If 2-73 helps to restore homeostasis in the gut that strengthens the argument that the MOA will have an effect on most (if not all) CNS diseases (and perhaps diseases of the heart, liver, etc).
Review OPEN ACCESS Published: 01 March 2019 Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis Qianquan Ma, Changsheng Xing, Wenyong Long, Helen Y. Wang, Qing Liu & Rong-Fu Wang Journal of Neuroinflammationvolume 16, Article number: 53 (2019) | Download Citation
Abstract Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders.
Introduction Abundant and diverse microbial communities coexist in humans and mice. Majority of these microorganisms including bacteria, archaea, fungi, and viruses reside in human gastrointestinal tract, and are collectively referred as gut “microbiota” [1]. Studies on the symbiotic microflora trace back to almost 30 years [2]. Accumulating evidence suggests that microbiota are involved in the physiology and pathology of cellular organisms, and hence has implications in both health and disease [3]. Distinct microbial flora, which is inherited maternally at birth, changes due to our dietary habits and environmental signals [4,5,6]. The role of microbiota in various physiological activities, including in immune system, has been well established previously [7]. In addition, alterations in gut microbes in response to critical immune signaling contribute to the illnesses in intestine and distal organs, such as inflammatory bowel disease, autoimmune disease, and various types of cancer [8, 9].
The maturation and development of human central nervous system (CNS) is regulated by both intrinsic and extrinsic factors. Studies mostly from germ-free (GF) animals or animals treated with broad-spectrum antibiotics show that specific microbiota can impact CNS physiology and neurochemistry [10]. GF mice that are devoid of associated microflora exhibit neurological deficiencies in learning, memory, recognition, and emotional behaviors [11, 12]. They display variations in important neurotransmitters (e.g., 5-HT, NMDA, and BDNF) compared to conventional mice [13,14,15]. In humans, evidence for interplay between gastrointestinal pathology and neuropsychiatric conditions has been reported in conditions such as anxiety, depression, and autism [12, 16]. Furthermore, gut microbiota has been shown to modulate the development and homeostasis of CNS in context to immune, circulatory, and neural pathways [17]. In this review, we first discuss recent findings related to the interaction between gut microbiota and immune system, particularly key innate and adaptive immunity and signaling pathways. We then discuss the contribution of microbiota in CNS and pathogenesis of CNS disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), and gliomas. Finally, we discuss the role of gut-brain interactions during development of nervous system and neurodegeneration, as well as potential approaches for treating CNS disorders.
Interplay and reciprocal regulation between microbiota and immune system The human immune system has evolved to maintain a symbiotic relationship between host and microbiota, and its disruption in dynamic immune-microbial interaction leads to profound effects on human health [18]. In this section, we discuss the interplay between resident microbiota and key immunological signaling, and implications of their relationship in CNS development and neurological diseases.
Inflammasome signaling pathway
Inflammasome is an innate immune signaling complex, which is activated in response to diverse microbial and endogenous danger signals. To date, various pattern-recognition receptors (PRRs) in different families, including NLRP1, NLRC3, NLRP6, NLRP7, NLRC4 and AIM2, have been identified to play a role in inflammasome activation. Inflammasomes activation recruits ACS (apoptosis-associated speck-like protein containing a caspase recruitment domain) and the cysteine protease caspase 1 through caspase activation and recruitment domain (CARD) to induce the proteolytic cleavage of pro-caspase1 to generate mature and active caspase 1, which further process pro-IL-1ß and pro-IL-18 to the final production of bioactive IL-1ß and IL-18 proteins [19]. We identified NLRC5 as a key protein that negatively regulates NF-?B and type I interferon (IFN-I) signaling to control the homeostasis of innate immune system [20]. Earlier reports indicate that elevated levels of short-chain fatty acids (SCFAs) fermented by commensal microbiome activate NLRP3 inflammasome in gut epithelium through binding to GPR43 and GPR109A [21]. Furthermore, inflammasome activation leads to the release of IL-18, which contributes to the gut homeostasis and provides a protective role in colitis [21]. The protective effects of SCFAs in gastrointestinal graft-versus-host disease require GPR43-mediated ERK phosphorylation and activation of NLRP3 inflammasome [22]. NLRP6 inflammasome signaling plays an important role in modulation of microbiota. For example, NLRP6 deficiency leads to distorted colonization in intestinal microenvironment and possibly causes dysbiosis-driven diseases [23]. Further studies reveal that ASC, Caspase-1, and IL-18 knockout exhibit altered microbiota colonization as compared with that of wild-type mice. The inflammasome-mediated dysbiosis impacts a number of diseases [24]. Major depressive disorders are often associated with activated inflammasome and elevated levels of proinflammatory cytokines, such as IL-1ß, IL-6, and IL-18 proteins [25, 26]. By contrast, inhibition of caspase-1 attenuates inflammation and anxiety-like behaviors and modulates the composition of gut microbiota. Anti-caspase-1-treated mice show increased flora of Akkermansia spp. and Blautia spp. related to the induction of Foxp3 regulatory T cells (Tregs), and suppression of IL-1ß- and IL-6-mediated pathways [27]. Collectively, these studies indicate that gut microbiota modulate inflammatory response via inflammasome signaling to affect anxiety- and depressive-induced behaviors.
