Gut Microbiome and Brain.docx

1、Gut Microbiome and BrainGut Microbiome and Brain-Gut Axis in Autism Aberrant Development of Gut-Brain Communication and Reward CircuitryElizabeth M. Sajdel-Sulkowska1and Romuald Zabielski21Dept. Psychiatry Harvard Medical School and BWH, USA2DDept. Physiological Sciences, Warsaw University of Life S

2、ciences, Poland1. IntroductionThe function of the gut microbiome and the bidirectional communication between the gastrointestinal tract (GIT) and the brain is increasingly recognized in health and disease and disruption in its composition is not unique to the autistic pathology. However, the bidirec

3、tional communication between the gut and the brain, “the gut-brain/brain-gut axis” in autism has been relatively understudied. In general, this communication between gut and brain occurs through a direct neuronal pathway via the vagus nerve, the hormonal pathway of several hormones involved in the r

4、egulation of food intake, such as cholecystokinin (CCK), ghrelin, leptin and insulin, and by the immunological signaling pathway involving cytokines. Recent studies indicate that the vagus nerve is involved in immunomodulation as suggested by its ability to attenuate the production of proinflammator

5、y cytokines in experimental models of inflammation (de Jonge and Ullola, 2007). Furthermore, the gut microbiome emerges as a major player not only in the maturation of GIT tissue and the gut brain axis but also in brain maturation, through its effect on both the immune and endocrine systems. Many to

6、xins, toxicants, infectious agents, diet or stress, affect an individuals gut microbiome, which may be especially sensitive during the critical developmental period. Disruption of the developing microbiome may have profound consequences on the developing gut-brain axis including the brain as well as

7、 long-term effects on both the physical and psychological development.This chapter attempts to bridge basic animal studies with clinical findings pertaining to the brain-gut and gut microbiome in autism, and includes a discussion of various strategies in managing autistic symptoms. The discussion al

8、so includes possible changes in the reward system(s) in autism as a consequence of altered gut microbiome. It is possible that aberrant regulation of the reward system(s) underlines behavioral abnormalities in ASD that could be targeted by future microbiome-targeting therapies.2. Effect of perinatal

9、 infection and toxicants on the developing brainIn a continuing quest to understand the nature of gene-environment interactions in ASD, we have recently completed two animal studies examining the effect of perinatal exposure of thimerosal (TM) and lipopolysaccharides (LPS) on the developing rat cent

10、ral nervous system (CNS). Both TM and infections (modeled by LPS exposure) have been implicated in autistic pathology.Organic mercury compounds are powerful toxicants with a range of harmful neurological effects in humans and animals. TM, which is metabolized to ethyl mercury, has been discontinued

11、as a preservative from infant vaccines but continues to be used in several vaccines including a flu vaccine administered to pregnant and lactating mothers(Sulkowski et al., 2012). Perinatal maternal exposure of two strains of rats, Sprague Dawley (SD) and spontaneously hypertensive (SHR) rats, to th

12、imerosal (200 ug/kg body weight) resulted in both sex- and strain-specific abnormalities in the neonatal rats (Sulkowski et al., 2012). Behavioral abnormalities included delayed startle response and decreased motor learning, with the effects being both sex- and strain-specific. TM exposure also resu

13、lted in a significant increase in cerebellar levels of an oxidative stress marker (3-nitrotyrosine) and a decrease in cerebellar type 2 deiodinase, responsible for local intrabrain conversion of thyroxine to the active hormone, 3,3,5,-triiodothyronine (T3). These effects were associated with an incr

14、eased expression of several genes negatively regulated by T3 (Sulkowski et al., 2012);Khan et al., 2012) suggesting that perinatal exposure to TM impacts the developing brain at the genetic level. As TM exposure during the postnatal phase coincided with lactation, some of the TM was delivered throug

15、h the milk to the GIT and may have had an effect on the developing gut microbiome known to be sensitive to heavy metal exposure (Lapanje et al., 2007). This effect may be in part due to competition with zinc resulting in a disturbance in metallothionein function and general chelating capacity for ot

16、her metals. Thus, at least part of the neonatal impact of TM/mercury could be mediated via its action on the gut microbiome.In a related study (Xu et al., submitted) we examined the effect of E.coli lipopolysaccharides (LPS) exposure during critical developmental periods on the developing brain empl

17、oying the animal model of infection. Clinical and epidemiological data suggest that maternal infection during pregnancy and nursing increases the probability of neonatal brain injury and may have a long-lasting impact on brain functions. Maternal infection during pregnancy has been linked to neurolo

18、gical and neurobehavioral disorders in humans such as cerebral palsy (Schendel, 2001; Schendel et al.,2002), neonatal strokes (Ferrieo, 2004), schizophrenia (Watson et al., 1999;Pearce, 2001) and affective disorders (Watson et al., 1999). Animal studies implicate bacterial infection in the pathology

19、 of Parkinsons disease (Carvey et al., 2003), and notably, schizophrenia and autism (Patterson, 2002). The triggering signals for cytokine production are endotoxins, major components of the outer membrane of Gram-negative bacteria.LPS exposure is one of the most acceptable models of infection; LPS i

20、s a sufficient trigger for cytokine production. LPS administered to the pregnant mother are transferred to the fetus through the placenta (Kohmura et al., 2000), and result in increased cytokines levels in the amniotic fluid (Urakabo et al., 2001;Gayle et al., 2004) and the fetal brain (Urakabo et a

21、l., 2001). Bacterial infection of lactating mothers also results in an increased level of cytokines in milk (Bannerman et al., 2004). Pretreatment of suckling rats with LPS (10 mg/kg-day x 5 days the dose which produces weak, transient signs of endotoxemia) results in reduced pancreatic secretion an

22、d attenuates acute pancreatitis at adult age due to an increased concentration of the antioxidative enzyme SO in the pancreatic tissue, and to the modulation of cytokines production (Jaworek at al., 2007a,b). This late-effect of LPS is accompanied by dose-dependent reduction of mRNA signal for CCK1

23、receptor on pancreatic acini as well as modified expression of acinar pro-apoptotic heat shock protein-60 (HSP60) and Bax proteins (Jaworek et al., 2007b,2008). Early postnatal LPS exposure results in inceased expression of toll-like receptor 4 (TLR4) and caspase-3 and 9- proteins in the pancreatic

24、tissue of adult rats (Bonior et al., 2012). These studies clearly indicate that perinatal exposure to LPS may have long lasting consequences on the GIT function, and as expected, though not studied in detail, on the brain-gut axis.Perinatal maternal exposure of two strains of rats, SHR or SD rat dam

25、s to LPS (200 g/kg body weight) resulted in increased rollover time, delayed startle, and decreased motor learning, with the effects being both strain- and sex-specific. LPS challenge also resulted in a trend towards an increase in cerebellar levels of 3-NT and a decrease in D2 activities in LPS-exp

26、osed pups (Xu et al., submitted). Several genes were affected by LPS. Notably Type 2 deiodinase 2 (DIO2) and brain derived neurotrophic factor (BDNF) expression was significantly elevated, while transthyretin (TTR) expression was decreased following LPS exposure.In vitro, acute exposure of cerebella

27、r cultures to LPS resulted in a decreased size of the dendritic area of Purkinje cells. Our data thus demonstrate that perinatal infection impacts the developing cerebellum in a sex- and strain-dependent manner via mechanisms involving oxidative stress, enzymes involved in maintaining local TH homeo

28、stasis, and downstream gene expression. Interestingly, gene changes observed in the brains of LPS-exposed rats were distinct from TM-associated gene effect suggesting that the underlying macromolecular mechanism may be trigger-specific.Perinatal LPS exposure could have a profound effect on the gut m

29、icrobiome similar to the effect of repeated treatment with antibiotics. Experiments in healthy mice have shown that disrupting the normal balance of the gut microbiome with antibiotics caused changes in mice behavior and was accompanied by changes in BDNF which has been linked to depression and anxi

30、ety (Bercik et al., 2011;Neufeld et al., 2011). Perinatal LPS exposure most likely affects gut motility as suggested by studies of irritable bowel syndrome (IBS), where mild bacterial overgrowth-associated motility disorder can be reversed by antimicrobials (Scarpignato and Pelosini, 1999). Animal s

31、tudies have also shown that stress can change the composition of the microbiome, where the changes are associated with increased vulnerability to inflammatory stimuli in the GIT. Could gut dysbiosis be induced by recurrent infections? We have observed an increase in neurotrophin levels in the cerebe

32、lla of rats exposed to LPS (Sajdel-Sulkowska et al, unpublished observation) and brain region-specific changes in neurotrophin levels in ASD (Sajdel-Sulkowska et al., 2011). Together these observations suggest that a bacterial infection could trigger the gut microbiome to induce cytokine overproduct

33、ion leading to an imbalance of brain neurotrophins and contribute to developmental abnormalities.3. Effect of environmental perturbations on the developing components of the brain-gut axis: Intestinal permeability, inflammation and gut microbiomeAs indicated above the perinatal development of the CNS structure and function greatly depends on t