European Review for Medical and Pharmacological Sciences 2018; 22: 7404-7413 Gut microbiota 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 gut microbiota in maintaining physiolog- and viruses. 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 flora 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 genus Candida with generative diseases such as Parkinson’s and about 160 species, 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 immune system, 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, host’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 mucus 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 inflammation”18, which is a rapid and effective in host cells and microbes. The intestine houses mechanism of defense against pathogens. Also, most of these microorganisms 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 bacteria, for a weight equal to 1 kg1. survival of pathogens, and producing molecules Two bacterial phyla, Firmicutes 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 Archaea, 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 cytokines tions. The gastrointestinal tract 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 disease, development of gastrointestinal pathologies28,29. Parkinson’s disease, amyotrophic lateral scle- The alteration of these functions is associated rosis, multiple sclerosis, atherosclerosis, 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 diabetes, osteoporo- Immunosenescence, defined as a deteriora- sis, cancer 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 hormone-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 immunodeficiency 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, Bacteroidetes 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: Clostridium 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 Proteobacteria, a termined age, depending on individual charac- phylum including many pathobionts, or poten- teristics related to race and ethnicity, drugs, life tially pathogenic bacteria, while several butyr- style and diet habits40.