DIAGNOSIS AND TREATMENT OF AUTISM SPECTRUM DISORDER Hsiao Elaine

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1. A method for improving behavioral in a subject, comprising: determining the level of an autism spectrum (ASD)-related metabolite in a subject in of treatment; and adjusting the blood of the ASD-related metabolite in the subject an improvement in the behavioral performance in the is observed.

2. The method of claim 1, the subject suffers from autism spectrum disorder or a pathological condition with one or of the symptoms of ASD.

3. The method of 2, wherein the subject suffers ASD.

4. The method of claim 1, adjusting the blood level of the metabolite comprises adjusting the of gut microbiota in the subject.

5. The method of 4, wherein adjusting the composition of gut of the subject comprises fecal

6. The method of claim 4, wherein the composition of gut microbiota of the subject administering the subject a composition Bacteroides bacteria.

7. The method of 6, wherein the Bacteroides bacteria is B. B. thetaiotaomicron, B. vulgatus . or a mixture

8. The method of claim 6, wherein the is a probiotic composition, a neutraceutical, a composition, or a mixture thereof.

9. The of claim 4, wherein adjusting the of gut microbiota of the subject comprises the level of Clostridia bacteria in the

10. The method of claim 9, wherein the bacteria is Lachnospiraceae.

11. The method of 4, wherein adjusting the composition of gut of the subject comprises increasing the of Ruminococcaceae, Erysipelotrichaceae, and/or bacteria in the subject.

12. The method of 1, wherein the ASD-related metabolite is one of the listed in Table 1.

13. The method of 12, wherein the ASD-related metabolite is a involved in tryptophan metabolism, a involved in fatty acid a metabolite involved in purine glycolate, imidazole propionate, or

14. The method of claim 13, wherein the involved in tryptophan metabolism is indolepyruvate, indolyl-3-acryloylglycine, or serotonin.

15. The of claim 1, wherein the ASD-related is 4-ethylphenylsulfate, indolepyruvate, glycolate, or proprionate.

16. The method of claim 1, adjusting the blood level of the metabolite in the subject comprises to the subject an antibody against the metabolite, an antibody against an for the in vivo synthesis of the ASD-related or an antibody against a substrate for the in synthesis of the ASD-related metabolite.

17. The of claim 16, wherein the ASD-related is 4-ethylphenylsulfate or indolepyruvate.

18. The method of 16, wherein adjusting the blood of the ASD-related metabolite in the subject inhibiting an enzyme involved in the in synthesis of the ASD-related metabolite.

19. The of claim 1, wherein adjusting the level of the ASD-related metabolite gastrointestinal (GI) distress of the

20. The method of claim 19, wherein the GI comprises abdominal cramps, diarrhea, constipation, intestinal or a combination thereof.

21. The method of 1, wherein adjusting the blood of the ASD-related metabolite reduces permeability of the subject.

22. The method of 1, further comprising determining the level of the metabolite in non-autistic

23. The method of claim 1, further determining the behavioral performance of the prior to and after adjusting the level of the ASD-related metabolite in the

24. The method of claim 23, wherein the behavioral performance of the subject using Autism Behavior (ABC), Autism diagnostic (ADI-R), childhood autism Scale (CARS), and/or Autism Diagnostic Observation (PL-ADOS).

25. A method for improving performance in a subject, comprising: the urine level of an autism disorder (ASD)-related metabolite in a in need of treatment; and adjusting the level of the ASD-related metabolite in the until an improvement in behavioral in the subject is observed.

26. The method of 25, wherein the ASD-related metabolite is 4-methylphenylsulfate or indolyl-3-acryloylglycine.

27. The method of 25, wherein adjusting the urine of the ASD-related metabolite comprises the composition of gut microbiota in the subject.

28. The of claim 27, wherein adjusting the of gut microbiota of the subject comprises the subject a composition comprising bacteria.

29. A method for assessing the of a subject suffering from spectrum disorder (ASD) to treatment, comprising: determining the level of a B. fragilis -responsive in the subject; and comparing the blood of the B. fragilis -responsive metabolite in the to a reference level of the metabolite in suffering from ASD and one or more disorders, wherein substantial between the blood level of the in the subject and the reference level that the subject is susceptible to the treatment.

30. The method of claim 29, adjusting the composition of gut microbiota of the

31. The method of claim 30, wherein the composition of gut microbiota of the subject administering the subject a composition Bacteroides bacteria.

32. The method of 31, wherein the Bacteroides bacteria is B. B. thetaiotaomicron, B. vulgatus . or a mixture

33. The method of claim 30, wherein the composition of gut microbiota of the subject fecal transplantation.

34. The method of 29, wherein the B. fragilis -responsive is one of the metabolites listed in Table 2.

35. A for relieving gastrointestinal (GI) of a subject suffering from spectrum disorder (ASD), reducing intestinal permeability in the

36. The method of claim 35, wherein the GI comprises abdominal cramps, diarrhea, constipation, intestinal or a combination thereof.

37. The method of 35, wherein reducing intestinal comprises adjusting the composition of gut in the subject.

38. A method for diagnosing spectrum disorder (ASD) in a comprising: determining the level of a in gut and the blood level of one or more metabolites in the subject; and detecting or not there is an alteration in the level of the in gut and the blood level of at least one or of the ASD-related metabolites in the subject as to a reference level of the cytokine and the in non-autistic subjects, whereby an in the amount of the cytokine in gut and the blood of at least one of the one or more metabolites that the subject suffers ASD.

39. The method of claim 38, the cytokine is interleukin-6 (IL-6).

40. A for diagnosing autism spectrum (ASD) in a subject, comprising: the blood level of two or more metabolites in the subject; and detecting or not there is an alteration in the blood of the two or more ASD-related metabolites in the as compared to a reference level of the in non-autistic subjects, whereby an in the blood level of at least two of the two or ASD-related metabolites indicates the subject suffers from

41. The method of claim 38, wherein the one or of the ASD-related metabolites are selected the metabolites listed in Table 1.

42. The of claim 38, comprising altering the of one or more ASD-related metabolites in the to improve behavioral performance in the if it is indicated that the subject from ASD.

43. The method of 40, wherein the one or more of the ASD-related are selected from the metabolites in Table 1.

44. The method of claim 40, altering the level of one or more metabolites in the subject to improve performance in the subject if it is indicated the subject suffers from

Description:

RELATED APPLICATIONS

The application claims priority 35 U.S.C. §119(e) to U.S. Application No. 61/694,679, filed on

29, 2012, which is herein incorporated by reference in its entirety.

REGARDING FEDERALLY SPONSORED RD

invention was made with support under grant no. awarded by the Army, Graduate grant No. 5 T32 GM07737 awarded by Institutes of Health, Graduate Fellowship No. DGE-0703267 awarded by Science Foundation, and grant No. awarded by National Institutes of Health.

The government has certain in the invention.

REFERENCE TO SEQUENCE

The present application is being along with a Sequence in electronic format. The Sequence is provided as a file entitled created Aug. 28, 2013, is 4 Kb in size.

The information in the electronic of the Sequence Listing is incorporated by reference in its entirety.

BACKGROUND

1. Field of the Invention

The application relates generally to the of diagnosing and treatment of autism disorders (ASD).

2. Description of the Art

Autism spectrum disorder is a serious neurodevelopmental disorder by stereotypic behaviors and deficits in and social interaction. The reported of autism has rapidly increased to 1 in 88 in the United States as of 2008 2012), representing a significant and social burden in the coming Reproducible molecular diagnostics for ASD not been developed and therapies for the core symptoms of ASD are limited, and molecular diagnostics have not developed. Much research autism spectrum disorder has focused on genetic, behavioral and aspects of disease, but primary for environmental risk factors et al.

2011), immune dysregulation and peripheral disruptions in the pathogenesis of ASD recently gained significant The striking heterogeneity among that share the same is consistent with the prevailing that there are a variety of for ASD. Moreover, the spectrum of ASD and challenges in identifying specific treatments and molecular biomarkers the need to better define the subtypes of ASD and provide tailored to subclasses of ASD individuals.

SUMMARY

embodiments disclosed herein are to a method for improving behavioral in a subject, where the method determining the blood level of an spectrum disorder (ASD)-related in a subject in need of treatment; and the blood level of the ASD-related in the subject until an improvement in the performance in the subject is observed.

In embodiments, the subject suffers anxiety, autism spectrum (ASD), or a pathological condition one or more of the symptoms of ASD. In embodiments, the subject suffers ASD.

In some embodiments, the blood level of the ASD-related comprises adjusting the composition of gut in the subject. In some embodiments, the composition of gut microbiota of the subject fecal transplantation. In some adjusting the composition of gut microbiota of the comprises administering the subject a comprising Bacteroides bacteria.

In embodiments, the Bacteroides bacteria is B. B. thetaiotaomicron, B. vulgatus . or a mixture

In some embodiments, the composition is a composition, a neutraceutical, a pharmaceutical or a mixture thereof.

In some adjusting the composition of gut microbiota of the comprises reducing the level of bacteria in the subject. In some the Clostridia bacteria is Lachnospiraceae. In embodiments, adjusting the composition of gut of the subject comprises increasing the of Ruminococcaceae, Erysipelotrichaceae, and/or bacteria in the subject.

In some the ASD-related metabolite is one of the metabolites in Table 1. In some embodiments, the metabolite is a metabolite involved in metabolism, a metabolite involved in acid metabolism, a metabolite in purine metabolism, glycolate, propionate, or N-acetylserine. In some the metabolite involved in tryptophan is 4-ethylphenylsulfate, indolepyruvate, indolyl-3-acryloylglycine, or In some embodiments, the ASD-related is 4-ethylphenylsulfate, indolepyruvate, glycolate, or proprionate.

In some embodiments, the blood level of the ASD-related in the subject comprises administering to the an antibody against the ASD-related an antibody against an intermediate for the in synthesis of the ASD-related metabolite, or an against a substrate for the in vivo of the ASD-related metabolite.

In some the ASD-related metabolite is 4-ethylphenylsulfate or

In some embodiments, adjusting the level of the ASD-related metabolite in the comprises inhibiting an enzyme in the in vivo synthesis of the ASD-related

In some embodiments, adjusting the level of the ASD-related metabolite gastrointestinal (GI) distress of the In some embodiments, the GI distress abdominal cramps, chronic constipation, intestinal permeability, or a thereof. In some embodiments, the blood level of the ASD-related reduces intestinal permeability of the

In some embodiments, the method determining the reference level of the in non-autistic subjects. In some the method includes determining the performance of the subject prior to and adjusting the blood level of the metabolite in the subject.

In some determining the behavioral performance of the comprises using Autism Checklist (ABC), Autism Interview-Revised (ADI-R), childhood Rating Scale (CARS), Pre-Linguistic Autism Diagnostic Schedule (PL-ADOS).

Also herein in some embodiments is a for improving behavioral performance in a where the method includes: the urine level of an autism disorder (ASD)-related metabolite in a in need of treatment; and adjusting the level of the ASD-related metabolite in the until an improvement in behavioral in the subject is observed. In some the ASD-related metabolite is 4-methylphenyl, or indolyl-3-acryloylglycine.

In some embodiments, the urine level of the ASD-related comprises adjusting the composition of gut in the subject. In some embodiments, the composition of gut microbiota of the subject administering the subject a composition Bacteroides bacteria.

Some provided here are related to a for assessing the susceptibility of a subject from autism spectrum (ASD) to probiotic treatment, the method includes: determining the level of a B. fragilis -responsive in the subject; and comparing the blood of the B. fragilis -responsive metabolite in the to a reference level of the metabolite in suffering from ASD and one or more disorders, wherein substantial between the blood level of the in the subject and the reference level that the subject is susceptible to the treatment.

In some embodiments, the includes adjusting the composition of gut of the subject.

In some embodiments, the composition of gut microbiota of the subject administering the subject a composition Bacteroides bacteria. In some the Bacteroides bacteria is B. fragilis, B. B. vulgatus . or a mixture thereof.

In embodiments, adjusting the composition of gut of the subject comprises fecal

In some embodiments, the B. fragilis metabolite is one of the metabolites listed in 2.

Some embodiments disclosed are related to a method for relieving (GI) distress of a subject from autism spectrum (ASD), comprising reducing permeability in the subject. In some the GI distress comprises abdominal chronic diarrhea, constipation, permeability, or a combination thereof. In embodiments, reducing intestinal comprises adjusting the composition of gut in the subject.

Also disclosed in some embodiments is a method for autism spectrum disorder in a subject, where the method determining the level of a cytokine in gut and the level of one or more ASD-related in the subject; and detecting whether or not is an alteration in the level of the cytokine in gut and the level of at least one or more of the metabolites in the subject as compared to a level of the cytokine and the metabolite in subjects, whereby an alteration in the of the cytokine in gut and the blood level of at one of the one or more metabolites indicates the subject suffers from

Further disclosed herein in embodiments is a method for diagnosing spectrum disorder (ASD) in a where the method includes: the blood level of two or more metabolites in the subject; and detecting or not there is an alteration in the blood of the two or more ASD-related metabolites in the as compared to a reference level of the in non-autistic subjects, whereby an in the blood level of at least two of the two or ASD-related metabolites indicates the subject suffers from

In some embodiments, the one or more of the metabolites are selected from the listed in Table 1. In some the one or more ASD-related metabolites a metabolite involved in tryptophan a metabolite involved in fatty metabolism, a metabolite involved in metabolism, glycolate, imidazole N-acetylserine, or any combination thereof. In embodiments, the metabolite involved in metabolism is 4-ethylphenylsulfate, indolepyruvate, or serotonin. In some embodiments, the is interleukin-6 (IL-6).

In some the method includes altering the of one or more ASD-related metabolites in the to improve behavioral performance in the if it is indicated that the subject from ASD.

BRIEF OF THE DRAWINGS

FIG. 1. MIA offspring deficient GI barrier integrity and expression of tight junction and cytokines. FIG. 1A.

Intestinal assay, measuring fluorescence of fluorescein isothiocyanate (FITC) in serum after oral of FITC-dextran. DSS: n=6, S: n=16; adolescent n=4, P: n=17; adolescent n=4. are normalized to fluorescence intensity in adult saline offspring. 1B.

Expression of tight junction relative to beta-actin in colons of saline and poly(I:C) offspring. for each gene are normalized to levels in saline offspring. FIG.

1C. Expression of cytokines and markers relative to beta-actin in of adult saline and poly(I:C) Data for each gene are to expression levels in saline n=6-21.

FIG. 1D. Protein of cytokines and chemokines relative to protein content in colons of saline and poly(I:C) offspring. Data are presented as mean±SEM. **p0.01, ***p0.001. DSS=dextran sulfate, S=saline+vehicle, P=poly(I:C)+vehicle.

For experiment, adult saline and offspring were treated vehicle at 3 weeks of age, and were collected simultaneously for B. fragilis treatment group.

2. B. fragilis treatment has little on tight junction expression and profiles in the small intestine. 2A. Expression of tight junction relative to beta-actin in small of adult saline and poly(I:C)

Data for each gene are to expression levels in saline n=8. FIG. 2B. Quantification of the of B. fragilis treatment on expression of tight junction components to beta-actin in small intestines of MIA

Data for saline and poly(I:C) are as in (A). n=8. FIG. 2C. levels of cytokines and chemokines to total protein content in intestines of adult saline, and poly(I:C)+ B. fragilis offspring.

is normalized to expression levels in offspring. Asterisks directly bars indicate significance to saline control (normalized to 1, as by the black line), whereas at the top of the graph denote statistical between poly(I:C) and poly(I:C)+ B. groups. n=8-10. Data are as mean±SEM. *p0.05, **p0.01, P=poly(I:C)+vehicle, P+BF=poly(I:C)+ B. fragilis

3. B. fragilis treatment has no effect on immune dysfunction in MIA offspring. 3A. Percent frequency of Foxp3+ T regulatory cells from a population of CD4+ TCRb+ measured by flow cytometry of from adult saline, and poly(I:C)+ B. fragilis offspring.


FIG. 3B. Percent frequency of T helper cells and CD11b+ and neutrophilic and monocytic cells a parent population of TER119− measured by flow cytometry of from adult saline, and poly(I:C)+ B. fragilis offspring.

FIG. 3C. Production of IL-17 and by splenic CD4+ T cells from adult saline and offspring, after in vitro with PMA/ionomycin. Treatment were assessed by repeated two-way ANOVA with post-hoc test. n=5.

3D. Production of IL-17 and IL-6 by T cells isolated from lymph nodes of adult and poly(I:C) offspring, after in stimulation with PMA/ionomycin. effects were assessed by measures two-way ANOVA Bonferroni post-hoc test.

FIG. 3E. Anxiety-like and locomotor in the open field exploration for adult MIA offspring treated mutant B. fragilis lacking of polysaccharide A (PSA). Data total distance traveled in the cm open field (right), spent in the 17×17 cm center (middle) and number of entries the center square (left) a 10-minute trial.

Data for poly(I:C) and poly(I:C)+ B. fragilis are as in FIG. 10. poly(I:C)+ B. fragilis PSA deletion: n=17. FIG. 3F.

burying of marbles in a 6×8 array in a trial. Data for saline, and poly(I:C)+ B. fragilis groups are as in 10. poly(I:C)+ B. fragilis with PSA n=17. Data are presented as *p0.05, **p0.01, ***p0.001.

P=poly(I:C)+vehicle, P+BF=poly(I:C)+ B. fragilis . B. fragilis with PSA deletion.

4. MIA induces alterations in the composition of the microbiota. FIG. 4A.

Richness of the gut as illustrated by rarefaction curves Faith’s Phylogenetic Diversity versus the number of sequences for treatment group. FIG. 4B. of the gut microbiota, as indicated by the Gini

FIG. 4C. Levels of B. fragilis 16S (top) and bacterial 16S sequence in fecal samples collected at 1, 2, and 3 post treatment of adult with vehicle or B. fragilis . mice colonized with B. were used as a positive Data are presented as quantitative cycling thresholds [C(t)], C(t)34 (hatched line) is negligible, and for C(t)34, lesser equates to stronger abundance. where each represents sample from 3-5 independent FIG.

4D. Levels of B. fragilis 16S (top) and bacterial 16S sequence in fecal samples collected at 1, 2, and 3 post treatment of adult with vehicle or B. fragilis . mice colonized with B. were used as a positive Data are presented as quantitative cycling thresholds [C(t)], C(t)34 (hatched line) is negligible, and for C(t)34, lesser equates to stronger abundance. where each represents sample from 3-5 independent

Data are presented as mean±SEM. P=poly(I:C)+vehicle, P+BF=poly(I:C)+ B. fragilis . B. fragilis.

FIGS. 5A-E. MIA exhibit dysbiosis of the intestinal FIG.

5A is an unweighted UniFrac-based 3D plot based on all OTUs, global differences in the gut microbiota adult MIA and control offspring. The variation explained by each coordinate (PC) is indicated on the FIG.

5B is an unweighted UniFrac-based 3D plot based on subsampling of and Bacteroidia OTUs (2003 per sample). FIG. 5C is an unweighted 3D PCoA plot based on of OTUs remaining after of Clostridia and Bacteroidia OTUs (47 per sample). FIG.

5D is a heat-map the relative abundance of unique of the gut microbiota (bottom, x-axis) for biological replicates from saline and poly(I:C) offspring y-axis), where red of increasing denotes increasing relative of a unique OTU for a particular sample. All that significantly discriminate treatment groups are plotted. taxonomic assignments as designated by the Database Project are indicated for OTU.

FIG. 5E shows relative abundance of OTUs by taxonomic assignments at the class for the most abundant taxa and least abundant taxa n=10. Data were collected and analyzed for poly(I:C)+ B. treatment group.

FIG. 6. B. treatment corrects deficits in GI integrity and colon expression of junction components and cytokines in MIA FIG. 6A.

Intestinal permeability measuring fluorescence intensity of isothiocyanate (FITC) detected in after oral gavage of Data are normalized to fluorescence observed in adult saline Data for DSS, saline and are as in FIG. 1. poly(I:C)+ B. fragilis . FIG.

6B. Expression of tight components relative to beta-actin in of adult saline, poly(I:C) and B. fragilis offspring. Data for gene are normalized to expression in saline offspring. Data for and poly(I:C) are as in FIG. 1. Asterisks above bars indicate compared to saline control to 1, as denoted by the black line), asterisks at the top of the graph denote significance between poly(I:C) and B. fragilis groups. n=8.

6C. Immunofluorescence staining for claudin 8. images for n=5. FIG. 6D.

levels of claudin 8 (left) and 15 (right) in colons from poly(I:C) and poly(I:C)+ B. fragilis as measured by Western blot. signals from the same are depicted below. Data are to signal intensity detected in offspring. n=3. FIG. 6E.

of IL-6 relative to beta-actin in of adult saline, poly(I:C) and B. fragilis offspring. Data is to expression levels in saline Data for saline and poly(I:C) are as in

1. poly(I:C)+ B. fragilis . n=3. 6F. Protein levels of cytokines and relative to total protein in colons of adult saline, and poly(I:C)+ B. fragilis offspring. is normalized to expression levels in offspring.

Data for saline and are as in FIG. 1. Asterisks directly bars indicate significance to saline control (normalized to 1, as by the black line), whereas at the top of the graph denote statistical between poly(I:C) and poly(I:C)+ B. groups. n=10. Data are as mean±SEM. *p0.05, **p0.01, n.s.=not significant.

DS S=dextran sulfate, S=saline+vehicle, P=poly(I:C)+vehicle, B. fragilis.

FIG. 7. IL-6 colon expression of claudin 8 and 15. 7A. Dose-dependent expression of claudin 8 and claudin 15 (right) relative to in colons of adult wild-type cultured for 4 hours ex vivo increasing concentrations of recombinant IL-6.

Data are normalized to levels detected in 0 ng/ml controls. n=3. FIG. 7B. expression of claudin 8 (left) and 15 (right) relative to beta-actin in of adult wild-type mice with 80 ng/ml recombinant IL-6. n=3.

FIG. 7C. of claudin 8 (top) and claudin 15 relative to beta-actin in colons of wild-type mice at 12 hours treatment with recombinant IL-6. n=3.

Data are presented as mean±SEM.

8. B. fragilis treatment alters the of the intestinal microbiota and corrects abnormalities in MIA offspring. FIG.

8A is an UniFrac-based 3D PCoA plot on all OTUs. The percent variation by each principal coordinate is indicated on the axes. Data for and poly(I:C) are as in FIG. 2. FIG. 8B.

abundance of key OTUs of the family (top) and order Bacteroidales that are significantly altered by MIA and restored by B. fragilis treatment. are presented as mean±SEM. FIG. 8C is a tree based on nearest-neighbor of 16S rRNA gene sequences for key presented in panel B. Clades in solid lines indicate of the family Lachnospiraceae and clades in broken lines indicate of the order Bacteriodales.

The 6 taxa with numbers indicate that are significantly elevated in offspring and corrected by B. fragilis n=10.

FIG. 9. There is no for persistent colonization of B. fragilis treatment of MIA offspring. FIG. 9A.

of B. fragilis 16S sequence (top) and 16S sequence (bottom) in fecal collected at 1, 2, and 3 weeks post of adult offspring with or B. fragilis . Germ-free mice with B. fragilis were as a positive control. Data are as quantitative RT-PCR cycling [C(t)], where C(t)34 line) is considered negligible, and for lesser C(t) equates to abundance. n=1, where represents pooled sample 3-5 independent cages. FIG.

9B. of B. fragilis 16S sequence (top) and 16S sequence (bottom) in fecal collected at 1, 2, and 3 weeks post of adult offspring with or B. fragilis . Germ-free mice with B. fragilis were as a positive control. Data are as quantitative RT-PCR cycling [C(t)], where C(t)34 line) is considered negligible, and for lesser C(t) equates to abundance. n=1, where represents pooled sample 3-5 independent cages.

Data are as mean±SEM. S=saline+vehicle, P=poly(I:C)+vehicle, B. fragilis . GF+BF=germ-free+ B. fragilis.

10. B. fragilis treatment ameliorates behavioral abnormalities in MIA offspring. 10A.

Anxiety-like and locomotor in the open field exploration as measured by total distance in the 50×50 cm open field duration spent in the 17×17 cm square (middle), and number of into the center of the field over a 10 minute trial. FIG. 10B. Sensorimotor in the pre-pulse inhibition assay, as by percent difference between the response to pulse only and response to pulse preceded by a 5 db or 15 db Treatment effects were by repeated measures two-way with Bonferroni post-hoc n=35-75.

FIG. 10C. burying of marbles in a 3×6 array a 10 minute trial. n=16-45. 10D.

Communicative behavior, as by total number (left), duration (middle) and total (right) of ultrasonic vocalizations by adult male mice a 10 minute social encounter. FIG. 10E shows deficits in in B. fragilis -treated MIA offspring.

10F shows deficits in social in B. fragilis -treated MIA offspring. represent cumulative results for 3-6 independent cohorts of mice.

are presented as mean±SEM. *p0.05, ***p0.001. S=saline+vehicle, P=poly(I:C)+vehicle, B. fragilis . Data were simultaneously for poly(I:C)+ B. fragilis and poly(I:C)+ B. thetaiotaomicron treatment

FIG. 11. Amelioration of autism-related in MIA offspring is not specific to B. fragilis FIG. 11A.

Anxiety-like and behavior in the open field assay, as measured by total traveled in the 50×50 cm open (right), duration spent in the cm center square (middle), and of entries into the center of the (left) over a 10 minute Poly(I:C)+ B. thetaiotaomicron . n=32. 11B.

Repetitive burying of in a 3×6 array during a 10 minute Poly(I:C)+ B. thetaiotaomicron . n=32. 11C.

Communicative behavior, as by total number (left), duration (middle) and total (right) of ultrasonic vocalizations by adult male mice a 10 minute social encounter. B. thetaiotaomicron . n=10. FIG. Sensorimotor gating in the pre-pulse assay, as measured by percent between the startle response to only and startle response to preceded by a 5 db or 15 db pre-pulse.

Treatment were assessed by repeated two-way ANOVA with post-hoc test. Poly(I:C)+ B. . n=32. For all panels, data for poly(I:C) and poly(I:C)+ B. fragilis are as in 10. Graphs represent cumulative obtained for 3-6 independent cohorts of

Data are presented as mean±SEM. **p0.01, ***p0.001. S=saline+vehicle, P+BF=poly(I:C)+ B. fragilis . P+BT=Poly(I:C)+ B.

FIGS. 12A-B. B. fragilis causes statistically significant serum metabolites, with changes in biochemicals relevant to acid metabolism and purine pathways. Levels of 103 metabolites are significantly altered in sera of B. -treated MIA offspring compared to controls, as measured by GC/LC-MS. indicate fold change to metabolite concentrations detected in offspring, where red hues increased levels compared to and green hues represent levels compared to controls legend on top left).

All changes are p0.05 by two-way ANOVA contrasts. P=poly(I:C), P+BF=poly(I:C)+ B. . n=8.

FIG. 13. B. fragilis corrects MIA-induced alterations in (4EPS), a microbe-dependent metabolite sufficiently induces anxiety-like FIG.

13A shows relative of metabolites detected by GC/LC-MS were significantly altered by MIA and by B. fragilis treatment. n=8. 13B shows concentrations of 4EPS by LC-MS in sera of adult (GF) versus conventionally-colonized pathogen-free, SPF) mice. n=1, where each pooled sera from 3-5

FIG. 13C. Anxiety-like and behavior in the open field assay for conventional wild-type treated with 4EPS or vehicle.

Data indicate distance traveled in the 50×50 cm field (right) and duration in the 17×17 cm center square over a 10 minute trial. is no difference between 4EPS− and mice in number of entries the center of the field (data not n=10. FIG.

13D. startle reflex in the pre-pulse assay in 4EPS-treated mice to controls. Data show the intensity of startle in response to a 120 db (left) and percent inhibition of the when it is preceded by a 5 db or 15 db pre-pulse n=10.

Data are presented as *p0.05, **p0.01, S=saline+vehicle, P+BF=poly(I:C)+ B. fragilis . SPF=specific (conventionally-colonized), GF=germ-free, Veh.=vehicle 4EPS=4-ethylphenylsulfate.

FIGS. 14A-B. of autism-associated metabolites by host-microbe FIG. 14A.

Diagram the synthesis of 4EPS (found in MIA serum and restored by B. fragilis and p-cresol (reported to be elevated in of individuals with ASD) by tyrosine metabolism and host FIG. 14B. Diagram the synthesis of indolepyruvate (found in MIA serum and restored by B. fragilis and indolyl-3-acryloylglycine (reported to be elevated in of individuals with ASD) microbial tryptophan metabolism and glycine conjugation. Solid represent known biological

Dotted arrow represents biological conversions.

FIGS. 4-ethylphenylsulfate (4EPS) synthesis, and in vivo experiments. FIG.

Diagram of 4EPS synthesis by 4-ethylphenol with sulfur in refluxing benzene to generate the salt followed by ion exchange K+ resin to generate the potassium FIG. 15B. Dose-response and linear regression analysis for concentrations of potassium 4EPS by LC/MS. FIG.

15C. increases in serum 4EPS a single i.p. injection of 30 potassium 4EPS into wild-type mice. FIG. Communicative behavior, as measured by number (left), average (middle) and total duration of ultrasonic vocalizations produced by male mice during a social encounter. n=5.

15 E. Repetitive burying of marbles in a 3×6 during a 10-minute trial. Data are presented as mean±SEM. (saline), 4EPS=4-ethylphenylsulfate.

DETAILED

In the following detailed description, is made to the accompanying drawings, form a part hereof. In the similar symbols typically similar components, unless dictates otherwise. The illustrative described in the detailed description, and claims are not meant to be limiting. embodiments may be utilized, and other may be made, without departing the spirit or scope of the subject presented herein.

It will be understood that the aspects of the disclosure, as generally described and illustrated in the Figures, can be arranged, combined, separated, and designed in a variety of different configurations, all of are explicitly contemplated herein.

spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behaviors and deficits in language and interaction. As described herein, metabolites are related to ASD. The of these metabolites in a subject can be and used to diagnose ASD, or for treating ASD, such as by behavioral performance of the subject.

In addition, as described herein, metabolites are responsive to B. fragilis and those metabolites can be used to the susceptibility of a subject suffering ASD to probiotic treatment.

In some the level of the metabolite in the circulation of a in need of treatment is determined and to improve behavioral performance in the The subject in need of treatment can be a suffering from anxiety, or a pathological condition with one or of the symptoms of ASD. The level of the in the circulation of the subject can be the blood for example the serum level or level, of the metabolite.

In some the urine or fecal level of the in the subject is determined and adjusted to behavioral performance in the subject.

In embodiments, the level of the metabolite in the of a subject is detected and compared a reference level of the metabolite in population to diagnose whether the has ASD or not. The level of the metabolite in the of the subject can be the blood level, for the serum level or plasma of the metabolite.

DEFINITIONS

Unless otherwise, technical and scientific used herein have the meaning as commonly understood by one of skill in the art to which the present belongs. See, e.g. et al. Dictionary of Microbiology and Molecular 2nd ed. J. Wiley Sons (New N.Y.

1994); Sambrook et al. Cloning, A Laboratory Manual, Springs Harbor Press Springs Harbor, N.Y.

For purposes of the present disclosure, the terms are defined below.

As herein, the term “subject” is a such as a mammal. The term is defined as an individual belonging to the Mammalia and includes, without humans, domestic and farm and zoo, sports, or pet animals, as sheep, dogs, horses, or cows. In some embodiments, the is human.

As used herein, the “condition/disorder/symptom” or “behavioral abnormality” to a symptom expressed by a subject but not limited to anxiety, Fragile X, syndrome, tuberous sclerosis, compulsive disorder, attention disorder, schizophrenia, autistic (classic autism), Asperger’s (Asperger syndrome), pervasive disorder not otherwise specified childhood disintegrative disorder or a pathological condition with one or of the symptoms of ASD.

As used the term “subject in need of the refers to a subject expressing or from one or more of the behavioral mentioned above. An appropriately person is able to identify an individual in need of treatment standard behavioral testing The same behavioral testing can also be used to determine there is improvement to the individual’s and/or symptoms.

As used the term “improvement in behavioral refers prevention or reduction in the or frequency, to whatever extent, of one or of the behavioral disorders, symptoms abnormalities expressed by individual from anxiety, ASD, or a condition with one or more of the of ASD. Non-limiting examples of the symptom include repetitive decreased prepulse inhibition and increased anxiety. The improvement is observed by the individual taking the themselves or by another person or otherwise).

As used herein, the “treatment” refers to a clinical made in response to a disease, or physiological condition manifested by a particularly a patient suffering ASD. The aim of treatment may include, but is not to, one or more of the alleviation or prevention of slowing or stopping the progression or of a disease, disorder, or condition and the of the disease, disorder or condition. In embodiments, “treatment” refers to therapeutic treatment and prophylactic or measures. Those in need of include those already by a disease or disorder or undesired condition as well as those in the disease or disorder or undesired condition is to be prevented.

For example, in embodiments treatment may improve performance of the subject, including behaviors. As used herein, the “prevention” refers to any activity reduces the burden of the individual expressing those behavioral This takes place at secondary and tertiary prevention wherein: a) primary prevention the development of symptoms/disorder/condition; b) secondary activities are aimed at early of the condition/disorder/symptom treatment, thereby opportunities for interventions to prevent of the condition/disorder/symptom and emergence of symptoms; and c) prevention reduces the negative of an already established condition/disorder/symptom by, for restoring function and/or any condition/disorder/symptom or related complications.

acceptable” carriers are ones are nontoxic to the cell or mammal exposed thereto at the dosages and employed. “Pharmaceutically acceptable” can be, but not limited to, organic or inorganic, or liquid excipents which is for the selected mode of application as oral application or injection, and in the form of a conventional pharmaceutical such as solid such as granules, powders, capsules, and such as solution, emulsion, and the like. Often the physiologically carrier is an aqueous pH buffered such as phosphate buffer or buffer. The physiologically acceptable may also comprise one or more of the antioxidants including ascorbic low molecular weight (less about 10 residues) polypeptides, such as serum albumin, immunoglobulins; hydrophilic polymers as polyvinylpyrrolidone, amino acids, including glucose, mannose, or chelating agents such as sugar alcohols such as or sorbitol, salt-forming counterions as sodium, and nonionic surfactants as Tween™, polyethylene glycol and Pluronics™.

Auxiliary, stabilizer, lubricant, binder, pH adjustor isotonic agent and other additives may also be added to the

The pharmaceutically acceptable or appropriate may include other compounds to be beneficial to an impaired situation of the GI (e.g. antioxidants, such as C, Vitamin E, Selenium or Zinc); or a composition. The food composition can be, but is not to, milk, yoghurt, curd, fermented milks, milk fermented products, ice-creams, cereal based products, based powders, infant tablets, liquid bacterial dried oral supplement, or wet supplement.

As used herein, the “neutraceutical” refers to a food (as a fortified food or a dietary that provides health Nutraceutical foods are not subject to the testing and regulations as pharmaceutical

As used herein, the term refers to live microorganisms, when administered in adequate confer a health benefit on the The probiotics may be available in foods and supplements (for example, but not to capsules, tablets, and powders). examples of foods containing include dairy products as yogurt, fermented and unfermented smoothies, butter, cream, kombucha, salad dressing, tempeh, nutrition bars, and juices and soy beverages.

As used the term “metabolite” refers to any involved in metabolism. Metabolites can be substrates, or intermediates in metabolic For example, the metabolite can be a primary a secondary metabolite, an organic or an inorganic metabolite.

Metabolites without limitation, amino peptides, acylcarnitines, monosaccharides, and phospholipids, prostaglandins, hydroxyeicosatetraenoic hydroxyoctadecadienoic acids, steroids, acids, and glycolipids and phospholipids.

As herein, the term “cytokine” to a secreted protein or active or mutant thereof that the activity of cells of the immune Examples of cytokines include, limitation, interleukins, interferons, tumor necrosis factors, factors for immune cell and the like.

As used herein, the “antibody” includes polyclonal monoclonal antibodies (including length antibodies which an immunoglobulin Fc region), antibody with polyepitopic specificity, antibodies (e.g. bispecific diabodies, and single-chain molecules, and fragments (e.g. Fab or F(ab′) 2 . and For the structure and properties of the different of antibodies, see e.g.

Basic and Immunology, 8th Edition, Daniel P. Abba I. Terr and Tristram G. (eds), Appleton Lange, Conn. 1994, page 71 and 6.

Autism Spectrum Disorder

Autism spectrum disorders are complex neurodevelopmental disabilities by stereotypic behaviors and deficits in and social interaction. The term refers to the wide range of skills, and levels of impairment, or that patients with ASD can ASD is generally diagnosed according to listed in the Diagnostic and Statistical of Mental Disorders, Fourth Revision (DSM-IV-TR). The manual defines five disorders, called pervasive developmental (PDDs), as ASD, including disorder (classic autism), disorder (Asperger syndrome), developmental disorder not otherwise (PDD-NOS), Rett’s disorder syndrome), and Childhood disintegrative (CDD).

Some patients are impaired by their symptoms, but are severely disabled. ASD encompasses a set of disorders with poorly etiologies, and no targeted cure

Recent studies highlight neural and peripheral immune in autistic individuals. Among comorbidities in ASD, gastrointestinal distress is of particular interest, its prevalence and correlation with the of core autism behaviors et al. 2011; Buie et al. 2010; et al. 2012; Gorrindo et al.

2013; et al. 2009; Wang et al. 2011).

A subset of ASD children exhibit (GI) complications, including intestinal permeability (or “leaky and altered composition of intestinal (Buie et al. 2010; Coury et al. D’Eufemia et al.

1996; de Magistris et al. de Magistris et al. 2013; Ibrahim et al.

Moreover, a recent multicenter of over 14,000 ASD individuals a higher prevalence of inflammatory disease (IBD) and other GI in ASD patients compared to controls et al. 2012). Altered nutrient food allergies and metabolic are also associated with and antibiotic treatment and restricted are reported to provide behavioral for some autistic children et al.

2010).

Maternal immune (MIA) is an important environmental factor for ASD. Several epidemiological studies have maternal viral and bacterial with increased autism in the offspring ((Atladottir et al. 2010; et al.

2012). Modeling this factor in mice by injecting females with the viral poly(I:C) has been show to offspring that exhibit the behavioral symptoms of autism, the hallmark symptoms of repetitive/compulsive as well as a common autism (spatially restricted deficits in cells) ((Boksa, 2010; et al. 2012; Schwartzer et al. 2013; Shi et al.

Recently, MIA offspring have been found to exhibit in the immune system and the gastrointestinal

Humans are colonized with a abundance and diversity of microbes, play a critical role in health and disease. Dysbiosis of the microbiota is implicated in the pathogenesis of human ailments, including obesity and cardiovascular disease and Powrie, 2012; Clemente et al.

Commensal bacteria also a variety of complex behaviors, social, emotional, nociceptive and behaviors (Amaral et al. 2008; et al. 2011; Desbonnet et al.

2013; et al. 2011), and contribute to brain and function in mice (Al-Asmakh et al. Collins et al. 2012; Cryan and 2012) and humans (Tillisch et al.

Long-range interactions between the gut and brain underlie the ability of therapies to treat symptoms of sclerosis and depression in mice et al. 2011; Hooper et al. 2012; et al. 2010) and the reported efficacy of in treating emotional symptoms of fatigue syndrome and psychological in humans (Messaoudi et al. 2011; Rao et al.

Numerous abnormalities related to the have been identified in individuals, including disrupted composition (Adams et al. 2011; 2011; Finegold et al. 2010; et al.

2012; Gondalia et al. 2012; et al. 2005b; Williams et al. 2011; et al. 2012) and altered peripheral of microbially-derived metabolites (Altieri et al. Frye et al.

2013; MacFabe, Ming et al. 2012b; Yap et al. 2010a).

for Improving Behavioral Performance

for improving behavioral performance in a in need of treatment are provided The subject in need of treatment can be a suffering from anxiety, or a pathological condition with one or of the symptoms of ASD.

The methods, in embodiments, include: determining the level of an ASD-related metabolite in a in need of treatment; and adjusting the level of the ASD-related metabolite in the until an improvement in the behavioral in the subject is observed.

The methods, in embodiments, include: determining the of an autism spectrum disorder metabolite in a subject in need of and adjusting the level of the ASD-related in the subject so that the level of the in the subject is substantially the same as a level of the metabolite in non-autistic thereby improving behavioral in the subject. In some embodiments, the can further include determining a level of the ASD-related metabolite in a of non-autistic subjects.

In some the methods include: determining the of an autism spectrum disorder metabolite in a subject in need of and adjusting the level of the ASD-related in the subject so that the level of the in the subject is substantially the same as a level of the metabolite in a population of that do not suffer ASD, or any pathological condition with one or of the symptoms of ASD, thereby behavioral performance in the subject. In embodiments, the methods can further determining a reference level of the metabolite in subjects that do not from ASD, anxiety or any condition with one or more of the of ASD.

The methods disclosed in some embodiments, can also measuring a baseline of behavioral prior to adjusting the level of the metabolite in the subject in need of and/or measuring the behavioral after adjusting the level of the metabolite in the subject in need of In some embodiments, the methods can comparing the behavioral performance to and after adjusting the level of the metabolite in the subject in need of and the comparison can be used to determine if and to extent the behavioral performance in the is improved.

In the method disclosed behavioral performance can be measured and using various parameters and For example, behavioral test can be to determine the presence and/or of restricted repetitive behavior stereotyped behavior patterns of the under test. In some the Autism Behavior Checklist Autism diagnostic Interview-Revised childhood autism Rating (CARS), and/or Pre-Linguistic Diagnostic Observation Schedule is used for the behavioral test.

The test can include, but is not limited to, the presence and/or extent of 1) with one or more stereotyped and patterns of interest that is in either intensity or focus, 2) adherence to specific, nonfunctional or rituals, c) stereotyped and repetitive mannerisms (such as hand finger flapping etc.), d) persistent preoccupation with of objects. Non-limiting examples of that can be included in a behavioral and suggest a need for improving performance in the subject under the include: a) sensory behaviors, poor use of visual discrimination learning, seems not to hear, so a hearing loss is suspected, shows no “startle response” to noise”, sometimes painful such as bruises, cuts, and evoke no reaction, often not blink when bright is directed toward eyes, ears at many sounds, frowns, or covers eyes in the presence of natural light, has no visual reaction to a “new” stares into space for periods of time; b) relating frequently does not attend to stimuli, has no social smile, not reach out when reached non-responsive to other people’s expressions/feelings, actively avoids eye resists being touched or is flaccid when held in is stiff and hard to held, not imitate other children at has not developed any friendships, often or very anxious, “looks people; c) body and object use whirls self for long of time, does not use toys insists on keeping certain with him/her, rocks for long periods of time, a lot of lunging and darting, flaps walks on toes, hurts by banging head, biting etc. twirls, spins, and objects a lot, will smell, and/or taste in the environment, gets involved in “rituals” such as lining up, etc. is very destructive; and d) behaviors: does not follow commands given once, has reversal, speech is atonal, not respond to own name when out among two others, seldom “yes” or “I”, does not simple commands involving gets desired objects by repeats phrases over and cannot point to more five named objects, 0-5 spontaneous words per day to communicate and needs, repeats sounds or over and over, echoes or statements made by others, at least 15 but less than 30 phrases daily to communicate, a simple task but “forgets” strong reactions to changes in has “special abilities” in one area of which seems to rule out retardation, severe temper and/or frequent minor hurts others by biting, kicking, etc. does not for needs to be met, difficulties toileting, does not dress without frequent help, unaware of surroundings, and may be oblivious to situations, prefers to manipulate and be with inanimate things, and A delay was identified at or before 30 of age. One of ordinary skill in the art appreciate that the attending would know how to identify a in need of treatment disclosed

After adjustment, the level of the metabolite in the subject can about about 60%, about about 80%, about about 95%, about about 99%, about about 101%, about about 105%, about about 120%, about about 140%, about or a range between any two of these of the reference level of the metabolite in subjects. In some embodiments, the of the ASD-related metabolite in the subject is 80%, about 90%, 95%, about 98%, 99%, about 100%, 101%, about 102%, 105%, about 110%, 120%, or a range between any two of values of the reference level of the in non-autistic subjects. In some the level of the ASD-related metabolite in the is about 95%, about about 99%, about about 101%, about about 105%, or a range any two of these values of the reference of the metabolite in non-autistic subjects.

The of the metabolite can be the level of the metabolite in of the subject. For example, the level of the can be the level of the metabolite in blood or body fluids (e.g. fluid, pleural fluid, fluid, semen, or saliva) of the In some embodiments, the level of the is the blood level of the metabolite in the The blood level of the metabolite can be, for serum level or plasma of the metabolite.

In some embodiments, the of the metabolite is the urine level of the in the subject.

In some embodiments, the suffers from anxiety, or a pathological condition with one or of the symptoms of ASD. Non-limiting of ASD include Autistic disorder autism), Asperger’s disorder syndrome), Pervasive developmental not otherwise specified (PDD-NOS), disorder (Rett syndrome), and disintegrative disorder (CDD). In embodiments, the subject suffers ASD.

In some embodiments, the suffers from autism.

methods can be used to adjust the for example blood level, of the metabolite in the subject. In some the level, for example blood of the metabolite is adjusted by adjusting the of gut microbiota in the subject. Adjustment of the of gut microbiota in the subject can be achieved by, for fecal transplantation (also as fecal microbiota transplantation fecal bacteriotherapy or stool

Fecal transplantation can include a of transplantation of fecal bacteria a healthy donor, for example a subject, to a recipient (e.g. a suffering from autism). The of fecal transplantation can include or multiple infusions (e.g. by of bacterial fecal flora the donor to the recipient.

In some adjusting the composition of gut microbiota in the includes administering the subject a comprising bacteria, for example, a comprising Bacteroides bacteria. The bacteria that can be used in the disclosed herein is not particularly In some embodiments, the Bacteroides comprise B. fragilis, B. thetaiotaomicron, B. . or a mixture thereof.

In some the Bacteroides bacteria can be B. fragilis . The comprising bacteria, for example a comprising Bacteroides bacteria, can be to the subject via various routes. For the composition can be administered to the subject via administration, rectum administration, administration, intranasal administration or In some embodiments, the composition is to the subject orally. The composition bacteria, such as Bacteroides can also be in various forms. For the composition can be a probiotic composition, a a pharmaceutical composition, or a mixture

In some embodiments, the composition is a composition. Each dosage for and animal subjects preferably a predetermined quantity of the bacteria in an amount sufficient to produce the effect. The actual dosage will depend on the particular employed and the effect to be achieved.

The comprising bacteria, for example, a comprising Bacteroides bacteria, can be alone or in combination with one or additional probiotic, neutraceutical, or agents. Administration “in combination one or more further additional neutraceutical, or therapeutic agents both simultaneous (at the same and consecutive administration in any order. can be chronic or intermittent, as deemed by the supervising practitioner, particularly in of any change in the disease state or any side effects. “Chronic” refers to administration of the composition in a manner while “intermittent” refers to treatment that is with interruption.

In some adjusting the composition of gut microbiota in the includes reducing the level of one or bacterial species in the subject. For the level of Clostridia bacteria as Lachnospiraceae) in the subject can be reduced to the composition of gut microbiota in the subject. In embodiments, the Lachnospiraceae is Roseburia . The of Bacterioidia bacteria (such as 524-7) can also be reduced to the composition of gut microbiota in the subject.

In embodiments, the Clostridia bacteria is Various methods can be used to the level of one or more bacteria in the subject. For example, a reduced diet can be provided to the subject to one or more intestinal bacterial

Without being bound to any theory, it is believed that a carbohydrate diet can restrict the material necessary for bacterial to reduce intestinal bacterial

In some embodiments, adjusting the of gut microbiota in the subject includes the level of one or more bacterial in the subject. For example, the level of Erysipelotrichaceae, and/or Alcaligenaceae in the subject can be increased to adjust the of gut microbiota in the subject.

ASD-Related

As used herein, the term spectrum disorder (ASD)-related refers to a metabolite whose is altered in a subject suffering ASD, anxiety, and/or any condition with one or more of the of ASD as compared to a non-autistic subject a subject that does not from ASD, anxiety or any condition with one or more of the of ASD. For example, the level of the may be altered in circulation of the subject from ASD as compared to a non-autistic In some embodiments, the level of the is altered in blood, serum, body fluids (e.g. fluid, pleural fluid, fluid, semen, or saliva), and/or feces of the subject from ASD as compared to a non-autistic In some instances, the ASD-related plays a causative role in the of ASD-related behaviors in the subject from ASD.

In some the alteration in the level of ASD-related is caused by ASD. The ASD-related can have an increased or decreased in the subject suffering from ASD as to a non-autistic subject or a subject does not suffer from anxiety or any pathological condition one or more of the symptoms of ASD.

One of skill in the art will appreciate variability in the level of metabolites may between individuals, and a reference can be established as a value representative of the of the metabolites in a non-autistic population, or a of subjects that do not suffer ASD, anxiety or any pathological with one or more of the symptoms of for the comparison. Various criteria can be to determine the inclusion and/or of a particular subject in the reference including age of the subject (e.g. the subject can be within the same age as the subject in need of treatment) and of the subject (e.g. the reference can be the same gender as the subject in of treatment). In some embodiments, the metabolite has an increased level in the suffering from ASD as compared to the level. In some embodiments, the metabolite has a decreased level in the suffering from ASD as compared to the level.

In some embodiments, the in the level of ASD-related metabolite can be partially or fully by adjusting the of gut microbiota in the subject suffering ASD.

Non-limiting examples of metabolites are provided in Table 1.

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