daily intake of Lactobacillus casei Shirota on respiratory symptoms and influenza vaccination immune response: a randomized, double-blind, placebo-controlled trial in healthy elderly nursing home residents. Am J Clin Nutr 2012;95:1165-1171.
53.
Bo L, Li J, Tao T, Bai Y, Ye X, Hotchkiss RS, Kollef MH, Crooks NH, Deng X: Probiotics for preventing ventilator-associated pneumonia. Cochrane Database Syst Rev 2014;10:CD009066.
54.
Cherniack EP: Use of complementary and alternative medicine to treat constipation in the elderly. Geriatr Gerontol Int 2013;13:533-538.
55.
Pitkala KH, Strandberg TE, Finne Soveri UH, Ouwehand AC, Poussa T, Salminen S: Fermented cereal with specific bifidobacteria normalizes bowel movements in elderly nursing home residents. A randomized, controlled trial. J Nutr Health Aging 2007;11:305-311.
56.
Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ: Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007;335:80.
57.
Gough E, Shaikh H, Manges AR: Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011;53:994-1002.
58.
Rampelli S, Candela M, Severgnini M, Biagi E, Turroni S, Roselli M, Carnevali P, Donini L, Brigidi P: A probiotics-containing biscuit modulates the intestinal microbiota in the elderly. J Nutr Health Aging 2013;17:166-172.
59.
Ebel B, Lemetais G, Beney L, Cachon R, Sokol H, Langella P, Gervais P: Impact of probiotics on risk factors for cardiovascular diseases. A review. Crit Rev Food Sci Nutr 2014;54:175-189.
60.
Bukowska H, Pieczul-Mroz J, Jastrzebska M, Chełstowski K, Naruszewicz M: Decrease in fibrinogen and LDL-cholesterol levels upon supplementation of diet with Lactobacillus plantarum in subjects with moderately elevated cholesterol. Atherosclerosis 1998;137:437-438.
61.
Bertolami MC, Faludi AA, Batlouni M: Evaluation of the effects of a new fermented milk product (Gaio) on primary hypercholesterolemia. Eur J Clin Nutr 1999;53:97-101.
62.
Anderson JW, Gilliland SE: Effect of fermented milk (yogurt) containing Lactobacillus acidophilus L1 on serum cholesterol in hypercholesterolemic humans. J Am Coll Nutr 1999;18:43-50.
63.
Kootte RS, Vrieze A, Holleman F, Dallinga-Thie GM, Zoetendal EG, de Vos WM, Groen AK, Hoekstra JB, Stroes ES, Nieuwdorp M: The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Obes Metab 2012;14:112-120.
64.
Ejtahed HS, Mohtadi-Nia J, Homayouni-Rad A, Niafar M, Asghari-Jafarabadi M, Mofid V, Akbarian-Moghari A: Effect of probiotic yogurt containing Lactobacillus acidophilus and Bifidobacterium lactis on lipid profile in individuals with type 2 diabetes mellitus. J Dairy Sci 2011;94:3288-3294.
65.
Sadrzadeh-Yeganeh H, Elmadfa I, Djazayery A, Jalali M, Heshmat R, Chamary M: The effects of probiotic and conventional yoghurt on lipid profile in women. Br J Nutr 2010;103:1778-1783.
66.
Jones ML, Martoni CJ, Prakash S: Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial. Eur J Clin Nutr 2012;66:1234-1241.
67.
Jones ML, Martoni CJ, Parent M, Prakash S: Cholesterol-lowering efficacy of a microencapsulated bile salt hydrolase-active Lactobacillus reuteri NCIMB 30242 yoghurt formulation in hypercholesterolaemic adults. Br J Nutr 2012;107:1505-1513.
68.
Million M, Angelakis E, Paul M, Armougom F, Leibovici L, Raoult D: Comparative meta-analysis of the effect of Lactobacillus species on weight gain in humans and animals. Microb Pathog 2012;53:100-108.
69.
Seppo L, Jauhiainen T, Poussa T, Korpela R: A fermented milk high in bioactive peptides has a blood pressure-lowering effect in hypertensive subjects. Am J Clin Nutr 2003;77:326-330.
70.
Aihara K, Kajimoto O, Hirata H, Takahashi R, Nakamura Y: Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension. J Am Coll Nutr 2005;24:257-265.
71.
Simons LA, Amansec SG, Conway P: Effect of Lactobacillus fermentum on serum lipids in subjects with elevated serum cholesterol. Nutr Metab Cardiovasc Dis 2006;16:531-535.
72.
Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S: Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 2011;108:3047-3052.
73.
Wang D, Ho L, Faith J, Ono K, Janle EM, Lachcik PJ, Cooper BR, Jannasch AH, D'Arcy BR, Williams BA, Ferruzzi MG, Levine S, Zhao W, Dubner L, Pasinetti GM: Role of intestinal microbiota in the generation of polyphenol-derived phenolic acid mediated attenuation of Alzheimer's disease β-amyloid oligomerization. Mol Nutr Food Res 2015;59:1025-1040.
74.
Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA: Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 2013;144:1394-1401.e1-e4.
75.
Borre YE, Moloney RD, Clarke G, Dinan TG, Cryan JF: The impact of microbiota on brain and behavior: mechanisms & therapeutic potential. Adv Exp Med Biol 2014;817:373-403.
76.
Santoro A, Pini E, Scurti M, Palmas G, Berendsen A, Brzozowska A, Pietruszka B, Szczecinska A, Cano N, Meunier N, de Groot CP, Feskens E, Fairweather-Tait S, Salvioli S, Capri M, Brigidi P, Franceschi C; NU-AGE Consortium: Combating inflammaging through a Mediterranean whole diet approach: the NU-AGE project's conceptual framework and design. Mech Ageing Dev 2014;136-137:3-13.
77.
Caracciolo B, Xu W, Collins S, Fratiglioni L: Cognitive decline, dietary factors and gut-brain interactions. Mech Ageing Dev 2014;136-137:59-69.
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