The structure of intestinal microbiota is strongly influenced by diet and environmental stressors such as drugs. It seems that these factors dominate over the impact of genotype on the gut flora composition [ 54 ]. Consequently, it has been recognized that it may be the optimal marker of susceptibility to express certain clinical phenotypes and, thus, the response to pharmacotherapy [ 55 ]. Since the concept of bidirectional signaling between the gut and the brain started to evolve, scientists have made attempts to discover microbial fingerprints in neurology and psychiatry. Emerging research suggested that gut-brain axis dysfunction may be involved in the etiology of depression and anxiety, schizophrenia, addiction, and neurodevelopmental and neurodegenerative diseases as well as age-related cognitive decline [ 14 59 ]. Major microbiota-related alterations in particular neuropsychiatric conditions are summarized in Table 1

Nevertheless, uninterrupted stress regulation is pivotal to mental health and altered stress response has been implicated in the origin of psychiatric diseases [ 58 ]. Numerous studies conducted in animals and humans have demonstrated that both acute and chronic stress interfere with intestinal barrier integrity and induce adverse alterations in intestinal microbiota composition. This has been confirmed in models of early-life [ 79 ] stress and prenatal stress [ 80 ]. Yarandi et al. [ 81 ] showed that water and ion in the gut might be reduced and elevated, respectively, under stressful conditions. This, in turn, impairs the physical protection of the gut barrier against both pathogenic microorganisms and nociceptive molecules. Furthermore, HPA activation, in particular corticotropin-releasing factor (CRF), showed a causative role in gut integrity disruption [ 82 ]. Elevated intestinal permeability was also found to be linked to stress-induced hypersensitivity of the rectum in animals, which were studied by means of partial restraint stress [ 83 ]. Winter et al. merged microbiome data from both animals and humans and selected bacterial genera that were either over-represented or appeared in a reduced number following stressor exposure. The first group included:andwhereas those found in reduced numbers were:, and 84 ].

Emerging New Concepts in the Development of Neurodegenerative and GI Disease—Gut Microbes, Innate Immunity, and Bone Marrow Stem Cells as Partners in Crime

Salmonella typhimirum infection has been shown to decrease the Wnt/β catenin-inducible gene Axin2 (a marker of stem cell renewal) in the gut endothelium. Mood and psychiatric disorders as well as numerous GI disorders are related to chronic inflammation [ 85 ]. For example, post-infectious IBS alters GI tract motility and behavior [ 86 ]. A similar effect appears in patients with FD [ 87 ]. Behavioral alterations predominate in chronic GI inflammatory disorders [ 88 ]. Chronic inflammation of the ENS can easily affect the CNS. However, knowledge on mechanisms behind this phenomenon is still scarce. For decades, inflammation in the brain, which were recently implicated in the pathogenesis of psychiatric diseases, has been considered “sterile.” However, recent reports reveal the presence of the gut-vascular barrier (GVB), which, in structure and function, resembles the blood brain barier (BBB) and their communication is mediated via blood and bone marrow systems [ 89 ]. GVB controls the dissemination of bacteria from the gut into the bloodstream and theinfection has been shown to decrease the Wnt/β catenin-inducible gene Axin2 (a marker of stem cell renewal) in the gut endothelium.

Importantly, the Wnt/β catenin signaling pathway is universally involved in trafficking (mobilization and proliferation) of stem cells deposited in adult tissues [ 90 ] including those located in GI tract [ 91 ]. Wnt/β catenin system has also been involved in the developmental control of BBB formation [ 92 ]. It has been demonstrated that various types of bone marrow-derived stem cells are mobilized into peripheral blood in patients and experimental animals in response to tissue/organ injury [ 93 ]. Examples include myocardial infarction [ 94 ], stroke [ 95 ], deep skin burns [ 96 ], and gut inflammation [ 97 ]. It has been previously shown that circulating peripheral bone marrow mononuclear cells (PBMNCs) were enriched with cells expressing mRNA of leucine-rich repeat-containing G-protein coupled receptor 5 (lgr-5), Achaete-scute complex homolog 2 (Ascl-2), Doublecortin Like Kinase 1 (Dclk-1), Male-specific lethal 1 homolog (MSL1), and B lymphoma Mo-MLV insertion region 1 homolog (BML-1). These markers are involved in the development of early intestinal lineage [ 97 ]. These circulating in PB cells could potentially be involved in reparatory mechanisms of peripheral tissues including the brain [ 98 ].

In fact, the release of very small embryonic-like stem cells (VSELs) and more differentiated neural stem cells (NSCs) from bone marrow into the peripheral blood in response to brain injury in rodents [ 99 ] and humans [ 95 ] has been well documented. Recent research indicates the involvement of other factors such as small bioactive lipids that may direct mobilization and trafficking of stem cells to injured organs [ 100 ]. Notably, release of sphingiosine-1-phosphate (S1P) correlates with the activation of the complement cascade and formation of the C5b-C9 membrane attack complex (MAC). Activation of proteolytic and fibrynolitis complement cascades. The release of cleavage fragments (e.g., C5a and desArgC5a fragments) could enhance the mobilization of stem cells from their niche in the bone marrow [ 101 ]. Moreover, these stem cells can be attracted from the bone marrow and from the intestinal epithelium in response to tumor or injured tissue derived plasma chemo-atractants such as stromal derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), zonulin, hepatocyte growth factor (HGF) or shphingosine-1-phosphate (S1P), ceramides, and extracellular nucleotides [ 102 103 ]. On the other hand, stem cells may secrete their own growth factors, cytokines, or even membrane-derived micro-vesicles that accelerate the regeneration process [ 104 ]. The previously mentioned factors have been frequently implicated in the pathogenesis of gastrointestinal and psychiatric disorders [ 89 105 ].

® Barrier, Amsterdam, The Netherlands) in a 12-week, placebo-controlled, randomized clinical study, which favorably modified both functional and biochemical markers (e.g., VEGF) of vascular dysfunction in obese postmenopausal women [ We envision that stem cells together with the GI microbiome are mutually involved in the pathogenesis of disorders of GBA by employing different mechanisms (e.g., autocrine, paracrine, or hormonal effects, immunomodulatory effects, replacement of damaged cells, cytotoxic effects, and neurotoxic effects) in distant tissues and organs. Further studies are needed to assess more accurately the mechanisms of cell-host-microbe interactions ( Figure 1 ). Knowledge around these mechanisms already allows the design of novel treatments targeting GBA. For example, structural analog of S1P —Fingolimod and Ozanimod, functional antagonists of S1P receptors have already been applied in the treatment of relapsing forms of multiple sclerosis [ 106 ] as well as ulcerative colitis [ 107 ]. Similarly, supplementation with multi-species probiotics (EcologicBarrier, Amsterdam, The Netherlands) in a 12-week, placebo-controlled, randomized clinical study, which favorably modified both functional and biochemical markers (e.g., VEGF) of vascular dysfunction in obese postmenopausal women [ 108 ].