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European Review for Medical and Pharmacological Sciences 2018; 22: 7404-7413 Gut and aging

F. MANGIOLA, A. NICOLETTI, A. GASBARRINI, F.R. PONZIANI

Division of Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy

Abstract. – The hypothesis of an important The microbiota is also composed by fungi role of in maintaining physiolog- and . The composition of this microbial ical state into the gastrointestinal (GI) system is populations has not yet well characterized as the supported by qualitative and quantitative alter- bacterial population, even if numerous studies ation of the intestinal in a number of phys- have been conducted in in vivo and in vitro mod- iological and pathological condition as shown in several studies. The evidence of the inflam- els. Furthermore, it has been demonstrated a pre- matory state alteration, highlighted in neurode- dominance of the taxa of the with generative such as Parkinson’s and about 160 , with particular abundance of Alzheimer’s strongly recalls the microbiota dis- C. albicans, C. glabrata and C. parapsilosis7-10. turbance, highly suggesting a link between the The gut microbiota changes markedly from gastrointestinal system and cognitive functions. the duodenum to the ileum, and the microbial Given this perspective, looking at the mutu- load increases further up to 1012 germs within al influence between microbiota products, in- 11 flammation mediators and , the the colon . This is due to the increase in pH, modulation of gut microbiota may help to facili- gastrointestinal transit, availability of nutrients, tate a physiological and non-pathological aging mucin secretion, immune function, ’s age and process and, perhaps, to contrast the progres- health12-14. sion of degenerating mechanisms. Some stud- The functions exerted by the gut microbiota ies have already characterized gut microbiota are varied. It promotes the constitution of in- in elderly, with promising results. Future stud- ies should be designed to better understand the testinal barrier and its maintenance through the correlation between the gut microbiota, the age- production of short chain fatty acids (SCFAs); ing process and degenerative diseases typical these molecules exert a trophic action on entero- of the elderly. cytes and stimulate production15,16. The gut microbiota is also involved in the immune system Key Words: Gut microbiota, Aging, Inflammaging, Neurode- priming, as it triggers innate immune response in generative diseases. early life leading to maturation of gut-associated lymphoid tissue (GALT) and shaping adaptive local and systemic immunity17. In adult life, the immune system is continu- Introduction ously kept under stimulation by gut microbiota, leading to a state of “low-grade physiological Human beings are superorganism, consisting ”18, which is a rapid and effective in host cells and microbes. The intestine houses mechanism of defense against . Also, most of these that are called “gut the gut flora exerts its protective role competi- microbiota” and include more than 15000 kinds tively metabolizing those nutrients necessary for of , for a weight equal to 1 kg1. survival of pathogens, and producing molecules Two , and Bacterio- that inhibit the growth of these microbes19. detes, are the most represented microorganisms The confirmation of the key role of the gut within the human gut microbiota2, but it is al- microbiota in the maintenance of host health so possible to recognize , Eukaryotes, is supported by several studies that correlate Fungi, and many viruses and bacteriophages3-6. its qualitative and quantitative alterations with At present, our knowledge mainly concerns the various gastrointestinal and systemic disor- sphere of bacteria, which will then be mostly ders16,20-27. Nevertheless, it is not surprising that considered in our discussion. changes in the gut microbiota have been asso-

7404 Corresponding Author: Francesca Mangiola, MD; [email protected] Gut microbiota and aging ciated with physiological conditions, such as pathologies30. The term “inflammaging” has been aging, characterized by a reduced performance first coined by Franceschi et al31 to describe a of the human organism. low-grade pro-inflammatory state characteristic of the aging process. Macrophages, cellular stress Aging as an Inflammatory Condition and genetic factors are the mainly involved medi- Aging is defined as a genetically-determined ators (Figure 1). and environmental-modulated process that leads This pro-inflammatory state is character- to a generalized decline of physiological func- ized by the increased expression of tions. The is involved in this such as IL-6 and TNF-α, and the activation of process, undergoing degeneration of the enteric transcription factors such as NF-kB. This con- nervous system (ENS), alteration of intestinal dition has been hypothesized to predispose the motility and of the mucosal barrier with relative organism to the development of various diseas- reduction of the defense function, favoring the es related to age, such as Alzheimer’s , development of gastrointestinal pathologies28,29. Parkinson’s disease, amyotrophic lateral scle- The alteration of these functions is associated rosis, multiple sclerosis, , heart with the change of the gut microbiota with conse- disease, age-related macular degeneration, in- quences on the gut-brain axis. sulin resistance and type 2 , osteoporo- Immunosenescence, defined as a deteriora- sis, and other diseases32-35. Conversely, tion of the immune system, plays a key role in centenarians show high levels of both pro- and the aging process. Through this mechanism, the anti-inflammatory mediators that may delay establishment of a state of basal inflammatory disease onset36. activity seems to be correlated with both mor- This low-grade inflammation also induces bidity and mortality in the elderly people, being an anti-inflammatory response sustained by a major risk factor for most of the age-associated cortisol, which elicits insulin resistance and

Figure 1. The inflammaging process in the elderly is associated with decline in physical and cognitive functions. The gut microbiota is involved in this process through the modulation of the immune system and brain function.

7405 F. Mangiola, A. Nicoletti, A. Gasbarrini, F.R. Ponziani hepatic production of -binding pro- Moreover, SCFAs have systemic actions, such teins, including cortisol binding globulin. This as the modulation of intestinal transit time and process results in cortisol inactivation and in insulin response, which is closely related to the the vanishing of the anti-inflammatory pro- metabolic syndrome53. cess due to the paradoxical coexistence of Such characteristics of these compounds are and inflammation34,35. Over permitted by the ability to influence cell prolif- time, the anti-inflammatory response causes a eration and differentiation and hormone produc- marked reduction of immunological functions; tion54,55. This has been demonstrated also in colon this condition and the concomitant increase of cancer cell lines, where they have been shown to circulating pro-inflammatory cytokines have a induce cell death by inhibiting histone deacetyl- negative impact on metabolism, bone density, ase56,57. This feature of SCFA explains their role strength, exercise tolerance, vascular system, in modulating the immune response by inhibiting cognitive function, and mood31, resulting in the the production of inflammatory mediators such inflammaging process. as TNF-α, IL-6, and NO or by promoting IL-10 production58. Gut Microbiota and Aging Biagi et al59 reported the gut microbiota of the Microbial colonization of the human body be- elderly has a peculiar composition. This study gins before birth, and increases after delivery has been conducted in a restricted area of Italy, when the baby comes in contact with several comparing four groups: 21 subjects aged 99 to microbial communities, including mother fecal, 104 years, 22 aged 63 to 76, 20 aged 25 to 40 vaginal and skin microbiota37. Then, the com- years and finally 21 offsprings of centenarians position of the gut microbiota is influenced by aged 59 to 78. age, sex, development of the immune system and Results showed that bacterial diversity is low: environmental factors, becoming more stable be- in particular, and Firmicutes still tween 6 and 36 months of age25,38,39. Thereafter, it dominate the gut microbiota of extremely old is possible to distinguish a constant endogenous people, but the relative proportion of Firmicutes flora, which is considered the “core microbiota”, subgroups changes: cluster XIVa is and bacteria that are still provisional, highly sen- decreased, whereas an increase in Bacilli, and a sitive to external perturbations. rearrangement of the Clostridium cluster IV have The age-related changes of the intestinal flora been observed. Moreover, the gut microbiota of begin after a genetically and environmental de- centenarians is enriched in , a termined age, depending on individual charac- including many pathobionts, or poten- teristics related to race and ethnicity, drugs, life tially , while several butyr- style and diet habits40. Most of the members of ate producers can be found in lower amounts the genus Firmicutes and Bacteroidetes remain ( obeum, Roseburia intestinalis, dominant, although Firmicutes microorganisms Eubacterium ventriosum, Eubacterium rectale, are predominant in adults, and Bacteroidetes in Eubacterium hallii, all belonging Clostridium the elderly. What mostly characterizes the gut cluster XIVa, Papillibacter cinnamovorans and microbiota composition in the elderly is a de- prausnitzii of the Clostridi- creased diversity, a reduced abundance of species um cluster IV). Interestingly, Faecalibacterium producing butyrate, and the presence of potential prausnitzii is a species protective against gut pathogens in the centenarians13,41-49. inflammation. Conversely, the butyrate producers The production of SCFAs has been regarded Anaerotruncus colihominis (Clostridium cluster as a central point in the relationship between IV), and Eubacterium limosum (Clostridium clus- the host and the gut microbiota, explaining the ter XV) increase. This probably suggests that correlation between alteration of the flora and specific components of the gut microbiota are increase of frailty in the elderly. characteristic of the long life. A decrease in Bi- , propionate and butyrate exert a mod- fidobacteria and increased levels of the mucin de- ulating activity on the gut microbiota through grading have also been the reduction of pH, the protective effect against detected in aged people compared to the young the overgrowth of pathogens such as Esche- adults. As already discussed, the study also in- richia coli, and the stimulation of the growth cluded a group of offsprings of the centenarian of beneficial bacteria belonging to the phylum patients. Although the overall structure of the gut Firmicutes50-52. microbiota was similar to that of other subjects

7406 Gut microbiota and aging of matching age (70 years-old in average), those treatment, the highest abundance of Bi- offsprings who lived in the same house with their fidobacteria was found in the community-dwell- centenarian parent showed an increased occur- ing group and the lowest in those in long-term rence of opportunistic or potentially pathogenic residential care. In the antibiotic-untreated group, bacterial groups, with respect to those who did Lactobacilli were higher in rehabilitation (hos- not share the living environment with their old pital stay < 6 weeks) as compared to long-stay parent. Therefore, co-housing can influence the or community-dwellers. In a study conducted in composition of the gut microbiota in these sub- Ireland on 161 healthy people aged 65 years or jects. more73, in most subjects the intestinal microbiota was distinct from that of the younger adults, with Factors Affecting the Gut Microbiota in a composition that appeared dominated by the the Elderly phylum Bacteroidetes followed by the Firmic- Diet is one of the most well-known factors utes, with inverse percentages compared to those potentially able to change the composition of the found in younger adults. Faecalibacterium repre- intestinal microbiota and this has been confirmed sented the most abundant genus with a prevalence in old subjects29,60-67. With aging, the diet under- of 6%, followed by Ruminococcus, Roseburia goes drastic changes that can be attributed to the and (the latter around 0.4%). loss of taste and smell and difficulty in chewing. These investigations have demonstrated that These conditions often lead to prefer foods rich variability of microbial communities composition in and fats, reducing the intake of foods of in elderly subjects may be due to several factors, plant origin68. Recently, the Healthy Food Diver- such as the increased morbidity associated with sity (HFD)69, which values healthy foods within age, the use of medications, and lifestyle changes the diet, has been created. The ELDERMET con- (Figure 2). sortium study confirmed the association between Finally, it should be noted that some changes in microbial components and a diet with low HFD the bacterial composition are less susceptible to score70. Claesson et al70 observed an association external factors and may probably represent the between microbial diversity, the functional inde- core features of the gut microbial community in pendence measure (FIM) and the performance in the elderly. Indeed, the decrease of Ruminococcus daily routine activities evaluated according to the and Blautia spp. and of other butyrate-producing Barthel index in elderly people in relation to their microorganisms (Clostridium cluster XIVa and condition of stay in community, in day-hospital, Clostridium cluster IV) reported across studies in rehabilitation or in long-term residential care. in the elderly compared to young subjects seem In particular, changes in the dietary habits of the to be less affected from diet59,70,74. Another fre- institutionalized elderly with respect to the com- quent observation is the increasing prevalence munity dwelling ones were found to affect the gut of facultative anaerobes such as coli microbiota composition: a less diverse diet was with aging and inflammation71. Probably, modifi- linked to reduced gut microbiota diversity. cations of the immune system function associated In another work71, age-related differences in with immunosenescence overcome the variability the gut microbiota composition between healthy related to dietary habits in determining these subjects form different European Countries show changes30,75,76. a characteristic colonization pattern. This may be associated with country specific dietary habits Gut Microbiota and Inflammaging and lifestyle, thus emphasizing the importance of Recent evidence77 suggests a role of the gut not generalizing about the gut microbiota struc- microbiota in the induction and maintenance of ture of subjects from different countries. the inflammaging process (Figure 1). However, the diet is not the only factor in- Fransen et al78 analyzed the effects of trans- volved in the variation in the composition of the ferring the gut microbiota of elderly mice to microbiota in the elderly72. In the research by young germ-free mice on the main lymphopoietic Claesson et al70, the decrease in microbial diver- organs such as spleen, lymph nodes and small sity correlated not only with diet but also with intestines. An important connection was found increased frailty, inflammatory markers and im- between the structure of the gut microbiota and paired health parameters. Residence location and inflammaging; in particular the lack of Akker- antibiotic treatment also had a role in the modula- mansia and the increased abundance of TM7 bac- tion of gut microbiota. Indeed, among patients on teria and Proteobacteria was associated with the

7407 F. Mangiola, A. Nicoletti, A. Gasbarrini, F.R. Ponziani

Figure 2. Gut microbiota modulation depends on several factors. Frailty, dietary habits, drugs (mainly ), and are associated with intestinal bacteria composition in the elderly. Conversely, a favorable microbial community may be selected through dietary implementation of fibers, or the use of pre- and pro-biotics. activation of the local and systemic inflammatory The alteration of inflammatory cytokines as- response. This gut microbiota structure promoted sociated with changes in the gut microbiota can small intestinal inflammation and the activation also module the function of the central nervous of T cells in the systemic compartment. system, in particular of microglia. Germ-free Inflammaging is correlated with the inflam- mice show altered maturation and global defect matory response induced by lipopolysaccharide of the microglial system; nevertheless, tempo- (LPS), a component of the Gram-negative bacte- rary complete or partial gut decontamination ria wall. can affect microglial function80,81. SCFAs are In the colon of elderly mice, the expression key regulators of the microglia integrity. This is of p16, a senescence marker, and of the ster- extremely relevant in the elderly, and contributes ile α-motif - and HD domain-containing to the cognitive decline82,83. protein 1 (SAMHD1), a regulator of cells cycle, Furthermore, there are some evidences that was increased, as well as the Firmicutes to Bac- compounds derived from the gut microbiota, ei- teroidetes ratio and levels of circulating LPS; ther constituents of bacterial structure or metab- in addition, the nuclear factor kappa B (NF-kB) olism, entering the bloodstream can activate mac- was activated. The lipopolysaccharide fraction rophages to a pro-inflammatory state responsible of fecal lysates (LFL) was able to induce the for atherosclerosis84. This process could cause the expression of NF-kB and SAMHD1 in Toll-Like development of cardiovascular disease as well as Receptor 4 (TLR-4) wild-type mice, but not in vascular dementia. TLR-4 deficient mice. Similarly, p16 was induced Hence a modification of the gut more potently in TLR-4 wild-type mice than in in neurodegenerative disorders has been suggest- knock-out mice79. ed85. Indeed, there is evidence that the modulation

7408 Gut microbiota and aging of the gut microbiota has a strong impact on the Conclusions inflammaging process. Indeed, oral administra- tion of brevis OW38 to aged mice Gut microbiota plays a key role in biologi- has been shown to strengthen intestinal barrier cal functions concurring in maintenance of host tight junctions, reduce the levels of circulating health. Age-related physiological and non-physi- LPS and the expression of pro-inflammatory cy- ological changes, associated with dietary habits tokines, inhibiting NF-κB activation. Further- and lifestyle, affect microbial diversity and com- more, Bacteroidetes increased while senescence position. markers p16, p53, and SAMHD1 in the colon and Chronic inflammation and changes in gut mi- the hippocampus were reduced. Consequently, crobiota profile related to age follow a similar hippocampal memory was restored as well as trajectory. the expression of brain-derived neurotrophic fac- Many works have shown a correlation between tors86. the composition of the gut microbiota and cogni- Alzheimer’s disease is characterized by the tive performance, frailty and comorbidity of the deposition of amyloid-β (Aβ) and tau in the elderly. brain, leading to degeneration of cognitive func- Given this perspective, the modulation of gut tion. The genesis is not yet defined, but it seems microbiota may help to facilitate a physiological that the intestinal microbiota can play a role and non-pathological aging process and, perhaps, in this process87,88. In particular, in vivo and in to contrast the progression of degenerating mech- vitro studies have shown a correlation with the anisms. Currently, available studies on the char- production of lipopolysaccharide (LPS), one of acterization and modulation of the gut microbiota the most important products of the microbiota89. in other diseases, such as IBS and diabetes, show These proteins are considered strongly amyloi- promising results. It is possible to hypothesize dogenic90,91. that these interventions may be beneficial in the Studies carried out on murine specimens have elderly (Figure 2). In particular, as direct and shown that LPS can promote the formation of indirect effects on the immune response can be amyloid bridles and their deposition92,93. expected, this could modify the risk of infec- Furthermore, brain tissue analysis of de- tious diseases that are frequently observed in the ceased patients with Alzheimer’s disease has elderly, indirectly reducing hospitalization and highlighted the presence of higher levels of long-term care. LPS and E. coli fragments compared to controls However, whether a stable modification of the within Aβ94. gut microbiota could be obtained and what its This hypothesis is supported by numerous long-term effects on parameters such as frailty studies that demonstrate how the production of and cognitive tests could be still need to be clar- peptides such as beta amyloid is generated by ified. pro-inflammatory responses stimulated by the Considering the paramount interest of this response to infectious agents via contact with topic, future researches should be designed to LPS, also contributing to the neurotoxic capacity better understand the correlation between the gut of this protein95-98. microbiota, the ageing process and degenerative Scholars96,98 have finally found how also viral diseases typical of the elderly. This should be infectious agents, such as HSV-1, can enhance the accompanied by a practical approach in the mod- production of Ab42. ulation of the gut microbiota easily applicable in On the other hand, studies conducted on over- the clinical context. expressed models – amyloid precursor protein and presenilin 1 (APPPS1), have shown that the alteration of the microbiota due to pro- Conflict of Interest longed antibiotic therapy influences the formation The Authors declare that they have no conflict of interests. and deposition of the amyloid protein99, through alteration of the inflammatory -depen- dent pattern. These results were also confirmed References by studies with antibiotic therapy performed at Clavijo V, Florez MJV. birth, asking the question of the effective timing 1) The gastrointestinal mi- crobiome and its association with the control of of the influence of the microbiota on neurodegen- pathogens in broiler chicken production: a review. 100 eration . Poult Sci 2017; 97: 1006-1021.

7409 F. Mangiola, A. Nicoletti, A. Gasbarrini, F.R. Ponziani

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