Inflammation is the body’s response to infections and tissue injury and the inflammatory response is orchestrated by the cells of the immune system; both from the “adaptive” branch (including T- and B-cells with the capacity to induce long-term memory of encountered pathogens, “immunisation”) and the “innate” branch (including monocytes, macrophages, dendritic cells, and mast cells, that are targeted against common pathogen antigens). Inflammation was first implicated in AD pathology and development in the 1990s, with the neuropathological finding of activated inflammatory cells (microglia and astrocytes) and inflammatory proteins (e.g. cytokines and complement), surrounding the amyloid plaques and the neurofibrillary tangles (Aisen and Davis, 1994). In addition to the epidemiological findings, patients suffering from arthritis and other patient groups with a high intake of non-steroidal anti-inflammatory drugs (NSAID) were observed to have had a lower proportion of individuals affected with AD. Many of the earliest results were at first dismissed as inaccurate given the perception of the brain as an “immune privileged” organ, i.e. an organ that does not elicit inflammation in response to antigens or damage. However, abundant literature can now be found in relation to the presence of acute phase proteins in Aβ plaques, activated microglial cells that stain for inflammatory cytokines, and components of the complement system in brain tissue of AD patients. Identifying inflammation-associated risk factors for AD could provide clues to the aetiology of AD and lead to novel strategies for combating the disease (Akiyama et al., 2000; Cacquevel et al., 2004). Since the initial discovery of a potential inflammatory ingredient to the AD cocktail, studies have diversified to look at a multitude of inflammation-associated risk factors for cognitive function, cognitive decline, AD, dementia and progression in dementia; including circulating inflammatory markers (Engelborghs et al., 1999; Yaffe et al., 2003; Tan et al., 2007; Zuliani et al., 2007), genetic sequence variation in immune-related genes (Arosio et al., 2004; Flex et al., 2004), and proxies of inflammatory load (Gatz et al., 2006).

Microbiota affect the development of the gut associated lymphoid system (GALT). The intestines contains 70% of the body’s circulating lymphocytes, many of which are found within the epithelium (Collins et al., 2012). In the lamina propria there are several lines of immune cells, key to the host response to microbiota, such as macrophages, dendritic cells and myofibroblasts (Otte et al., 2003; Bilsborough and Viney, 2004). Gut lymphoid tissue, and surface and circulating immunoglobulin concentrations show a substantial rise in observation of bacterial addition to the gut (Macpherson and Harris, 2004). In the early stages of the human life cycle, pioneering species in the gut interact through surface cell receptors on the immune cells of the gut, such as caspase-recruitment-domain protein (CARD), and toll-like receptors (TLRs), to promote the expression of host genes that generate an intraluminal and mucosal environment that further favors their colonization (Silva et al., 1987; Hooper et al., 2001). In addition to the TLRs there is another family of membrane-bound receptors for detection of proteins called NOD-like receptors (NLRs). NRLs are located in the cytoplasm and are involved in the detection of bacterial pathogen-associated molecular patterns (PAMPs) that enter the mammalian cell. NRLs are especially important in tissues where TLRs are expressed at low levels (Philpott et al., 2001). In addition to intestinal epithelial cells, the epithelium includes specialized cells such as goblet cells, which secrete the protective mucus layer, limiting the contact between bacteria and epithelial cells, and Paneth cells, which reside in the crypts of the small intestine and secrete bactericidal peptides as well as the predominant class of immunoglobulin IgA was also found in intestinal secretions (Cash et al., 2006). These mucosal immune responses are lessened when exposed to heat-treated bacteria in comparison to live organisms, suggesting that such mechanisms involve the metabolic products of bacterial activity as well as bacterial cell-receptor mediated sensing (Macpherson and Uhr, 2004). It should be noted that it is not only gram-negatives and lipopolysaccharides (LPS) that can induce inflammation; other cell components and metabolites can be involved, and there are also several gram-positive pathogenic (such as Enterococcus, which is often found as a contaminant in foods) and opportunistic pathogenic bacteria (such as Bifidobacterium) that can induce inflammation (Gonzalez-Navajas et al., 2008). An endeavour searching for the connection between gut microbiota and systemic inflammation showed that approximately 9% of the total variability of the microbiota was correlated to the pro-inflammatory cytokines IL-8 and IL-6 (Biagi et al., 2010). All taxa that showed a slightly positive association with either IL-6 or IL-8 belonged to the phylum Proteobacteria (Biagi et al., 2010). It is possible that low-grade systemic inflammation constitutes a common denominator in neurodegenerative and vascular diseases, possibly via detrimental effects on the vasculature and leading to a dysfunctional brain-blood barrier and inflammatory stimuli of the brain. Elevated peripheral inflammation could also affect brain inflammation by the “priming” of neurones, i.e. making them more prone to a pro-inflammatory response in the presence of tissue damage (Holmes et al., 2009). In addition, chronic inflammation during foetal and childhood development could negatively affect brain development and lower the “cognitive reserve” (Borenstein et al., 2006).

The researchers noted that the affected AD brains are largely inflamed, glial cells rushing to the brain regions that become ill and trying to clean up waste products from cells and plaque, but once up to this area, they in fact are urged to liberate more Aβ harmful, precipitate in the formation of plaque, which attracts more accurate glial cells, and so on. According to Balin et al and other studies, amyloid proteins play a part in the disease, but only in response to the initial inflammation caused by the microbial infection, that is attacking the brain (Balin and Hudson, 2014). Recent study showed that Aβ may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis and that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide, which mean that Aβ serves to protect the brain from invading microbes (Kumar et al., 2016). In vitro study of Chlamydia pneumoniae showed that the infection of monocytes could stimulate innate and adaptive immune responses relevant to those in AD (Balin and Hudson, 2014; Lim et al., 2014; Little et al., 2014). Hoban et al, elucidated the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of germ-free mice within the prefrontal cortex, and showed that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes (the formation of fatty sheathing that insulates nerve fibres), with clear implications for cortical myelination at an ultrastructural level (Hoban et al., 2016). Experiments by Lee et al also showed that the germ-free mice were protected from causing the case experimentally, similar to multiple sclerosis, characterized by the demise of myelin, which encases nerve fibers (Lee et al., 2011). There is also the possibility that these hypothetical pathways are tangled and that e.g. Aβ deposits in the cerebrovascular wall will elicit a peripheral inflammatory response that will in turn enhance brain inflammation (Fig. 1).