Prebiotic, Probiotic, and Synbiotic Consumption Alter Behavioral Variables and Intestinal Permeability and Microbiota in BTBR Mice

Given that prebiotics have been shown to improve gut microbiota composition, gastrointestinal symptoms and select behaviors in autism spectrum disorder (ASD), we hypothesized that prebiotic supplementation would improve sociability, communication, and repetitive behaviors in a murine model of ASD. We also examined the effect of a synbiotic (probiotic + prebiotic). Juvenile male BTBR mice were randomized to: (1) control; (2) probiotic (1 × 1010 CFU/d Lactobacillus reuteri RC-14®; now known as Limosilactobacillus reuteri); (3) prebiotic (10% oligofructose-enriched inulin); (4) prebiotic + probiotic (n = 12/group) administered through food for 3 weeks. Sociability, communication, repetitive behavior, intestinal permeability and gut microbiota were assessed. Probiotic and symbiotic treatments improved sociability (92 s and 70 s longer in stranger than empty chamber) and repetitive behaviors (50% lower frequency), whereas prebiotic intake worsened sociability (82 s less in stranger chamber) and increased the total time spent self-grooming (96 s vs. 80 s CTR), but improved communication variables (4.6 ms longer call duration and 4 s higher total syllable activity). Mice consuming probiotics or synbiotics had lower intestinal permeability (30% and 15% lower than CTR). Prebiotic, probiotic, and symbiotic treatments shifted gut microbiota to taxa associated with improved gut health. L.reuteri may help alleviate ASD behavioral symptom severity and improve gut health. The potential use of prebiotics in an ASD population warrants further research.

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The Role of Gut Microbiota in Gastrointestinal Symptoms of Children with ASD

Medicina ◽

10.3390/medicina55080408 ◽

2019 ◽

Vol 55 (8) ◽

pp. 408 ◽

Cited By ~ 7

Author(s):

Agustín Ernesto Martínez-González ◽

Pedro Andreo-Martínez

Keyword(s):

Systematic Review ◽

Gut Microbiota ◽

Neurodevelopmental Disorder ◽

Repetitive Behavior ◽

Gastrointestinal Symptoms ◽

Autism Spectrum ◽

Future Research ◽

Healthy Controls ◽

Children With Asd ◽

Gi Symptoms

Background and objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, social interaction disorder, and repetitive behavior. Dysbiotic gut microbiota (GM) could be a contributing factor to the appearance of ASD, as gastrointestinal (GI) symptoms are comorbidities frequently reported in ASD. As there is a lack of reviews about the role played by GM in the GI symptoms of ASD, this work aimed to carry out a systematic review of current studies comparing the GM of children with ASD and GI symptoms with those of healthy controls in the last six years. Materials and Methods: The systematic review was performed following the PRISMA guidelines. The databases chosen were Web of Science, Scopus, PubMed, and PsycINFO, and the keywords were (gut* OR intestine* OR bowel* OR gastrointestinal*) AND (microbiota* OR microflora* OR bacteria* OR microbiome* OR flora* OR bacterial* OR bacteria* OR microorganism* OR feces* OR stool*) AND (autistic* OR autism* OR ASD*). Results: A total of 16 articles were included. Ten articles performed correlations analysis between GI symptoms and ASD. Among those 10 articles, 7 found differences between the GI symptoms present in children with ASD and healthy controls. The most common GI symptom was constipation. Among the seven articles that found differences, three performed correlations analysis between GI symptoms and gut microbe abundance. Candida, Prevotella, Streptococcus, and Veillonella showed higher and lower abundance, respectively, in children with ASD and GI symptoms in more than one article. Bacteroidetes, Firmicutes, Actinomyces, Dorea, Lactobacillus, Faecalibacterium prausnitzii, and Bacteroidetes/Firmicutes ratios showed abundance discrepancies. Conclusions: It is still too early to draw a conclusion about the gut microbes involved in GI symptoms of ASD. Future research should consider the relationship between ASD behavior, GM, and GI symptoms in a multidisciplinary way and homogenize sample characteristics.

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Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry

Communications Biology ◽

10.1038/s42003-021-02015-2 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Natasha Bertelsen ◽

◽

Isotta Landi ◽

Richard A. I. Bethlehem ◽

Jakob Seidlitz ◽

...

Keyword(s):

Repetitive Behavior ◽

Resting State Fmri ◽

Neural Circuitry ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Typically Developing ◽

Out Of Sample ◽

Genetic Mechanisms ◽

Social Communicative ◽

The Eu

AbstractSocial-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.

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Sex-dependent role for EPHB2 in brain development and autism-associated behavior

Neuropsychopharmacology ◽

10.1038/s41386-021-00986-8 ◽

2021 ◽

Author(s):

Ahlem Assali ◽

Jennifer Y. Cho ◽

Evgeny Tsvetkov ◽

Abha R. Gupta ◽

Christopher W. Cowan

Keyword(s):

Pyramidal Neurons ◽

De Novo ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Male Mice ◽

Sensory Sensitivity ◽

Hyperactivity Disorder ◽

Specific Effects ◽

Layer V

AbstractAutism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A de novo nonsense mutation in EPHB2 (Q857X) was discovered in a female patient with ASD [13], revealing EPHB2 as a candidate ASD risk gene. EPHB2 is a receptor tyrosine kinase implicated in axon guidance, synaptogenesis, and synaptic plasticity, positioning it as a plausible contributor to the pathophysiology of ASD and related disorders. In this study, we show that the Q857X mutation produced a truncated protein lacking forward signaling and that global disruption of one EphB2 allele (EphB2+/−) in mice produced several behavioral phenotypes reminiscent of ASD and common associated symptoms. EphB2+/− female, but not male, mice displayed increased repetitive behavior, motor hyperactivity, and learning and memory deficits, revealing sex-specific effects of EPHB2 hypofunction. Moreover, we observed a significant increase in the intrinsic excitability, but not excitatory/inhibitory ratio, of motor cortex layer V pyramidal neurons in EphB2+/− female, but not male, mice, suggesting a possible mechanism by which EPHB2 hypofunction may contribute to sex-specific motor-related phenotypes. Together, our findings suggest that EPHB2 hypofunction, particularly in females, is sufficient to produce ASD-associated behaviors and altered cortical functions in mice.

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The Dysbiosis of Gut Microbiota Caused by Low-Dose Cadmium Aggravate the Injury of Mice Liver through Increasing Intestinal Permeability

Microorganisms ◽

10.3390/microorganisms8020211 ◽

2020 ◽

Vol 8 (2) ◽

pp. 211 ◽

Cited By ~ 3

Author(s):

Yehao Liu ◽

Yuhui Li ◽

Yuhong Xia ◽

Kaiyong Liu ◽

Lingling Ren ◽

...

Keyword(s):

Gut Microbiota ◽

Intestinal Permeability ◽

Health Risks ◽

Low Dose ◽

Underlying Mechanism ◽

Mice Liver ◽

Hepatic Transcriptome ◽

Cd Exposure ◽

Gut Microbiota Composition

Cadmium (Cd), widely present in food and drinking water at low doses, can cause health risks. However, the mechanistic effects of long-term Cd exposure at low dose through dietary intake is poorly studied. The aim of this study is to elucidate whether the dysbiosis of gut microbiota caused by Cd at an environmental low dose can aggravate the injury of mice liver, and the possible mechanism is investigated. In order to explore the potential underlying mechanism, the analyses of the variation of gut microbiota composition, intestinal permeability, and hepatic transcriptome were conducted. Our results showed that gut microbiota was disturbed. The rise of intestinal permeability induced by the dysbiosis of gut microbiota resulted in more Cd ions accumulating in mice liver, but it could be restored partly through depleting gut microbiota by antibiotics cocktail. Transcriptomic analyses indicated that 162 genes were significantly differentially expressed including 59 up-regulated and 103 down-regulated in Cd treatment. These genes were involved in several important pathways. Our findings provide a better understanding about the health risks of cadmium in the environment.

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Probiotics Prevents Sensitization to Oral Antigen and Subsequent Increases in Intestinal Tight Junction Permeability in Juvenile–Young Adult Rats

Microorganisms ◽

10.3390/microorganisms7100463 ◽

2019 ◽

Vol 7 (10) ◽

pp. 463 ◽

Cited By ~ 2

Author(s):

Tulyeu ◽

Kumagai ◽

Jimbo ◽

Watanabe ◽

Yokoyama ◽

...

Keyword(s):

Food Allergy ◽

Young Adult ◽

Gut Microbiota ◽

Tight Junction ◽

Intestinal Permeability ◽

Lactobacillus Reuteri ◽

Intestinal Barrier ◽

Mucosal Inflammation ◽

Adult Rats ◽

Epithelial Barrier Function

Increased intestinal permeability is thought to underlie the pathogenesis of food allergy. We explore the mechanism responsible for changes in the morphology and function of the intestinal barrier using a rat model of food allergy, focusing on the contribution of intestinal microbiota. Juvenile–young adult rats were sensitized with ovalbumin and treated with antibiotics or probiotics (Clostridium butyricum and Lactobacillus reuteri), respectively. The serum ovalbumin-IgE levels, intestinal permeability, histopathological features, tight junction (TJ)-associated proteins, Th2 cytokines, and gut microbiota in feces were analyzed in each group. Sensitized rats showed an increase in ovalbumin-IgE levels and intestinal permeability with gut mucosal inflammation, whereas rats that received probiotics were only mildly affected. Rats given ovalbumin, but not those given probiotics, showed a reduction in both TJ-related protein expression and localization. Th2 cytokine levels were increased in the sensitized rats, but not in those given probiotics. TJs in rats treated with ovalbumin and antibiotics were disrupted, but those in rats administered probiotics were undamaged. Clostridiaceae were increased in the probiotics groups, especially Alkaliphilus, relative to the ovalbumin-sensitized group. Gut microbiota appears to play a role in regulating epithelial barrier function, and probiotics may help to prevent food sensitization through the up-regulation of TJ proteins.

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Gastrointestinal problems are associated with increased repetitive behaviors but not social communication difficulties in young children with autism spectrum disorders

Autism ◽

10.1177/1362361320959503 ◽

2020 ◽

pp. 136236132095950

Author(s):

Payal Chakraborty ◽

Kimberly L H Carpenter ◽

Samantha Major ◽

Megan Deaver ◽

Saritha Vermeer ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Symptom Severity ◽

Gastrointestinal Symptom ◽

Gastrointestinal Symptoms ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Behavioral Symptoms ◽

Behavioral Symptom ◽

Communication Difficulties

Individuals with autism spectrum disorder are more likely than typically developing individuals to experience a range of gastrointestinal abnormalities, including chronic diarrhea, constipation, food sensitivities, and abdominal pain. These gastrointestinal symptoms have been associated with higher levels of irritability and aggressive behavior, but less is known about their relationship with core autism spectrum disorder symptoms. We investigated the relationship between autism spectrum disorder and gastrointestinal symptom severity while accounting for three associated behavioral symptom domains (Irritability, Aggressiveness, and Specific Fears), in a sample of 176 children (140 males and 36 females) ages 2–7 years old with autism spectrum disorder. Most participants had at least one reported gastrointestinal symptom (93.2%) and had more than one gastrointestinal symptom (88.1%). After accounting for each associated behavioral symptom domain, repetitive behaviors and stereotypies were positively associated with gastrointestinal symptom severity. Social and communication difficulties were not significantly associated with gastrointestinal symptom severity after accounting for associated behavioral symptoms. Our findings replicate a previously described association between irritability and aggression and gastrointestinal symptoms. Furthermore, gastrointestinal symptom severity is associated with repetitive behaviors, a subset of core autism spectrum disorder symptoms. This suggests that gastrointestinal symptoms may exacerbate repetitive behaviors, or vice versa, independent from other associated behavioral symptoms. Lay Abstract Individuals with autism spectrum disorder are more likely than typically developing individuals to experience a range of gastrointestinal abnormalities, including chronic diarrhea, constipation, food sensitivities, and abdominal pain. These gastrointestinal symptoms have been associated with higher levels of irritability and aggressive behavior, but less is known about their relationship with core autism spectrum disorder symptoms. We investigated the relationship between autism spectrum disorder symptom severity and gastrointestinal symptoms while accounting for three associated behavioral symptom domains (Irritability, Aggressiveness, and Specific Fears), in a sample of 176 children (140 males and 36 females) ages 2–7 years old with autism spectrum disorder. A large majority (93.2%) of the sample had at least one reported gastrointestinal symptom, and most (88.1%) participants had more than one gastrointestinal symptom. Various types of gastrointestinal symptoms were reported; the most common symptoms reported were constipation, food limits, gas/bloating, and stomach pain. After accounting for each associated behavioral symptom domain, repetitive behaviors and stereotypies were significantly associated with gastrointestinal symptom severity. Increased severity of autism spectrum disorder symptoms was correlated with increased gastrointestinal symptom severity. Social and communication difficulties were not significantly associated with gastrointestinal symptom severity after accounting for associated behavioral symptoms. Our findings replicate a previously described association between irritability and aggression and gastrointestinal symptoms. Furthermore, we found that repetitive behaviors, but not social or communication symptoms, are associated with gastrointestinal symptom severity, even after accounting for associated behavioral symptoms. This suggests that gastrointestinal symptoms may exacerbate repetitive behaviors, or vice versa, independent from other associated behavioral symptoms.

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A diet of U.S. military food rations alters gut microbiota composition and does not increase intestinal permeability

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2019.108217 ◽

2019 ◽

Vol 72 ◽

pp. 108217 ◽

Cited By ~ 3

Author(s):

J. Philip Karl ◽

Nicholes J. Armstrong ◽

Holly L. McClung ◽

Robert A. Player ◽

Jennifer C. Rood ◽

...

Keyword(s):

Gut Microbiota ◽

Intestinal Permeability ◽

Microbiota Composition ◽

Gut Microbiota Composition

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Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder

Scientific Reports ◽

10.1038/srep45356 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 48

Author(s):

Lorena Coretti ◽

Claudia Cristiano ◽

Ermanno Florio ◽

Giovanni Scala ◽

Adriano Lama ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Mouse Model ◽

Gut Microbiota ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Microbiota Composition ◽

Btbr Mouse ◽

Gut Microbiota Composition

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Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome

Brain Sciences ◽

10.3390/brainsci10040239 ◽

2020 ◽

Vol 10 (4) ◽

pp. 239

Author(s):

Debra L. Reisinger ◽

Rebecca C. Shaffer ◽

Nicole Tartaglia ◽

Elizabeth Berry-Kravis ◽

Craig A. Erickson

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Motor Behaviors ◽

Sensory Motor ◽

Adolescents And Adults ◽

Males And Females ◽

The Impact

Restricted repetitive behaviors (RRBs) are a core area of impairment in autism spectrum disorder (ASD), but also affect several other neurodevelopmental disorders including fragile X syndrome (FXS). Current literature has begun to describe the RRB profile in FXS up through adolescence; however, little is known about the subtypes of RRBs in adolescents and adults. Further, literature on the RRB profile of females with FXS is limited. The present study examines the RRB profile across subtypes and specific items in both males and females with FXS while assessing for differences based on age, ASD diagnosis and the impact of IQ. Participants included 154 individuals with FXS (ages 2 to 50 years old). Results revealed a peak in RRB severity in FXS between 7–12 years for the majority of RRB subscales with the exception of Sensory-Motor behaviors peaking between 2 and 12 years before declining. Distinct RRB profiles in males and females with FXS emerged in addition to significant overlap among the item and subscale levels of RRBs across gender. Further, an added diagnosis of ASD significantly increased rates of RRBs across all subscale levels, but not necessarily across all items. Lastly, IQ did not solely account for the presence of RRBs in FXS, with Sensory-Motor behaviors being driven by comorbid ASD in males with FXS, and Restricted Interest behaviors being driven by comorbid ASD regardless of gender. These findings build on the current understanding of RRBs in FXS based on gender and comorbid ASD and lay important groundwork for the development of targeted behavioral and pharmacological treatments.

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Effect of an Intermittent Meat Protein Diet on Colon Homeostasis

Current Developments in Nutrition ◽

10.1093/cdn/nzab038_036 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 424-424

Author(s):

Xiaohui Li ◽

Chunbao Li ◽

Guanghong Zhou

Keyword(s):

Body Weight ◽

Gut Microbiota ◽

Proinflammatory Cytokines ◽

Dietary Protein ◽

Real Life ◽

Protein Diet ◽

Microbiota Composition ◽

Gut Health ◽

Junction Protein ◽

Gut Microbiota Composition

Abstract Objectives The level of dietary protein is a major factor determining gut health. The level of dietary protein is fluctuated in real life, which may affect colon homeostasis. However, it is still less known about it. Here, we investigated how an intermittent protein diet affected inflammatory, gut barrier and microbiota. Methods Six-week-old male C57BL/6J mice received either a casein or pork protein with (i) 20% protein (C), (ii) 5% protein, (iii) 40% protein, or intermittent diet, a diet alternating weekly between 5% protein and 40% protein ((iv) ending on 40% protein or (v) ending on 5% protein)) for up to 16 weeks. The gene expression of inflammatory cytokines, tight junction protein and gut microbiota composition were measured. Results The intermittent intake of casein decreased body weight, but intermittent pork protein diet didn't affect body weight. In casein group, the proinflammatory factors were highly upregulated in intermittent group ending on 5% protein, but the proinflammatory cytokines of intermittent group ending on 40% protein were not significantly affected. However, the two intermittent pork protein groups reduced the expression of proinflammatory cytokines. Additionally, intermittent diet altered gut microbiota composition. Intermittent casein group ending on 40% protein increased richness of gut microbiota, but intermittent pork protein group ending on 5% protein decreased richness and microbial diversity. Conclusions Intermittent diet indeed altered microbiota structure and colon health. In addition to protein level and source, dietary pattern is also an important parameter for host health. Funding Sources This work was funded by Ministry of Science and Technology (10000 Talent Project).

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