Microbiota and neurologic disease1.docx

1、Microbiota and neurologic disease1Microbiota and neurologic diseases: potential effects of probiotics GiuliaUmbrelloand SusannaEspositoEmail authorJournal of Translational Medicine201614:298DOI:10.1186/s12967-016-1058-7 The Author(s)2016Received:21August2016Accepted:10October2016Published:19October2

2、016AbstractBackgroundThe microbiota colonizing the gastrointestinal tract have been associated with both gastrointestinal and extra-gastrointestinal diseases. In recent years, considerable interest has been devoted to their role in the development of neurologic diseases, as many studies have describ

3、ed bidirectional communication between the central nervous system and the gut, the so-called “microbiota-gut-brain axis”. Considering the ability of probiotics (i.e., live non-pathogenic microorganisms) to restore the normal microbial population and produce benefits for the host, their potential eff

4、ects have been investigated in the context of neurologic diseases. The main aims of this review are to analyse the relationship between the gut microbiota and brain disorders and to evaluate the current evidence for the use of probiotics in the treatment and prevention of neurologic conditions.Discu

5、ssionOverall, trials involving animal models and adults have reported encouraging results, suggesting that the administration of probiotic strains may exert some prophylactic and therapeutic effects in a wide range of neurologic conditions. Studies involving children have mainly focused on autism sp

6、ectrum disorder and have shown that probiotics seem to improve neuro behavioural symptoms. However, the available data are incomplete and far from conclusive.ConclusionsThe potential usefulness of probiotics in preventing or treating neurologic diseases is becoming a topic of great interest. However

7、, deeper studies are needed to understand which formulation, dosage and timing might represent the optimal regimen for each specific neurologic disease and what populations can benefit. Moreover, future trials should also consider the tolerability and safety of probiotics in patients with neurologic

8、 diseases.KeywordsAutism spectrum disorderBrainGut microbiotaMicrobiotaProbioticsBackgroundIn recent years, the gut microbiota residing in the gastrointestinal tract have emerged as a topic of great interest in medical research. The gut microbiota consist of trillions of microorganisms representing

9、many different species of known bacteria, as well as viruses, fungi,protozoaandarchaea1,2. Among the various bacteria, the most abundant phyla areBacteroidetesandFirmicutes, followed byProteobacteriaandActinobacteria, whileFusobacteriaandVerrucomicrobiaare less common. Butyrate-producing bacteria an

10、d lactic acid bacteria are thought to have beneficial effects to the host through anti-inflammatory, anti-tumourigenic and pathogen-exclusion properties 3.The deep influence of the gut microbiota on human health and homeostasis has many clinical manifestations. Studies have shown how dysbiosis (i.e.

11、, a disruption of the balanced composition of the gut microbiota) is associated with gastrointestinal 4,5,6,7 and extra-gastrointestinal diseases 8,9,10. Moreover, recent investigations have also advocated a possible role for microbiota in the pathogenesis of several brain disorders 11,12,13. The em

12、erging idea of the microbiota as a modulator of neural physiology has recently been investigated through the concept of the “microbiota-gut-brain axis”, which represents a composite model of interaction between the intestinal microbes and the brain. Despite the evidence of such communication, the ef

13、fect, magnitude and clinical relevance of the disruption of the microbiota in neurologic diseases have yet to be clearly elucidated.In view of these considerations, the potential role of probiotics in the prevention and treatment of neurologic diseases presents an attractive possibility. Probiotics

14、are living non-pathogenic microorganisms that confer a health benefit and improve physiological conditions in the host when administered in adequate amounts, as a food ingredient, supplement or drug 14. Probiotics are mainly composed of lactic-acid bacteria, such asLactobacilli, LactococciandBifidob

15、acteriaor yeasts asSaccharomycetes; to date,Lactobacillus rhamnosus GG, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus johnsonii, BifidobacteriumandSaccharomyces boulardiiare the most widely studied strains 15.Although the exact mode of action of probiotics remains uncertain, it is like

16、ly that several mechanisms operate together. Probiotics exert a microbiological function by preventing opportunistic pathogens from occupying functional niches in the gut microbial community, blocking epithelial attachment of pathogenic bacteria, inhibiting their growth with the production of lactic

17、 acid, propionic acid, acetic acid, bacteriocins and reactive oxygen species 16,17,18,19; they also play a nutritional role by producing several vitamins, lactase and health-promoting compounds 16,17,18,19. In addition, they regulate intestinal transit and reinforce the gut barrier. Furthermore, pro

18、biotics play an important role in the regulation of both the innate and adaptive immune systems by activating macrophages, NK cells and cytotoxic T cells, modulating the production of IgA, stimulating toll-like receptors and modifying the cytokine-expression profile 16,17,18,19.Some differences in b

19、iological properties and clinical effects have been reported among the various probiotic strains, mainly caused by genetic diversity and host-bacteria interactions 20. A great deal of evidence has established that the effects of probiotics may be genus-specific and even species- or strain-dependent

20、21,22,23 and that their efficacy is influenced by the dose 24. Moreover, there are differences even between single- and multi-strain probiotic formulations; however, it is not clear whether supplementation with mixtures is better than using a single strain. On examination of 16 comparative studies,

21、probiotic combinations appeared to be more effective than single components taken alone in 12 cases (75%) 25, although in many studies, this comparison is biased because of differences in dose. It is possible that the presence of a wide variety of probiotic genera in a multi-strain preparation leads

22、 to lower efficacy because of mutual inhibition by different species. However, there are data supporting the idea that mixtures have superior effectiveness over single strains, possibly because of a greater concentration of probiotics, a broader range of action and synergistic effects 26.Probiotics

23、are used as an adjuvant therapy for many paediatric gastrointestinal and extra-intestinal diseases, but few data are available on their use in brain disorders. The main aims of this review are to analyse the relationship between the gut microbiota and brain disorders and to evaluate the current evid

24、ence for the use of probiotics in neurologic conditions. Particular attention is paid to factors that condition the modification of the gut microbiota and the possibility of managing neurological diseases by modifying the gut microbial composition. PubMed was used to search for all of the studies pu

25、blished over the last 15years using the key word “microbiota” and “gut” or “intestinal” and “nervous system”. More than 350 articles were found, and only those published in English and providing data on aspects related to neurologic diseases were included in the evaluation.DiscussionThe microbiota-g

26、ut-brain axisAccumulating evidence has shown that gut microbiota influence human brain development and function 27,28,29,30. The exchange of regulatory signals through an integrative, bidirectional communication between the gastrointestinal tract and the central nervous system represents the gut-bra

27、in axis 31,32. In this relationship, the gut microbiota play a pivotal role. This complex system acts via direct and indirect mechanisms that involve neural, hormonal and immunological pathways 33,34,35.In top-down signalling, the central nervous system influences the gut microbiota, mainly through

28、the autonomic nervous system and the hypothalamuspituitaryadrenal axis. Indeed, several studies have demonstrated that a stressful event, especially early in life, can disrupt the microbiota profile, limit its richness and diversity, and affect bacterial species 36,37,38,39,40, inducing a shift in m

29、icrobial composition that may promote the translocation of species known to induce inflammation, such asClostridia, and reduce the proportion of anti-inflammatory bacteria, such asLactobacillus.Another pathway that can produce effects on the brain and behaviour involves the vagus nerve 41. The modul

30、ation of the gut microbiota usingLactobacillus rhamnosusstimulated the transcription of -aminobutyric acid (GABA) receptors and induced behavioural and psychological responses with marked dependence on vagal integrity 42. However, vagus-independent mechanisms are involved as well 33. The intestinal

31、microbiota has a profound influence on several neurotransmitters and neuromodulators, such as monoamines, serotonin, GABA, and brain-derived neurotrophic factor 43,44,45,46, which deliver signals to the brain trough enteric nerves, enterochromaffin cells 27 and the systemic circulation, crossing the

32、 bloodbrain barrier 34, whose permeability appears to be regulated by the microbiota in experimental models 47.Moreover, the gut microbiome induces maturation of the host immune system, contributes to establishing a durable immune repertoire and modulates the innate and adaptive immune systems to support the dominance of regulatory networks that prevent inflammation or immune-mediated disease and inflammatory responses 48,49. In addition, microbiota protect the intestinal barrier by improving epi