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Toward Effective Probiotics for Autism and Other Neurodevelopmental Disorders

2013; Cell Press; Volume: 155; Issue: 7 Linguagem: Inglês

10.1016/j.cell.2013.11.035

1097-4172

Jack A. Gilbert, Rosa Krajmalnik‐Brown, Dorota L. Porazinska, Sophie Weiss, Rob Knight,

Infant Nutrition and Health

Hsaio and colleagues link gut microbes to autism spectrum disorders (ASD) in a mouse model. They show that ASD symptoms are triggered by compositional and structural shifts of microbes and associated metabolites, but symptoms are relieved by a Bacteroides fragilis probiotic. Thus probiotics may provide therapeutic strategies for neurodevelopmental disorders. Hsaio and colleagues link gut microbes to autism spectrum disorders (ASD) in a mouse model. They show that ASD symptoms are triggered by compositional and structural shifts of microbes and associated metabolites, but symptoms are relieved by a Bacteroides fragilis probiotic. Thus probiotics may provide therapeutic strategies for neurodevelopmental disorders. Rapid advances in analytical and sequencing technologies have spurred a renaissance of research into connections between the microbial communities that inhabit our gut and physiological conditions. Given the complexity of gut microbial communities, estimated to contain 500–1,000 species that considerably expand our metabolic potential beyond what the human genome encodes, it is perhaps unsurprising that they can influence many aspects of our physiology and gut-linked health and disease. For example, TLR5 knockout mice can become obese because an altered microbial community, instead of affecting metabolic efficiency, increases its appetite (Vijay-Kumar et al., 2010Vijay-Kumar M. Aitken J.D. Carvalho F.A. Cullender T.C. Mwangi S. Srinivasan S. Sitaraman S.V. Knight R. Ley R.E. Gewirtz A.T. Science. 2010; 328: 228-231Crossref PubMed Scopus (1533) Google Scholar), or in a mouse model of multiple sclerosis, demyelination only occurs in the context of the gut microbiota (Lee et al., 2011Lee Y.K. Menezes J.S. Umesaki Y. Mazmanian S.K. Proc. Natl. Acad. Sci. USA. 2011; 108: 4615-4622Crossref PubMed Scopus (950) Google Scholar, Berer et al., 2011Berer K. Mues M. Koutrolos M. Rasbi Z.A. Boziki M. Johner C. Wekerle H. Krishnamoorthy G. Nature. 2011; 479: 538-541Crossref PubMed Scopus (895) Google Scholar). In addition, microbial impacts on neurology are also evident, including anxiety and sociability in mice (Collins et al., 2013Collins S.M. Kassam Z. Bercik P. Curr. Opin. Microbiol. 2013; 16: 240-245Crossref PubMed Scopus (146) Google Scholar) and changing emotions in humans who received fermented milk with probiotics (Tillisch et al., 2013Tillisch K. Labus J. Kilpatrick L. Jiang Z. Stains J. Ebrat B. Guyonnet D. Legrain-Raspaud S. Trotin B. Naliboff B. Mayer E.A. Gastroenterology. 2013; 144 (e1–e4): 1394-1401Abstract Full Text Full Text PDF PubMed Scopus (765) Google Scholar). In this issue of Cell, Hsaio et al., 2013Hsaio E.Y. McBride S.W. Hsien S. Sharon G. Hyde E.R. McCue T. Codelli J.A. Chow J. Reisman S.E. Petrosino J.F. et al.Cell. 2013; 155 (this issue): 1451-1463Abstract Full Text Full Text PDF PubMed Scopus (2065) Google Scholar make a striking contribution to our understanding of the influence of gut bacteria using an animal model that replicates autism-like behaviors in mouse offspring following maternal immune activation (Figure 1). They show that microbial shifts within the gut of a mouse resulted in changes of metabolites in the serum and that these lead to the onset of autism-like behaviors. Moreover, administering a beneficial bacterium, Bacteroides fragilis, reversed the physiological, neurological, and immunological anomalies. Autism diagnoses have increased rapidly over the last decade (currently 1 in 88 births, versus 1 in 150 reported in 2000; http://www.cdc.gov/ncbddd/autism/data.html), but no clear relationships between genetic factors and ASD symptoms have yet been found. However, gastrointestinal ASD symptoms suggest a potential breakdown in normal symbiotic relationships between the host and its microbes (a dysbiosis), which may affect health via systemic as well as direct pathways, including immune system interactions. In some ASD cases, gut barrier integrity is reduced, increasing permeability. This condition, together with maternal immune activation (MIA), can increase the abundance of certain bacterial metabolites in the serum of offspring, which if aberrant could influence host behavior. Although current literature regarding microbiota associated with ASD patients is limited and contradictory, there is evidence that ASD patients lack certain beneficial bacteria in their gut, e.g., Prevotella (Kang et al., 2013Kang D.W. Park J.G. Ilhan Z.E. Wallstrom G. Labaer J. Adams J.B. Krajmalnik-Brown R. PLoS ONE. 2013; 8: e68322Crossref PubMed Scopus (603) Google Scholar). To bring these issues into sharper focus in an experimentally tractable system, Hsaio and colleagues used the MIA paradigm to model autism-like behaviors in mice. In this animal model, pregnant mice were injected with an immunostimulant, polyinosinic:polycytidylic acid (poly(I:C)), which mimics a viral infection. MIA results in offspring with ASD-like behavioral symptoms and neuropathology. They showed that this mouse model for MIA reduced intestinal integrity through altered gut bacterial community. In offspring with reduced gut barrier integrity, the authors identified ∼8% of assayed bacterial metabolites that differed significantly in abundance compared to those with intact gut barrier function. When the MIA offspring mice were fed with Bacteroides fragilis, a gut microbe with positive effects on the immune system, the abundance of 34% of these metabolites changed back, gut barrier integrity was improved, the gut-microbiome was restored to a state similar to control mice, and a number of ASD-related behavioral abnormalities were ameliorated. In addition, a 46-fold increase of 4-ethylphenylsulfate (4EPS) in the serum of MIA offspring returned to normal levels. The authors demonstrated the gut bacteria may generate 4EPS by showing that germ-free mice have undetectable serum concentrations of 4EPS. Interestingly, 4EPS accumulates in patients with chronic renal failure and is related to p-cresol, which is present in urine of children with ASD and is suggested as a human autism biomarker (Persico and Napolioni, 2013Persico A.M. Napolioni V. Neurotoxicol. Teratol. 2013; 36: 82-90Crossref PubMed Scopus (101) Google Scholar), although additional studies would be needed to confirm the generality of this finding. Coincidently, the MIA mice in this study had p-cresol in their serum, but it was not at significant levels. When the authors added synthetic 4EPS to wild-type mice, they induced anxiety-like behavior similar to that observed in MIA mice. A second metabolite elevated in the MIA serum, and normalized by treatment with B. fragilis, was indolepyruvate. Indolepyruvate is generated by microbial tryptophan catabolism and is related to indolyl-3-acryloylglycine, another human autism marker. Indolepyruvate elevation could be linked to increased serum levels of serotonin, yet another human autism biomarker. Application of the B. fragilis probiotic increased many other metabolites, including N-acetylserine, which the authors hypothesize may provide protection against some ASD symptoms. This groundbreaking study provides some of the first conclusive evidence of the impact of MIA on GI tract integrity that is reversible via administration of a specific probiotic. It also shows that a suite of metabolic markers is generated by bacteria, altered in dysbiosis, and normalized by probiotic treatment. Importantly, the authors demonstrate that elements of the MIA phenotype can be caused by a specific microbial metabolite. This is an excellent example of how a combination of bacterial community profiling, mouse models, germ-free mice, and metabolomics can be used to mechanistically understand the effects of the gut microbiome on health and disease states and to develop therapeutic strategies to treat key conditions. The broader potential of this research is obviously an analogous probiotic that could treat subsets of individuals with ASD. The observation that 4EPS imparts anxiety-like symptoms in normal mice suggests that other neurodevelopmental illnesses may also be linked to microbial metabolites in serum. If probiotics, such as B. fragilis that ameliorate 'bad' metabolites along with their negative neurological consequences could be identified in relevant mouse models, the implications for the mental health of humans are extraordinary. MIA has been linked to a range of human conditions, including depression and schizophrenia (Knight et al., 2007Knight J.G. Menkes D.B. Highton J. Adams D.D. Mol. Psychiatry. 2007; 12: 424-431PubMed Google Scholar), and several reports indicate that probiotics can treat anxiety and posttraumatic stress disorder (PTSD) in mouse models, including one model that requires an intact vagus nerve for gut-brain signaling (Bravo et al., 2011Bravo J.A. Forsythe P. Chew M.V. Escaravage E. Savignac H.M. Dinan T.G. Bienenstock J. Cryan J.F. Proc. Natl. Acad. Sci. USA. 2011; 108: 16050-16055Crossref PubMed Scopus (2228) Google Scholar). Therapies that target our microbial side may hold the key to making progress against a wide range of notoriously difficult psychiatric illnesses. R.K.B. is supported by the Autism Research Institute (ARI) and Bhare Autism Foundation, and R.K is supported by the Howard Hughes Medical Institute. Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental DisordersHsiao et al.CellDecember 5, 2013In BriefAn alteration in gut microbiota composition may drive the gastrointestinal and behavioral abnormalities associated with neurodevelopmental disorders. Full-Text PDF Open Archive