Gut Microbiota and Undigested Food Molecules Cooperate in the Set Up of Neuroinflammatory Diseases

Here, we have shown that pro-inflammatory dietary habits may give rise to a sequence of events triggering neuroinflammation and neurodegenerative diseases. The route to disease involves the participation of both the microbiota and undigested food fragments, as well as requiring the disruption of the intestinal barrier and of the blood-brain barrier. The suggested sequence of events is the following: (1) pro-inflammatory diets, protracted over time, change the composition of gut microbiota and induce gut dysbiosis; (2) the enteric immune system is activated and intestinal inflammation rises, T cells are activated, the Th 17/Treg ratio and LPS level increase; (3) the intestinal barrier becomes leaky and the luminal content (microbes, undigested food molecules, endotoxins, T cells and cytokines) comes out, and triggers a chronic systemic inflammation; (4) the immune response against undigested food fragments resembling brain molecules addresses the pro-inflammatory molecules to the BBB and causes its breakdown; (5) the passage through the BBB of activated pro-inflammatory cells and molecules causes the activation of microglial cells and astrocytes and the onset of inflammatory processes in different brain areas.

The gut microbiota has a key role in this sequence of events and requires special attention. Accordingly, after a long time in which it was completely neglected, many papers on the microbiota have been published in recent years: 12,900 from 2013 to 2017 and a good 4000 in 2017 alone [ 98 ]. As the number of papers published on intestinal microbiota in 2018 was 4735, still increasing compared to the previous year, it is possible to state that the role of the microbiota is increasingly recognized as central to human health. However, if we only gave importance to the gut microbiota, we would be wrong. As a matter of fact, the gut microbiota depends on our diet for its sustenance, and what we choose to eat and how much we eat is decisive for eubiotic or dysbiotic gut microbiota [ 99 ]. It is food that initiates gut inflammation and probably addresses the inflammatory autoimmune response to the brain. Therefore, we can say that microbiota and food are related to each other, in sickness and in health.

In the present paper we highlight the possible role of undigested food fragments as pro-inflammatory agents and the importance of the integrity of the two barriers, the intestinal and the BBB, for human health. If the intestinal barrier becomes leaky, fragments of undigested food also escape from the luminal space together with bacteria, endotoxins, immunocompetent molecules and cells. All this material, that was supposed to remain segregated in the intestine, is now in circulation. We are usually concerned with the dissemination of bacteria, but the dissemination of undigested food that passes through the intestinal barrier and goes into the bloodstream should not be overlooked.

non-self ), were on the way to become like us ( self ), thus their probability of molecular mimicry with our peptides may be increased after a partial digestion. In the course of gut dysbiosis and intestinal inflammation, T cells are activated. As T cells are activated, B cells are switched on to produce antibodies. These antibodies against food antigens may recognize self-antigens and trigger an autoimmune response. For example, it has been suggested that antibodies against wheat and milk proteins in blood donors may contribute to neuroimmune activities [ In the intestine, not completely digested peptides, though still different from us (), were on the way to become like us (), thus their probability of molecular mimicry with our peptides may be increased after a partial digestion. In the course of gut dysbiosis and intestinal inflammation, T cells are activated. As T cells are activated, B cells are switched on to produce antibodies. These antibodies against food antigens may recognize self-antigens and trigger an autoimmune response. For example, it has been suggested that antibodies against wheat and milk proteins in blood donors may contribute to neuroimmune activities [ 39 ].

Thus, the undigested peptides and their antibodies may reinforce inflammatory and autoimmune activities, and may address them towards one of the different organs, but cooperation with the microbiota is needed.

The need for cooperation between gut microbiota and antigens in setting up diseases was shown for the first time by Berer et al. (2011) [ 100 ]. In their study, it was shown that the myelin oligodendrocyte glycoprotein (MOG), a myelin autoantigen, was able to trigger experimental autoimmune demyelination, but only in the presence of gut microbiota, in germ-free mice it was not possible to activate T and B cells and there was only a poor production of anti-MOG autoantibodies. Revisiting their paper we can try to give a new interpretation that may serve in the present context, which is about the relationship between food and chronic neuroinflammatory diseases. In light of what we have described, partially digested dietary antigens may be taken into account instead of the autoantigen MOG of the Berer study. According with our model, MOG could be now a food molecule, the same MOG or a similar one such as butyrophilin (BTN). BTN is a major protein of the milk fat globules membrane (MFGM) and cow’s milk BTN is very similar to MOG (64% similarity), induces EAE as MOG does and cross-reacts with MOG antibodies [ 31 ]. Once the T cells are activated, the availability of dietary antigens ensures the recruitment and activation of antibody-producing B cells and antibodies may attack those structures sharing a similarity with the dietary antigen.

In conclusion, we suggest that what determines the organ specificity of an autoimmune inflammatory process may depend on the food antigens resembling proteins of the organ being attacked. This applies to the brain and neuroinflammatory diseases, as to other organs and other diseases, including cancer. The role of the microbes and their endotoxins in the brain should be evaluated in depth, as the microbes crossing over the BBB, may continue to reside in the brain. Besides sustaining chronic neuroinflammation, they could alter synaptic connections and brain morphology with diverse modalities in different neurological disorders [ 101 ]. We probably have to await new technological tools that could prove the presence of a brain microbiome and its role in neurodegenerative diseases [ 102 103 ].

Understanding the cooperation between microbiota and undigested food in inflammatory diseases, may clarify organ specificity and the mechanisms leading to neurological disorders, as well as allow the setting up of adequate experimental models of disease and targeted dietary interventions.