Is inflammageing influenced by the microbiota in the aged gut? A systematic review

Abstract

Ageing is characterized by a low-grade chronic inflammation marked by elevated circulating levels of inflammatory mediators. This chronic inflammation occurring in the absence of obvious infection has been coined as inflammageing and represents a risk factor for morbidity and mortality in the geriatric population. Also, with ageing, important perturbations in the gut microbiota have been underlined and a growing body of literature has implicated age-related gut dysbiosis as contributing to a global inflammatory state in the elderly. Notwithstanding, very little attention has been given to how gut microbiota impact inflammageing. Here, we investigate the available evidence regarding the association between inflammageing and gut microbiota during ageing. PubMed, Web of Science and Scopus were systematically screened, and seven relevant articles in animals or humans were retrieved. The animal studies reported that Parabacteroides, Mucispirillum, Clostridium and Sarcina positively associate with the pro-inflammatory MCP-1 while Akkermansia, Oscillospira, Blautia and Lactobacillus negatively correlate with MCP-1. Furthermore, “aged”-type microbiota were associated with increased levels of IL6, IL-10, Th1, Th2, Treg, TNF-α, TGF-β, p16, SAMHD1, Eotaxin, and RANTES; activation of TLR2, NF-κB and mTOR; and with decreased levels of cyclin E and CDK2. On the other hand, the study on humans demonstrated that bacteria of the phylum Proteobacteria exhibited a positive correlation with IL-6 and IL-8, while Ruminococcus lactaris et rel. portrayed a negative correlation with IL-8. We conclude that changes in “aged”-type gut microbiota are associated with inflammageing.

Introduction

The elderly population, particularly the oldest old group, is growing very rapidly. It was estimated that in 2020, for the first time in human history, people aged 60 and older will outnumber the children aged five and younger (https://www.thelancet.com/series/ageing). Moreover, by 2050, the elderly are expected to comprise more than one-fifth of the world's population (Lutz et al., 2008). These unprecedented demographic transformations have resulted in the emergence of new trends in epidemiology, with the rise of chronic diseases (Ezzati et al., 2002). Indeed, one of the most prominent manifestations of ageing - in both humans and non-human animals - is low grade chronic inflammation (LGCI), known as inflammageing (Fulop et al., 2017; Lencel and Magne, 2011; Chung et al., 2019). Serum levels of pro-inflammatory cytokines including, but not limited to, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are commonly elevated in the elderly when compared to young persons, even in healthy persons, in the absence of overt infection (Bruunsgaard and Pedersen, 2003). This LGCI is thought to underlie many age-related manifestations, including increased vulnerability for diseases, morbidity, and mortality (De Martinis et al., 2006). There is supportive evidence for a direct role of LGCI in the development of disability and dependence in elderly persons (Hubbard et al., 2009; Schmaltz et al., 2005). As a result, chronic inflammatory conditions commonly encountered in the geriatric population have become major health concerns.

Several possible sources of LGCI observed during ageing have been postulated, including, among others, cell senescence, dysregulation of innate immunity, and changes in gut integrity (Lasry and Ben-Neriah, 2015; Licastro et al., 2005; Buford, 2017). In the gut, the intestinal epithelial cells represent the first barrier against invading microorganisms. They secrete antimicrobial substances such as mucins and defensins, and are able to sense pathogens (via recognition by Toll-like receptors), sample them and transfer the information to immune cells (Miron and Cristea, 2012; Kraehenbuhl and Neutra, 2000). However, several studies have reported major alterations in immune responses of the aged gut in both humans and non-human animal models (Dicarlo et al., 2009; Biagi et al., 2013; Larbi et al., 2008; Simioni et al., 2007). For instance, a reduction in the secretion of mucin by intestinal epithelial cells and a greater permeability of mucosal membranes have been observed in older persons (Tran and Greenwood-Van Meerveld, 2013). This condition facilitates the entry of microorganisms into the mucosal layers, resulting in the release of heightened levels of lipopolysaccharides, which, in turn, may lead to pro-inflammatory signaling through pattern recognition receptors (Chassaing and Gewirtz, 2014; Cani et al., 2008; Cerf-Bensussan and Gaboriau-Routhiau, 2010; Mehal, 2013). In this perspective, increasing evidence has implicated age-related deterioration of the gut barrier against bacteria as contributing to inflammaging and age-related chronic health conditions (Chassaing and Gewirtz, 2014).

Emerging studies have shown that perturbations in gut microbiota configuration could play a role on mouse health and disease. Indeed, transplantation of fecal matter from twins discordant for obesity into germ-free (GF) mice resulted in variation of the mice's body composition measurements that were associated with differences in meta-transcriptome profiles of the transplanted microbial communities', suggesting a role of the gut microbiota in obesity (Ridaura et al., 2013). Also, changes in aged gut microbiota in mice is associated with modifications in lipid classes and in fatty acid profile (in decreasing polyunsaturated fatty acids and in increasing monounsaturated fatty acid content) in the cortex, which has been reported to have a profound impact on brain physiology (Albouery et al., 2019). Another pathologic situation that is impacted by gut microbiota is Parkinson's disease, whose major risk factor is the clustering of α-synuclein in brain neurons. Mice that overexpressed α-synuclein developed α-synuclein clusters with corresponding defects in motor function and gut motility, while genetically-modified GF mice overexpressing α-synuclein show significantly fewer α-synuclein clusters. Moreover, fecal samples from Parkinson's patients increase motor dysfunction in mice, revealing the causative role of the gut microbiota in α-synuclein clustering and the resulting pathology (Sampson et al., 2016). More so, the sequence of bacterial 16S rRNA from fecal samples of transgenic mice expressing amyloid-β precursor protein - a critical risk factor for Alzheimer's disease - was found to have a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. The colonization of GF amyloid-β precursor protein transgenic mice with microbiota from conventionally-raised amyloid-β precursor protein transgenic mice increased cerebral amyloid-β pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral amyloid-β levels (Harach et al., 2017).

Also, in humans, dysbiosis in gut microbiome is known to be an important contributing factor of age-associated pathological states. Indeed, many pathological conditions including cardiovascular diseases, insulin resistance, diminished motor activity, and hepatic steatosis have been associated with gut dysbiosis (Nicholson et al., 2012; Burcelin et al., 2011). Moreover, age-related changes in gut microbiota have been shown to impact gut-brain axis in humans, thereby leading to diseases of the central nervous system such as anxiety, multiple sclerosis, depression, neurodegeneration and Alzheimer's disease (Collins et al., 2012; Luna and Foster, 2015; Friedland, 2015). The microbiome of older people suffering from Alzheimer's disease shows a lower proportion and prevalence of bacteria with potential to synthesize butyrate and a corresponding increase in the proportion of taxa that are responsible for proinflammatory states (Haran et al., 2019).

Thus far, our understanding of the effects of multiple deregulations in the gut microbiota in mediating inflammageing with advancing age is incomplete. In the aged population, there is reduction in the number of intestinal commensal bacteria that maintain immune tolerance in the gut (Claesson et al., 2012; Kumar et al., 2007), while most of the opportunistic bacteria whose numbers are generally elevated with age are known to stimulate intestinal inflammation (Kelly et al., 1994; Pamer, 2007). Indeed, Toward et al. (2012) reported an age-related decrease in the abundance of anti-inflammatory microbiota including Bifidobacterium spp. and Faecalibacterium prausnitzii. In contrast, the presence of pro-inflammatory microbiota, such as Streptococcus spp., Staphylococcus spp., Enterococcus spp., and Enterobacter spp. was found to increase with age (Toward et al., 2012). Also, a decline of bifidobacterial with a corresponding increase of Bacteroides has been observed with ageing (Hopkins et al., 2002; Hopkins et al., 2001; Biagi et al., 2010; Claesson et al., 2011). On the other hand, He et al. (2004) reported an age-related upregulation of Ruminococcus, Eubacterium, Lactobacillus and Enterococcus, contrasting with a reduction of Faecalibacterium and Bacteroides both anti-inflammatory microbiota reported to prevent intestinal inflammation (Mazmanian et al., 2008) through suppression of the pro-inflammatory IL-17 production and the induction of Foxp3+ regulatory T cells that produce IL-10 (Round and Mazmanian, 2010). In this framework, the current systematic review aimed at evaluating the literature on the effects of aged gut microbiota on inflammageing.