Amyloid proteins are made by bacteria harbored in the gut (Hufnagel et al., 2013) and may be an initiating factor in the disease process of AD, PD, and ALS (Chen et al., 2016). Most ALS and AD phenotypes cannot be attributed to hereditary or genetic factors; rather, the diseases occur at the level of translation and/or post-translation (Cohen et al., 2016; Horowitz 2016; Walker et al., 2016; Maguire, 2017). Amyloids developed by the Staphylococcus aureus PSMα3 bacterium differ in secondary structure, exhibiting helices instead of sheets, when compared to amyloids associated with AD (Tayeb-Fligelman et al., 2017). Whether the helical amyloids will seed AD-type amyloids with plate structure is unknown but is likely given that seeding can occur from fibril formation (Lundmark et al., 2005).

In AD, evidence exists that the aggregation of a protein other than PrP can be instigated in the human brain by exogenous seeds, but in neither case was full-blown AD induced, nor do the findings suggest that AD can be transmitted from person to person under ordinary circumstances. Further, Creutzfeldt-Jakob disease patients who had received PrP prion-contaminated dura mater transplants many years earlier were also found to have significantly increased Aβ plaques and cerebral amyloid angiopathy (Frontzek et al., 2016), suggesting a generalized seeding phenomenon for proteins. Seeding could potentially occur in our gut given that prions have recently been discovered in bacteria (Yuan and Hochschild, 2017). Intestinal microbiota contributes to the protective activities of polyphenol preparations in AD (Wang et al., 2015).

Bifidobacteria have been shown to trigger autophagy (Lin et al., 2014) and modulate proteasome function, of which both processes are known to be dysfunctional in many neurological disorders, including ALS patients (Sasaki, 2011) and animal models of ALS (Wu et al., 2015). Autophagy and proteasome function are important to clearing misfolded proteins. Recent studies suggest that dysbiosis of the gut microbiota promotes amyloid beta pathology in a model of AD (Minter et al., 2016), consistent with aberrant autophagy and proteasome activity.

Interestingly, amyloid-β has been shown to have antimicrobial properties (Kumar et al., 2016). Could it be that the prion-like proteins in neurological diseases have evolved to fight infection? If this is true, the chronic para-inflammatory state associated with many neurodegenerative diseases may elicit a spreading prion-like state in certain proteins, such as amyloid-β (Kumar et al., 2016) or α-Syn (Sampson et al., 2016), to combat infection associated with the inflammation, whether the infection is real or not (Medzhitov, 2008).

ALS patients express significantly more neuronal transglutaminase 6 (TG6) than do control subjects. The TG6 antibody titer is dependent on gluten ingestion and is an indication of a celiac-like gluten sensitivity. Samsel and Seneff (2013) propose that glyphosate, the active ingredient in the herbicide Roundup, is the most important causal factor in the gluten intolerance epidemic. Some have suggested that the recent surge in celiac disease is simply due to better diagnostic tools. However, a recent study tested frozen sera obtained between 1948 and 1954 for antibodies to gluten and compared the results with sera collected from a matched sample of people living today (Rubio-Tapia et al., 2009). The results show a fourfold increase in the incidence of celiac disease in the recent cohort compared to the older cohort. Further, the undiagnosed celiac disease is associated with a fourfold increased risk of death, mostly due to increased cancer risk. The authors concluded that the prevalence of undiagnosed celiac disease has dramatically increased in the USA during the past 50 years, coinciding with the introduction of Roundup to the market. Epidemiological studies are important to understanding human health and, when coupled to experimental studies, provide important coupled data sets for understanding causality.

Glyphosate suppresses 5-enolpyruvylshikimic acid-3-phosphate synthase, the rate-limiting step in the synthesis of the aromatic amino acids, tryptophan, tyrosine, and phenylalanine, in the shikimate pathway of bacteria, archaea, and plants (de María et al., 1996). Glyphosate, patented as an antimicrobial (Monsanto Technology LLC, 2010), has been shown to disrupt gut bacteria in animals, preferentially killing beneficial forms and causing an overgrowth of pathogens. Two other properties of glyphosate also negatively impact human health – chelation of minerals such as iron and cobalt and interference with cytochrome P450 enzymes, which play many important roles in the body. Further studies indicate that Roundup was the most toxic herbicide and insecticide among the nine tested, and 125 times more toxic than its principal component glyphosate (Mesnage et al., 2014). The toxicity of Roundup, acting to reduce tissue levels of manganese, has been suggested to be involved in neurological diseases associated with prion-like protein formation, including ALS and PD (Samsel and Seneff, 2015).

Acetate, propionate (PPA), butyrate, and pentanoate, having respectively two, three, four, and five carbon atoms, are SCFAs, largely produced by microbial fermentation of complex polysaccharides in the colon. SCFAs are absorbed into the colonic epithelium where, primarily, butyrate is consumed as a preferred fuel source by colonocytes (Donohoe et al., 2011). SCFAs produced by microbiota enter the bloodstream through the portal circulation of the host and the distal colon. Then the SCFAs are transported to recipient tissues where they are used in a variety of cellular responses, including the regulation of gene expression (Alenghat and Artis, 2014) and energy for the brain. So-called olfactory receptors, Olfr78 and Gpr41, are located in our kidneys and sense two SCFAs, acetate and PPA, that are released by commensal bacteria in our guts. Ninety-nine percent of these two fatty acids in the blood are produced by the commensal bacteria and are key to regulating blood pressure. The regulation occurs through Olfr78 leading to the production of renin to increase blood pressure, whereas Gpr41 lowers blood pressure. The two act as a push-pull regulatory system to maintain appropriate pressure; eat just enough, and pressure is lowered. However, if one eats too much, then Olfr78 is activated so that pressure does not continue to lower to dangerous levels. Thus, overeating may raise blood pressure through a commensal bacteria mechanism (Pluznick, 2017). Constant constriction of blood vessels in the brain may contribute to neurodegeneration.

Addition of the SCFA butyrate, produced by bifidobacteria, to the drinking water of mice resulted in restoration of intestinal microbial homeostasis, improved gut integrity, and prolonged life span compared with those of control mice. At the cellular level, abnormal Paneth cells – specialized intestinal epithelial cells that regulate the host-bacterial interactions – were significantly decreased in the ALS mice treated with butyrate. In both ALS mice and intestinal epithelial cells cultured from humans, butyrate treatment was associated with decreased aggregation of the G93A superoxide dismutase 1 mutated protein (Zhang et al., 2017).

In a mouse model, treatment with SCFAs, PPA most potently, enhanced differentiation and proliferation of CD4+CD25+Foxp3+ Treg cells and ameliorated autoimmune encephalomyelitis disease course. In contrast, medium chain fatty acid or long chain fatty acid such as lauric acid or palmitic acid enhanced Th1 and Th17 cell differentiation and contributed to a more severe course of experimental autoimmune encephalomyelitis (Haghikia et al., 2015).

Drugmakers sold nearly 30 million pounds of antibiotics for livestock in 2011 – the largest amount yet recorded and about 80% of all reported antibiotic sales that year (Kessler, 2013). Those antibiotics will then be ingested with the meat we eat (Sajid et al., 2016; Stępień-Pyśniak et al., 2016).

Stress is a major cause of dysbiosis (Bailey and Coe, 1999) and can be hereditary through transgenerational epigenetic programming from the father (Rodgers et al., 2015) or mother (Weaver, 2007; Franklin et al., 2010). Epidemiological studies suggest that gestational exposures to environmental factors such as stress are strongly associated with an increased incidence of neurodevelopmental disorders, including attention deficit-hyperactivity disorder, schizophrenia, autism spectrum disorders, and depression (Brown, 2012).

Circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases (Voigt et al., 2014). Ong et al. (2018) are first to utilize machine learning methods to directly link diet with gut microbiome populations and brain structure. That is, high fiber diets will have positive effects on the microbiome and brain structure.

Air pollution (AP) contributes to global burden of many diseases, including stroke (Feigin et al., 2016). AP consists of numerous reactive oxygen species (ROS) that are associated with the development of disease (Tao et al., 2003). ROS are reactive molecular species with an unpaired electron in their outer orbit that can easily extract a second electron from a neighboring molecule. Dysfunction of mitochondria or NADPH-oxidase and activation of inflammatory cells to produce ROS and reactive nitrogen species are also caused by particulate matter (PM). Although extracellular ROS can be mitigated or delayed by antioxidants in biological systems, an overload of ROS is able to attack local tissues leading to cell injury, including mitochondrial and DNA damage, and consequently result in necrotic and apoptotic cell death (Li et al., 2003).

Proteins are extensively oxidized by ROS, and these oxidized proteins are degraded by proteasome and autophagic proteolytic systems for bulk degradation. Approximately 90% of damaged proteins are degraded into small peptides by the ubiquitin-proteasome pathway (Rock et al., 1994).

In addition to the ubiquitin-proteasome pathway, autophagy is also an essential pathway to degrade oxidized proteins. Autophagy is a regulated cellular mechanism for degrading proteins that is mediated by lysosomal-dependent processing. The autophagosome then fuses with and delivers its contents to the lysosome. Lysosomal enzymes subsequently facilitate degradation to regenerate metabolic precursor molecules (Mizushima and Komatsu, 2011).

Many factors will influence neuroinflammation, including diet and environmental chemical exposure, and even environmental enrichment will reduce inflammation (Xu et al., 2016). Feeding mice a Western diet, comprising high-calorie, high-fat, low-fiber, and fast food, led to significant inflammatory changes after just 1 month. The experimental group of mice showed changes throughout their bodies that are similar to the strong inflammation reactions that occur in bacterial infections (Christ et al., 2018). The acute inflammation response was quelled after the Western diet mice were fed their normal cereal diet for 4 weeks. However, switching to the more healthful diet failed to reverse the fundamental alterations in the innate immune system, and many of the genes that had been activated by the Western diet stayed active. As previously shown, this is another example that the innate immune system has a form of memory (Sun et al., 2014) and is another means for establishing chronic para-inflammation. AP, including diesel particulate, is another means for inducing neuroinflammation, microglia activation, and neurodegeneration (Block and Calderón-Garcidueñas, 2009) leading to significant changes in human electroencephalograms, for example (Crüts et al., 2008; Levesque et al., 2011).

Induction of a very low grade endotoxemia by injection of Escherichia coli endotoxin can impair memory in humans (Krabbe et al., 2005), and epidemiological investigations have demonstrated an association between low-grade peripheral inflammation and age-related decline in cognitive function (Engelhart et al., 2004). Inflammatory responses occurring at the site of pathology have been linked to neurodegeneration in CNS disorders such as AD (Wyss-Coray and Rogers, 2011) and PD (Hirsch et al., 2009).

At the cellular level in the CNS, glaucoma has been associated with oral dysbiosis, thought to be associated with a parainflammatory state in the retinal ganglion cells and optic tract as demonstrated in a mouse model (Astafurov et al., 2014).

Damage to the lining of the intestinal tissue, the introduction of pathogenic microbes, or exposure to molecules that induce immune reactions can increase the inflammatory state of the intestinal environment. In turn, enteric inflammation can induce a number of effects that ultimately alter CNS function and the neuroinflammatory condition.

In the CNS, the microglia are the innate sentinel immune cells that can detect subtle changes in molecules in their locality (Kim and de Vellis, 2005; Tremblay et al., 2011) and ultimately are responsible for neuroinflammatory processes (Kettenmann et al., 2011; Yamasaki et al., 2014; Ransohoff et al., 2015). Immune cells can directly communicate with neurons (Pavlov and Tracey, 2015). The extent of the functional impact of neuro-immune synapses is not known, but it is clear that activated immune cells can modulate neuronal activity via the release of neurotransmitters and cytokines. In a mouse model, host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be partially rectified by complex microbiota (Erny et al., 2015). A diverse GI microbiota is necessary for the maintenance of microglia in a healthy functional state. In contrast, the absence of a complex host microbiota led to increased microglial populations with defects in microglia maturation, activation state and differentiation, and alterations to microglia morphology. A compromised immune response to bacterial or viral infection was also demonstrated (Erny et al., 2015). Inhibition of microglia formation is neuroprotective in a mouse model (Tikka and Koistinaho, 2001).

A recent study conducted by Cattaneo et al. (2017) found that the Escherichia and Shigella bacterial genera were increased in Alzheimer’s patients compared to that of the control group. This type of bacteria is associated with facilitating inflammation (Sherwin et al., 2017). DNA sequences for bacteria have also been found in the brain of Alzheimer’s patients (Emery et al., 2017). Inflammation and abnormality in the GI system have been linked with the development of neurological disorders like autism and dementia, as well as neuropsychiatric disorders like schizophrenia and bipolar disorder (Mangiola et al., 2016). While autism and Alzheimer’s have been the most studied diseases when it comes to the influence of the gut, studies exploring microbiota’s connection to other disorders are becoming more and more telling.

Evidence suggests that inflammation promotes the selective survival of pathogenic microbes possessing mechanisms for preventing or tolerating proinflammatory host immune responses, characteristic features of pathogens (Scher et al. 2015). Thus, under inflammatory conditions, intestinal bacteria typically exhibit more pathogenic and less commensal activity, further exacerbating inflammation and increasing the likelihood of persistent immune responses in the intestine.

Amino acids are important to maintaining gut health, but we will see that amino acids derived from plants have advantages over those derived from animals. For example, hydrolyzed casein slowed GI transit compared with hydrolyzed soy (Dalziel et al., 2017). This is important for autophagy, where slowed transit time in the GI reduces autophagy (Kim et al., 2017). Molecular components of the autophagy pathway are involved in the digestion and transport of lipids across the intestinal epithelium (Khaldoun et al., 2014), the secretion of cargo from specialized cell types (Dupont et al., 2011; Cleyrat et al., 2014; Vandussen et al., 2014; Bel et al., 2017; Kimura et al., 2017; Liu et al., 2015), and microbial containment and clearance, called antimicrobial autophagy (Wild et al., 2011; LaRock et al., 2015; Schwerd et al., 2016). Thus, intrinsic autophagy in the gut is necessary for the control of inflammation and the immune response to adventitious agents, and also in the maintenance of intestinal stem cells and for intestinal regeneration following irradiation (Asano et al., 2017).

Studies of rats (Keelan et al., 1985) and humans (Warren et al., 1978) have shown age-related losses in villous and enterocyte heights (Höhn et al., 1978), and aged rats demonstrated altered rates of the uptake of saturated fatty acids in the jejunum (second section of small intestine). Environmental regulation of the cells in the intestine includes factors such as zinc intake (Duff and Ettarh, 2002). Irradiation, even at low doses, during cancer treatment is also another factor that diminishes microvilli size, structure, and function (Wróblewski et al., 2002).

The composition of the microbiota largely determines the levels of tryptophan in the systemic circulation and, hence, indirectly, the levels of serotonin in the brain (O’Mahony et al., 2015). Some microbiota synthesize neurotransmitters directly, e.g. γ-amino butyric acid (Barrett et al., 2012), while modulating the synthesis of neurotransmitters, such as dopamine, norepinephrine, and BDNF.

Furthermore, the neurotransmitter and hormone 5-hydroxytryptamine (5-HT) not only helps to synthesize serotonin production, but it also greatly impacts the GI system. Ninety percent of 5-HT is produced in the gut and activates a number of different 5-HT receptor subtypes and immune cells. Recent GF mice studies have shown that gut microbes influence the level of 5-HT in the blood and in the colon (Yano et al., 2015). Imbalances in serotonin have been associated with the presence of certain mood disorders, including major depressive disorder and a range of anxiety disorders.

One study found that animals brought up in a sterile environment presented an increased hypothalamic pituitary adrenal response to psychological stressors (Dinan and Cryan, 2012) suggesting that overexposure to antibiotics or over-sterilization of an environment in early life could lead to anxiety-like behavior and perhaps even an anxiety disorder.

Intestinal microbiota regulate expression of proteins that build the tight junction (Al-Asmakh and Hedin, 2015) and many proinflammatory cytokines secreted by activated immune cells. The secreted cytokines include TNF, IL-1β, and IL-6 that act on tight junctions to increase barrier permeability (Al-Sadi and Ma, 2007; Capaldo and Nusrat, 2009) so that additional immune cells and components from circulation can be recruited to the sites expressing an inflammatory state. Although weakening of the intestinal barrier facilitates a wider engagement of the immune system, a compromise in the containment of gut contents, especially the molecules that microbes release, will result. Leakage from the intestine into the peritoneal cavity and into the circulation can then occur, eliciting a systemic proinflammatory immune response (Al-Asmakh and Hedin, 2015). Many microbial pathogenic secretions or components such as LPS that enter the circulation following increased intestinal permeability are immunogenic and can trigger systemic inflammatory responses. Proinflammatory cytokines and oxidative stress have been causally linked to neuron death, including dopaminergic neurons, and neuroinflammation is now considered a key factor in numerous neurodegenerative diseases. However, if the source of the immune induction is rapidly cleared, proinflammatory responses usually terminate, and then the gut barrier function can be restored. However, unique features of the intestine render the gut particularly susceptible to the development of a chronic inflammatory state and resultant barrier dysfunction. Many of the resulting diseases, such as PD, are associated with aging, and given that intestinal inflammation and forms of intestinal permeability have been shown to increase with age (Man et al., 2015), immune mediation of gut-brain interactions may be particularly relevant in the pathology of neurodegenerative diseases of aging. For example, under physiological conditions αSYN is mostly localized in synapses. However, a portion of αSYN is secreted to the extracellular space, where it must be sequestered. If not sequestered, inflammatory responses in neighboring cells could be induced, where activation of pro-inflammatory TLR4 pathways occurs in astrocytes (Ranniko et al., 2015). Further, over-expression of αSYN has been shown to produce αSYN aggregation in the intestines and brains of mice and humans (Hallett et al., 2012). We hypothesize that one way the αSYN is not properly sequestered in the tissue surrounding neurons is because of the breakdown in matrix caused by inflammation due to a leaky gut. Here the leaky gut is causing a ‘leaky matrix’. The same ‘leaky structure’ may follow for other forms of matrix, including, for example, perineuronal nets that are so critical to neuronal function and possibly to preventing neurodegeneration (e.g. Maguire, 2017). Another way that the disrupted epithelial lining can lead to toxicity of cells is through the resulting absence of ciliary signaling of flow. Normally, the flow of fluids through the gut, such as milk from a neonatal diet, generates a shear stress on the unilaminar epithelium lining the lumen, thereby inducing mechanical autophagy (Kim et al., 2017).

Again, the luminal surface of the intestine limits the access of pathogenic microorganisms to the underlying gut tissues. Protection of the surface derives from mucous and a single layer of epithelial cells bound by tight junctions. Within the villus epithelium and follicle-associated epithelium (FAE) of the Peyer’s patch are microfold cells (M cells), a unique form of epithelial cell that specializes in the transepithelial transport of macromolecules and particles. M cells enable the host’s immune system to sample the intestinal lumen and mount an appropriate immune response. However, some pathogenic microorganisms exploit M cells and use them to gain entry into mucosal tissues (Kraehenbuhl and Neutra, 2000). M cells have been shown to actively transcytose prions to the basolateral side of the epithelium, and studies in mice suggest that prions might likewise be translocated across the FAE by M cells in vivo (Foster and Macpherson, 2010). Here again, we see another form of leaky gut that may be induced by microorganisms to translocate their malformed proteins to the host organism. The actin-rich microvilli of the epithelial cells sense the flow of intestinal fluid, inducing macroscopic transport of fluids across the cells and activating a noncanonical autophagy (Kim et al., 2017). Without autophagy, the cells will not be able to clear debris and toxins. Thus, the potentially destructive debris and toxins may spread as the cells are known to expunge internal molecules when autophagy is inoperable.

Stress acting through cortisol is another means by which increases in intestinal permeability occur (Vanuytsel et al., 2014), allowing bacterial translocation from the gut to distant sites. Given that the leprosy bacterium, Mycobacterium leprae, reprograms through dedifferentiation the Schwann cells to mesenchymal-like stem cells by downregulating lineage determinants and upregulating endothelial-mesenchymal transition genes (Masaki et al., 2013), it is clear that bacteria can have profound direct effects on the nervous system. Dedifferentiation has been considered as a reversal to an earlier developmental stage in the Schwann cell (SC) lineage (Chen et al., 2007), until a recent study challenged this view. The study demonstrated that dedifferentiated SC upregulate a specialized repair-promoting transcriptional program orchestrated by c-jun and suggested that injury reprograms cells into ‘repair cells’ (Arthur-Farraj et al., 2012). Additional work of Clements et al. (2017) supports this idea and confirms that dedifferentiated SCs are more closely related to embryonic stem cells than their developmental progenitors.

Fortunately, probiotics can reduce cortisol levels in response to stress (Bravo et al., 2011), and in a clinical study E. coli Nissle 1917 has been shown to maintain remission of ulcerative colitis (Kruis et al., 2004), acting, at least partially, through increasing the barrier function of epithelial cells (Hering et al., 2014). Circulating LPS is found in ALS and major depression patients, and PD patients early in the sequelae (Maes et al., 2008; Zhang et al., 2009; Forsyth et al., 2011), an indication of leaky gut occurring early in these conditions. Human studies have shown that through mucociliary transport inhaled PM are quickly cleared from the lungs and translocated into the intestine (Möller et al., 1985). Furthermore, pollutant PM contaminates both our food and water supply in significant amounts. Hence, pollutant PM can account for additional oral route exposure (Beamish et al., 2011). Short-term treatment of wild-type mice with PM altered immune gene expression; enhanced pro-inflammatory cytokine secretion in the small intestine; increased gut permeability, oxidative stress, and disruption of tight junctions; and induced hyporesponsiveness in splenocytes (Mutlu et al., 2011; Kish et al., 2013).

The composition of the microbiota determines the levels and nature of tryptophan catabolites which in turn has profound effects on aryl hydrocarbon receptors, thereby influencing epithelial barrier integrity and the presence of an inflammatory or tolerogenic environment in the intestine and beyond. The composition of the microbiota also determines the levels and ratios of SCFAs such as butyrate and PPA. Butyrate is a key energy source for colonocytes. Dysbiosis leading to reduced levels of SCFAs, notably butyrate, therefore may have adverse effects on epithelial barrier integrity, energy homeostasis, and the T helper 17/regulatory/T cell balance (Vinolo et al., 2011). Moreover, dysbiosis leading to reduced butyrate levels may increase bacterial translocation into the systemic circulation. Fermentation of fiber making propionic acid by gut bacteria will also have a profound effect on regulating T cells. Linker’s lab has shown that fermentation of fiber into propionic acid downregulates Th1 and Th17 cells, upregulates Treg cells in animal models and humans, and leads to a reduction of symptoms in multiple sclerosis (MS) patients (Haghikia et al., 2015; Duscha et al., 2017).

Because NK cells and cytotoxic T lymphocytes depend on a well-orchestrated process to specifically deliver their lytic granules to target cells without delivery to surrounding healthy cells (Hsu et al., 2016), we suggest that dysbiosis may interrupt the specificity of lytic granule targeting and lead to destruction of the cells in the gut’s lining through non-specific delivery of lytic granules to healthy cells.

Proper gut function in the prevention of neurodegenerative disease is highlighted by a study showing that middle-aged men who defecated less than once a day had an over fourfold increased risk for PD diagnosis over the next 24 years compared to men with regular bowel movements (Abbott et al., 2001).

Blue arrows indicate psychobiotic processes and effects, while red arrows indicate processes associated with leaky gut and inflammation (Figure 1). Probiotics directly introduce beneficial bacteria such as Lactobacilli and bifidobacteria into the gut. Prebiotics (e.g. inulin) support the growth of such bacteria. The following are noted:

Figure 1:

Overview of some important pathways in brain-gut connection.

• –

  Postbiotics, including SCFAs and gut hormones. Both probiotics and prebiotics increase production of SCFAs, which interact with gut mucosal enteroendocrine cells and catalyze the release of gut hormones such as cholecystokinin, peptide tyrosine tyrosine, and glucagon-like peptide-1. Prebiotics may have stronger effects in this regard in comparison to probiotics. SCFAs and gut hormones enter circulation and can migrate into the CNS. Gut hormones are also secreted by tissues other than enteroendocrine cells.

• –

  Neurotransmitters. Psychobiotics enhance neurotransmitter production in the gut, including dopamine, serotonin (5-HT), noradrenaline, and γ-aminobutyric acid (GABA), which likely modulate neurotransmission in the proximal synapses of the ENS.

• –

  Vagal connections. The vagus nerve synapses on enteric neurons and enables gut-brain communication.

• –

  Stress, barrier function, and cytokines. Barrier dysfunction is exacerbated through stress-induced glucocorticoid exposure. This enables migration of bacteria with pro-inflammatory components, increasing inflammation directly and also triggering a rise in pro-inflammatory cytokines via the immunogenic response. These cytokines impair the integrity of the blood-brain barrier and permit access to potentially pathogenic or inflammatory elements. Pro-inflammatory cytokines (red circles) also reduce the integrity of the gut barrier. Psychobiotic action restores gut barrier function and decreases circulating concentrations of glucocorticoids and pro-inflammatory cytokines. They also increase concentrations of anti-inflammatory cytokines (blue circles) that enhance integrity of the blood-brain barrier and the gut barrier and reduce overall inflammation. Cytokines clustering at the brain represent cytokine interaction with the blood-brain barrier. SCFAs can pass the blood-brain barrier as an energy source for the brain.

• –

  Central lymphatic vessels. Cytokines may interact more directly with the brain than previously appreciated through the recently discovered central lymphatic vessels (taken with permission from Sakar et al., 2016).

Without proper immune system function, stem cell function (at least transplanted stem cell function) does not have therapeutic benefit (Galleu et al., 2017). Maintenance and repair of gut lining is highly dependent on stem cell function, probably mostly from intrinsic stem cells and not those from bone marrow (Leibowitz et al., 2014; Yin et al., 2016). Although nonsteroidal anti-inflammatory drugs (NSAIDs) reduce inflammation, and many had hoped they would prove useful for neurodegenerative diseases, NSAIDs can cause ulcers and probably leaky gut (Thiéfin and Beaugerie, 2004), and we suggest that this is, at least partially, a reason why NSAIDs fail to have positive effects in human neurodegenerative diseases (Schwartz and Shechter, 2010).

Meat and meat proteins increase the risk of neurodegeneration, including ALS (Pupillo et al., 2017). Increased death risk primarily associated with red meats, eggs, and dairy is not found among those with healthy lifestyle in which plant protein is consumed (Giovannucci et al., 2016). Among women with a history of gestational diabetes, a low-carbohydrate dietary pattern, particularly with high protein and fat intake mainly from animal-source foods, is associated with higher type 2 diabetes risk, whereas a low-carbohydrate dietary pattern with high protein and fat intake from plant-source foods is not significantly associated with risk of type 2 diabetes (Bao et al., 2015). Here we have provided evidence of why adding some dietary plant ingredients to your diet is healthful. The proliferation of books by those without scientific training promoting a diet rich in fat and little or no grains is helping to cause a long-term health crisis. The Atkins diet, the South Beach diet, Grain Brain, and the Paleo diet, promoting diets that are high in proteins and fats and devoid of or highly reduced in grains, are serving to induce a number of diseases and dysbiosis (Ornish, 2004; Russell et al., 2011; Fung et al., 2015). Animal-based diets promote a gut microbiome with an increased population of B. wadsworthia that are capable of triggering inflammatory bowel disease (David et al., 2014). Indeed, high-fat diets have been shown to create dysbiosis, induce a leaky large intestine (Hamilton et al., 2015), and increase oxidative stress and inflammation (Barbaresco et al., 2013; Montonen et al., 2013; Ley et al., 2014). Red meat and chicken are also associated with an increased risk of type 2 diabetes (Talaei et al., 2017).

These results change previous notions of the Paleo diet and shed light on hominin abilities to adjust to new environments and exploit different flora, facilitating population diffusion, survival, and colonization beyond Africa. A vegetarian diet provides all of the essential amino acids (McDougall, 2002), and while vitamin B12 is a concern, that may be supplied by the bacteria in our guts (Albert et al., 1980) and some fermented foods and seaweed (Rizzo et al., 2016). However, given modern sterility, and the dysbiosis of our guts, vegans are recommended to supplement their diet with vitamin B12 (McDougall and McDougall, 2013). The whole idea of eating a fatty diet and excluding whole grains is therefore unfounded. Organic food is advised given the food supply is tainted with many toxins, antibiotics, and pesticides such as glyphosate (Samsel and Seneff, 2015). Inclusion of a plant-based diet with whole grains will even lead to healthier DNA, inducing increased levels of telomerase and lengthening the telomeres (Ornish et al., 2013), the protective caps at the ends of DNA strands (Blackburn and Epel, 2017). The benefits of a plant-based diet are many-fold, including their antiangiogenic effects (Li et al., 2012), and an increase in their consumption includes a rapid increase in the feeling of well-being and happiness (Mujcic and Oswald, 2016).

A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine. Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Carboxymethylcellulose and polysorbate-80 have been shown to induce dysbiosis, low-grade inflammation, and obesity/metabolic syndrome in wild-type mice and promoted colitis (Chassaing et al., 2015).

Bacteria send signals throughout the body by releasing extracellular vesicles, which are exosome-like nanoparticles (Maguire, 2016). In somatic cells, the content, including microRNA, and functional characteristics of exosomes on other cells has been shown to be regulated by environmental inputs (Lo Cicero et al., 2015). Outer membrane vesicles released from bacteria are similar to exosomes (Sjöström et al., 2015), and therefore, this is an important area for future research.

In the 1920s, the psychiatrist Henry Cotton performed colectomies to treat psychiatric problems, believing, without evidence, that the agent causing the neurological condition was the colon in a state of dysbiosis (Skull, 2005). Others during that time recognized that the dysbiosis underlying the psychiatric condition could be treated with probiotics (Phillips, 1910). The emergence of overwhelming data in humans, and animal models, indicate that dysbiosis can be overcome by changing one’s diet (David et al., 2014). Meat can induce dysbiosis (David et al., 2014), and a diet rich in vegetables and low in meat and dairy may even increase brain volume (Gu et al., 2015).

To treat neurodegenerative diseases, several strategies involving the gut are proposed: (1) Introduce bacteria to the gut that supply beneficial metabolites, (2) recolonize the gut with commensal bacteria, (3) provide prebiotics that feed the endogenous and exogenous commensal bacteria but not the pathogenic bacteria, (4) supply the gut with amino acids that are known to be beneficial to building the integrity of the intestinal lining and in rebuilding the microvilli of the gut’s epithelial cells, and (5) provide the gut and hence the circulation and brain with postbiotic anti-inflammatory molecules.

Arguments have been put forth to develop therapeutics in a non-reductionist manner, incorporating multiple molecules to target the multiple pathways that underlie the condition (Maguire, 2014). Likewise, similar arguments have been offered for the development and analysis of nutrients (Campbell, 2014).

The gut has gained momentum in public health discourse recently, with a shift towards understanding the gut and brain as symbiotic and bi-directional rather than isolated entities when it comes to overall health and diseases prevention. Now, research is beginning to discover convincing findings, which will hopefully bring to light the reciprocal relationship between neurological, physiological, and psychological health and the gut, to help guide physicians and mental health care providers with an expanded range of treatment options.

Our approach based on current evidence is to deliver as a supplement a combination of prebiotics, probiotics, and postbiotics, along with amino acids to rebuild the gut wall and to restore homeostasis to the gut. Restoration of homeostasis to the gut and repaired gut wall to eliminate leaky gut syndrome will then lead to brain homeostasis, especially proteostasis, and help restore normal function to the nervous system. We now highlight what is included in the proposed supplement.

According to the International Scientific Association for Probiotics and Prebiotics (ISAPP), probiotics are defined as ‘live microorganisms that, when administered in adequate amounts, confer a health benefit on the host’ (Hill et al., 2014).

Butyrate has potent anti-inflammatory properties so it probably also has tumor-suppressive properties that are not cancer cell autonomous. For example, butyrate ameliorates the inflammation associated with colitis in both rodent models and human patients (Hamer et al., 2008). Some of these effects are probably due to histone deacetylase inhibition and epigenetic regulation of gene expression, but there is also evidence that it can signal through G-protein-coupled receptors to stimulate the expansion of Treg cells (Smith et al., 2013).

Scientists have identified more than 200 human milk oligosaccharides (HMOs) which are prebiotic (Karav et al., 2016). The risk of MS is reduced in those who were breast fed (Conradi et al., 2013). How does this protection arise? Bifidobacterium longum infantis digests HMOs, and in turn releases SCFAs, which feed an infant’s gut cells. Through direct contact, B. infantis also encourages gut cells to make adhesive proteins that seal the gaps between them, keeping microbes out of the bloodstream. Anti-inflammatory molecules are also produced. These changes only happen when B. infantis feeds on HMOs; if it feeds on lactose instead, it survives but does not engage in any symbiosis with the baby’s cells. In other words, the microbe’s full beneficial potential is unlocked only when it feeds on breast milk. Likewise, for a child to reap the full benefits that milk can provide, B. infantis must be present in the gut. Probiotics are those products that can survive in the human gut and impact microbes which colonize the gut. However, many probiotic strains do not colonize the gut and are no longer recoverable in stool 1–4 weeks after stopping their consumption. For example, a fermented milk product with probiotic strains matching the commercially available Activia was recently studied (McNulty et al., 2011). The study showed that the probiotic product did not change the gut’s bacterial composition, but instead altered gene expression patterns relevant to carbohydrate metabolism in the host’s resident gut microbes. These changes in the human fecal gut function were confined only to the time of probiotic consumption. Thus, a sustained benefit and colonization of the bacteria was not achieved. These data show that babies require mother’s breast milk for optimal health, and that the bacteria in milk, but not the milk itself, is beneficial to adult health. In a model of childhood malnutrition using gnotobiotic mice, certain long-term dietary practices may impair responses to dietary interventions, necessitating the introduction of diet-responsive bacterial lineages present in other individuals and identified as beneficial (Wagner et al., 2016).

Below will summarize some of the important bacteria to human health.

1. Ruminoccus brummi breaks down resistant starch and feeds other bacteria (a keystone bacterium).

2. Faecalibacterium prausnitzii has been shown to respond to prebiotic supplementation using a mixed chain length fructan supplement. Faecalibacterium prausnitzii is also able to use pectin for growth which may enable a more targeted approach to boosting numbers of this bacterial species. Reduced numbers of F. prausnitzii are present in Crohn’s disease patients, and since this bacterium has also been shown to have an anti-inflammatory effect, it is a strong target for disease therapy (Scott et al., 2015).

3. Bifidobacterium animalis subsp lactis (strain number I-2494 in the French National Collection of Cultures of Micro-organisms, Paris, France) is referred to as DN-173 010. Tillisch et al. (2013) has shown this bacterium to modulate brain activity.

4. Lactobacillus rhamnosus JB-1, an effective modulator of the gut microbiota, was proved to be able to increase GABA (Aα2) in the hippocampus of mice (Bravo et al., 2011).

5. Oxalobacter formigenes ferments oxylates, which are toxic if not broken down (Noonan and Savage, 1999).

6. Lactobacillus reuteri clade II strain 6475 attenuates colonic inflammation (Gao et al., 2015).

7. Lactobacillus GG alleviates the intestinal inflammation and pulmonary exacerbations rate in cystic fibrosis patients (Bruzzese et al., 2004).

8. The acetate-producing Bifidobacterium species have been shown to promote gut epithelial integrity (Fukuda et al., 2011).

9. Prevotella and a lower proportion of Bacteroides are associated with a higher production of SCFAs, such as butyrate (Ou et al., 2013).

10. Consider the independent contribution of gut microbiota-derived metabolites versus metabolites derived directly from food, such as tryptophan metabolites and ω-3 fatty acids. Indole-3-aldehyde, one tryptophan metabolite produced by lactobacilli, is an aryl hydrocarbon receptor (AhR) agonist (Zelante et al., 2013). AhR-dependent gene expression includes genes involved in the production of mediators important for gut homeostasis (Li et al., 2011).

11. A study conducted at the University of Toronto found a significant decrease in anxiety symptoms in patients who took the probiotic Lactobacillus casei after 60 days (Rao et al., 2009).

12. Escherichia coli Nissle 1917 modulates natural immunity in the gut (Trebichavsky et al., 2010).

13. Bacillus coagulans is a very well studied probiotic in the spore family that has a profound effect on inflammatory conditions such as irritable bowel syndrome and Crohn’s disease. Bacillus coagulans offers an expanded effect of controlling these common inflammatory bowel conditions in addition to its potent immune-boosting activity. Bacillus coagulans has the unique attribute of producing lactic acid and specifically the L+ optical isomer of lactic acid, which has been shown to have a more profound effect on immune stimulation and gut defense than the other forms of lactic acid produced by conventional probiotics. Bacillus coagulans is also a tremendous colonizer and thus assures proper colonization, which in turn will produce the beneficial effects required. Bacillus coagulans also plays a key role in digestion of food and absorption of nutrients. Bacillus coagulans can digest incoming fat to reduce the uptake of cholesterol. Bacillus coagulans adds another dimension given its potent ability to fight inflammatory conditions, aid in digestion, and prevent the growth of harmful bacteria.

14. Bacillus subtilis HU58 is one strain that has been shown in studies to actually alter the GI flora when it colonizes (Tam et al., 2006).

15. NCFM strain of Lactobacillus acidophilus, developed at North Carolina State University from a human intestinal tract, L. acidophilus HMF, and the L. acidophilus DDS-1 strain produce a number of positive benefits for the host (Sanders and Klaenhammer, 2011).

16. Faecalibacterium prausnitzii has a protective role in inflammatory bowel disease (Underwood, 2014).

17. VLS#3 has been shown to attenuate the signs and symptoms of colitis (Mencarelli et al., 2011) and contains the following bacteria: Streptococcus thermophiles, Bifidobacterium breve, B. longum, Bifidobacterium infantis, L. acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, and Lactobacillus delbrueckii subsp. bulgaricus.

The amino acids and carbohydrates in food help the bacterial spores move from their dormant (spore state) to their active (vegetative state) form in the GI. There are tremendous immune benefits if the spores are made to germinate into their vegetative state in the upper GI itself, and so taking a supplement just after a meal (10–60 min after) is ideal.

Multiple elements of tryptophan catabolism facilitate gut homeostasis (Thorburn et al., 2014). Tryptophan builds barrier function by regulating the expression of tight junction proteins in intestinal epithelial cells (Alvarez et al., 2016).

N-acetylcysteine improves the microbiota composition and barrier function in the gut (Oz et al., 2007; Xu et al., 2016) and prevents premature senescence of endothelial cells (Khan et al., 2017). N-acetylcysteine reduced ROS while increasing growth and ATP production in the fibroblasts of patients with mitochondrial disease (Douiev et al., 2016). Oral administration can improve brain function in a number of neurodegenerative indications (Shahipour et al., 2014).

However, an overabundance of amino acids, including N-acetylcysteine and tryptophan, can lead to inflammation (Rieber and Belohradsky, 2010; Koeth et al., 2013; Zhenyukh et al., 2017). mTORC1 mediates pro-oxidant and pro-inflammatory activation of blood cells by branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Daily BCAA supplementation could reach elevated blood levels around 3–6 mmol/l concentrations used in the in vitro studies showing the BCAAs to have pro-oxidant and pro-inflammatory effects (Zhenyukh et al., 2017).

Prebiotics are defined according to the ISAPP as ‘a selectively fermented ingredient that results in specific changes in the composition and/or activity of the GI microbiota, thus conferring benefit(s) upon host health’ (Gibson et al., 2010). Fibers, such as starches, are composed mostly of many sugar units bonded together. However, unlike most starches, the bonds in fiber cannot be broken down by digestive enzymes and therefore pass relatively intact into the large intestine. Fiber is fermented by commensal bacteria to produce large quantities of acetate, PPA, and butyrate (~40, 20, and 20 mm, respectively) (Tan et al., 2014). Dietary fiber is listed on the Nutrition Facts panel, and 25 g of dietary fiber is the currently recommended amount in a 2000-kcal diet. Manufacturers are allowed to call a food item a ‘good source of fiber’ if it contains 10% of the recommended amount (2.5 g/serving) and an ‘excellent source of fiber’ if the food contains 20% of the recommended amount (5 g/serving). Dietary fiber on food labels includes both dietary fiber and functional fiber. Most people in the United States do not consume adequate amounts of fiber, and 80% are nutrient deficient (Marriott et al., 2010).

Gum arabic is a soluble fiber that promotes healthy gut and enhances neurological function (Binjumah et al., 2016). It acts as a prebiotic to increase Lactobacilli and Bacteroides, and the numbers of Bifidobacteria, Lactobacilli and Bacteroides were significantly higher for gum arabic than for inulin (Calame et al., 2008).

Inulin-type fructans, arabinose, and arabinoxylan-oligosaccharides are prebiotics that stimulate both bifidobacteria and the production of butyrate (Falony et al., 2009; De Vuyst and Leroy, 2011; De Vuyst et al., 2014; Rivière et al., 2014). Green pea and chickpea-supplemented diet alters the gut microbiome and enhances gut barrier integrity in mice (Bibi et al., 2017; Monk et al., 2017).

Here I define postbiotics as those molecules released by bacteria and other microorganisms that when administered in adequate amounts confer health benefits to the host. Tryptophan metabolites, including tryptamine and indole-3-propionic acid, have been shown to rebuild the gut lining (Jennis et al., 2017). Fermented foods are great for the GI, but the benefits do not typically derive from the microorganisms colonizing the gut; rather the benefits derive from the ferment itself. The many nutrients the bacteria make, what I call the postbiotics, while fermenting the foods, are what are beneficial to the GI and the immune system.

Amino acids have been shown to increase electrolyte absorption and improved mucosal barrier functions (Yin et al., 2016). Enterocytes are absorptive cells, formed as simple columnar epithelial cells that are found in the small intestine. The brush border on the apical surface of enterocytes is a highly specialized structure well adapted for efficient digestion and nutrient transport, while at the same time providing a protective barrier for the intestinal mucosa. The brush border is constituted of a densely ordered array of microvilli, protrusions of the plasma membrane, which are supported by actin-based microfilaments and interacting proteins and anchored in an apical network of actomyosin and intermediate filaments, the so-called terminal web. The highly dynamic, specialized apical domain is both an essential partner for the gut microbiota and an efficient signaling platform that enables adaptation to physiological stimuli from the external and internal milieu. Nevertheless, inherited alterations or various pathological stresses, such as infection, inflammation, and mechanical or nutritional alterations, can jeopardize this equilibrium and compromise intestinal functions.

Lactobacillus reuteri treatment substantially counteracted the detrimental effects of E. coli and preserved the barrier function. Lactobacillus johnsonii and Lactobacillus GG also achieved barrier protection, partly by directly inhibiting enterotoxigenic E. coli attachment. Specific strains of Lactobacillus can enhance gut barrier function through cytoprotective heat shock protein induction and fortify the cell protection against an E. coli challenge through tight junction protein modulation and direct interaction with pathogens (Liu et al., 2015).

The proposed supplement should be taken about 1 h following a meal. This allows the food to clear well enough for the amino acids to interact with the gut and also allows for the pH of the stomach to become more alkaline due to the food, thus allowing better translocation of the probiotics through the acidic stomach (Lawrence, 1998).

Synthetic biology is hugely promising for developing therapeutics; however, the technology is currently used to engineer bacteria and yeast for the secretion of a particular molecule (Eisenstein, 2016), representing the continuation of a reductionist approach for treating disease (Maguire, 2014). Another promising methodology for the production of therapeutics are cell-free expression and purification of proteins (Sullivan et al., 2016) using lysates of bacteria and yeast. However, such approaches may not benefit from the synergistic properties of the systems therapeutic where a broader collection of therapeutic molecules are included (Maguire, 2014), and the packaging of the molecules into exosomes that provide protection and delivery properties to the molecules is present, as well as possible important post-translational modifications made within the exosome (Maguire, 2016). Because bacteria secrete molecules and exosomes, using the secretome of commensal bacteria may provide a much more useful therapeutic. In the diagnostic realm, scientists and engineers at Massachusetts Institute of Technology have now developed an ingestible sensor of various compounds (Mimee et al., 2018). Using a bioengineered bacterium that fluoresces coupled with a sensor to measure the emitted light signal, they were able to measure molecules in the gut, including heme to quantify GI bleeding. These sensors could be engineered to measure many types of molecules in the gut depending on the bacterial construct used in their micro-bio-electronic device. This is one possible means to help develop personalized gut medicine potentially leading to specific supplements for the amelioration of patient-specific neurological diseases.