**5. Interplay between HIM and GBA in the context of ASD**

About 40–60% of ASD children suffer from gastrointestinal comorbidities [8], although due to their social and communicative impairments, the real prevalence of gastrointestinal issues among ASD patients may be higher. Such intestinal dysfunction in this group of patients may be caused by disturbances in the pathways underlying the GBA, with a central role of the HIM and including an immune component.

Several studies have demonstrated HIM dysbiosis in ASD subjects; however, little or null correlation between studies has been obtained, mainly due to variations in study groups, control groups, and the use of diverse methods for microbiota/ microbiome determinations and analysis (**Table 2**) [67, 72]. In short, 13 of the 15 studies showed some degree of dysbiosis among ASD patients as compared with controls (total combined sample of 585 individuals, 339 ASD, 61 control siblings, and 185 unrelated neurotypical controls), whereas 2 of the 15 studies found no significant differences among ASD subjects as compared with siblings controls (no neurotypical controls were included).

Altogether the microbiome data from the studies showed in **Table 2** suggests some important features among stool samples of ASD subjects: (a) levels of clostridia, *Desulfovibrio*, and *Sutterella* seem consistently elevated; (b) on the opposite, levels of *Prevotella* and bifidobacteria appears to be reduced; (c) the Bacteroidetes/ Firmicutes ratio showed inconsistent results over different cohorts. There are significant, but not consistent, distinctive different microbiome compositions in ASD patients, regardless of gastrointestinal problems, compared to controls [73–90]. Moreover, the presence of HIM dysbiosis may correlate with ASD phenotype [91].

Dysbiosis in ASD is also associated with increased permeability of the GI tract, the leaky gut, which leads to the entry of endotoxins, and other bacterial products into the bloodstream [92]. Bacterial lipopolysaccharide (LPS) can alter neuronal as well as microglial activity in brain regions involved in emotional control [93–95]. In fact, serum levels of LPS were significantly higher among ASD subjects compared to healthy individuals and correlated with impaired social behavioral scores [96].

Serotonin synthesis in the gut and the brain depends on the availability of dietary tryptophan. High levels of blood serotonin were found in children with ASD [97–99], which contrasts with finding of decreased brain serotonin synthesis in ASD subjects [100]. A significant correlation between whole-blood serotonin levels and low-grade intestinal inflammation in ASD was demonstrated [101]. Regarding these findings, a likely explanation was proposed by de Theije et al. (2011) [91]: After GI inflammation, the intestinal serotonin release provokes changes in motility, secretion, vasodilation, and permeability, leading to functional intestinal dysmotility, stool inconsistency, and abdominal pain. Since the majority of dietary tryptophan is transformed in serotonin by HIM during inflammation, less tryptophan (and serotonin) will be available for the brain resulting in mood and cognitive dysfunction in ASD and increased autistic behavior [102].

Propionic acid, a major SCFA produced by clostridia, *Bacteroides*, and *Desulfovibrio,* has been associated with ASD, since it can induce ASD-like behavioral deficits in rats [103, 104]. Detrimental effects of propionic acid are suggested to be through mitochondrial and epigenetic modulation of ASD-associated genes. In fact, elevated levels of SCFAs are described in the stool of ASD children [82, 105].


**229**

**Country (Year)**

**ASD (GI+/GI**

Australia (2012)

USA (2013) Italy (2013) USA (2015) Slovakia (2015)

USA (2017)

14 (14/0)


21 (15/6)

Rectal

16S rDNA PCR

and sequencing

HPLC of

↓

mucosal

supernatant.

biopsies

10

10

10

Stool

59 (25/34)

44 (13/31)


Stool

16S rRNA gene

sequencing

Targeted qPCR

10

10

10

Stool

20 (20/0)

–

20 (0/20)

Stool

51 (28/23)

53 (4/49)

–

Stool

16S rRNA gene

sequencing

16S rRNA gene

↓

*Prevotella, Coprocuccus, Veillonellaceae*

[85]

sequencing

16S rRNA gene

↓ ↓

*Eubacterium, Bifidobacterium*

↓SCFA (except PPA)

↑ Phenol, 4-(1,1-dimethylethyl)-phenol, and p-cresol.

↑ Free amino acids (Proteolytic bacteria)

No differences ↓Bacteroidetes/Firmicutes

↑

*Lactobacillus* spp.

(↑Clostridia cluster I and *Desulfovibrio*, NS.)

*Desulfovibrio* spp.: strong positive association with ASD

severity

↑ Clostridiales (*C lituseburense, Lachnoclostridum bolteae, L* 

[89]

*hathewayi, C aldenense*, and *Flavonifractor plautii*)

*Dorea formicigenerans, Blautia luti, Sutterella* spp.

↓Tryptophan (correlation with ↑*Erysipelotrichaceae*, *C.* 

*lituseburense*, and *Terrisporobacter* )

↑ Serotonergic metabolites, including 5-HIAA (associated

with abdominal pain and with the following:

*Akkermansia muciniphila*, *Coprococcus catus*, *Odoribacter* 

*splanchnicus*, *C. lactatifermentans*, and *Ruminococcus* 

*lactaris;*

*L. bolteae, L. hathewayi*, and *F. plautii)*.

↑

↓

*Caloramator, Sarcina, Clostridium, Sutterellaceae*

sequencing

GC-MS/SPME

**−)**

**SIB (GI+/GI**

**−)**

**NTC (GI+GI**

**−)**

**Study Group**

**Specimen type**

**Analytical method**

**Changes in fecal microbiome in ASD**

No differences

[84]

**Refs.**

*Interplay between Human Intestinal Microbiota and Gut-to-Brain Axis…*

[87]

[88]

*DOI: http://dx.doi.org/10.5772/intechopen.89998*

[86]

#### *Microorganisms*


*Interplay between Human Intestinal Microbiota and Gut-to-Brain Axis… DOI: http://dx.doi.org/10.5772/intechopen.89998*

*Microorganisms*

[73]

**228**

**Country (Year)**

**ASD (GI+/GI**

13

–

8

Stool

Bacterial

↑ Nine species of *Clostridium*

cultures

USA (2002) USA (2004) United Kingdom

58

12

10

Stool

(2005)

USA (2010) USA (2011) Poland (2011)

USA (2011,

23 (23/0)

–

9 (9/0)

Intestinal

16S rRNA gene

sequencing

Targeted qPCR

GC

HPLC

biopsies

Stool

2012)

Australia (2011,

23 (9/14)

22 (6/16)

9 (1/8)

2012 2013)

41

–

10

Stool

Bacterial

cultures

58 (58/0)

–

39 (0/39)

Stool

Bacterial

↓ ↑ ↑

*Clostridium perfringens*

↓ Bacteroidetes

↑ Firmicutes, Proteobacteria, *Sutterella*

↓*Bifidobacterium* spp., *Akkermansia muciniphilia*

↑

*Sutterella* spp.

(↑ Relative abundance of *Clostridium difficile* in ASD, NS)

*Ruminococcus torques* (only in ASD-GI+).

↑Ammonia and SCFA (acetic, butyric, isobutyric, valeric,

isovaleric acids), likely microbial-derived.

No differences in phenol and p-cresol levels

↑

[78]

[79, 80]

[81–83]

*Bacillus* spp. *(Lactobacillus)*

*Bifidobacterium* and *Enterococcus*

[77]

cultures

33 (33/0)

7 (0/7)

8 (0/8)

Stool

16S rRNA gene

sequencing

15

–

8

Stool

16S rRNA gene

↑

*C. bolteae* and cluster I/IX

[74]

[75]

[76]

sequencing

FISH analysis

↑

*C. histolyticum* and cluster I/II.

Siblings show intermediate levels.

↑ Bacteroidetes and Proteobacteria: *Desulfovibrio,* 

*B. Alkaliflexus, Acetanaerobacterium, Parabacteroides*

↓ Firmicutes and Actinobacteria: *Clostridium*, *Weissella*,

*Turicibacter*, *Anaerofilum*, *Ruminococcus*, *Streptococcus,* 

*Pseudoramibacter*,

**−)**

**SIB (GI+/GI**

**−)**

**NTC (GI+GI**

**−)**

**Study Group**

**Specimen** 

**Analytical** 

**Changes in fecal microbiome in ASD**

**Refs.**

**method**

**type**


#### **Table 2.**

*Studies on gut microbiome in ASD.*

**231**

*Interplay between Human Intestinal Microbiota and Gut-to-Brain Axis…*

Scientific literature supports the notion that the HIM plays a crucial role in the pathogenesis of ASD, so scientists are now targeting gut microbiome as a thera

peutic approach for such disorder (reviewed in [106]). First, modification of high lipid and sugar diet for a fiber- and protein-containing one showed improved skills while ameliorated ASD behavioral deficits. Second, supplementation with prebiot

ics (inulin, fructo-oligosaccharides, galacto-oligosaccharides, and lactulose) allows specific changes, both in the composition and/or activity of the gut microflora, mainly inducing the growth of indigenous lactobacilli and bifidobacteria. Third, probiotics administration, either *Bacteroides fragilis* or *Lactobacillus reuteri*, there were improvements in ASD-associated behaviors, counteract effect of harmful infections and stimulation of the host's immune system. Fourth, fecal microbiota transplant, usually applied for treating recurrent *Clostridium difficile* infection and other GI disorders, consists of a sample containing about a thousand indig

enous bacterial species of the GI from a neurotypical donor, treatment showed sustained improvement of both GI- and ASD related symptoms (up to 8 weeks

After the complete sequencing of the human genome was achieved, the scien

In this landscape, an increasing body of evidence suggests that HIM has a key role in gut and brain development and functionality but also in pathogenesis of mental disorders, including ASD. Studies on ASD have showed that HIM dysbiosis, with altered Bacteroidetes/Firmicutes ratio, presence of detrimental key species, and dysregulation of bacterial metabolite release, appears to correlate with severity of ASD symptoms. In this regard, intervention measures to restore HIM homeosta

However, the part concerning the microbiota is only one more piece of the puzzle that are ASDs, mainly because the etiology of such disorders remains elusive.

The following Mexican institutions supported this paper: National Autonomous

FJDG. Thanks to my beloved son, Manuel, a youngster with ASD who encour

University of Mexico, the National Institute of Perinatology and the National

The authors have declared that no competing interests exist.

ages me to understand how the world is seen through their eyes.

tific community began, in the second half of the past decade, the task of mapping the human microbiota, mainly the intestinal microbiota. In parallel, the notion that the ENS interplay with the intestinal microbiota, generating responses in the CNS, through the GBA and HPA axis, has opened an avenue for the study of gastrointesti

nal, metabolic, and/or neuropsychiatric disorders.








*DOI: http://dx.doi.org/10.5772/intechopen.89998*

posttreatment).

**6. Conclusion**

sis are likely promising.

**Acknowledgements**

Polytechnic Institute.

**Conflict of interest**

**Notes/thanks/other declarations**

*Interplay between Human Intestinal Microbiota and Gut-to-Brain Axis… DOI: http://dx.doi.org/10.5772/intechopen.89998*

Scientific literature supports the notion that the HIM plays a crucial role in the pathogenesis of ASD, so scientists are now targeting gut microbiome as a therapeutic approach for such disorder (reviewed in [106]). First, modification of high lipid and sugar diet for a fiber- and protein-containing one showed improved skills while ameliorated ASD behavioral deficits. Second, supplementation with prebiotics (inulin, fructo-oligosaccharides, galacto-oligosaccharides, and lactulose) allows specific changes, both in the composition and/or activity of the gut microflora, mainly inducing the growth of indigenous lactobacilli and bifidobacteria. Third, probiotics administration, either *Bacteroides fragilis* or *Lactobacillus reuteri*, there were improvements in ASD-associated behaviors, counteract effect of harmful infections and stimulation of the host's immune system. Fourth, fecal microbiota transplant, usually applied for treating recurrent *Clostridium difficile* infection and other GI disorders, consists of a sample containing about a thousand indigenous bacterial species of the GI from a neurotypical donor, treatment showed sustained improvement of both GI- and ASD related symptoms (up to 8 weeks posttreatment).
