Gut Microorganisms and Autism: the Latest Research

LPS and Autism

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Treatments for LPS

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LPS and the Brain LPS and Thyroid LPS and GI System LPS and Immunity Other Effects of LPS
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Anorexia and LPS NF-κB and LPS Mitochondria and LPS Liver and LPS Ammonia and LPS
Hypoglycemia and LPS Kidney and LPS Allergy and Bacteria Copper, Zinc and LPS Glutathione and LPS

Leaky Gut Research Articles about Bacteria Creating the Leaky Gut
Research Articles about LPS Inducing the Leaky Gut
Research Article about a Diet with Easy to Digest Foods Healing the Leaky Gut
Research Article about Yogurt Healing the Leaky Gut

Microorganisms Create "Leaky Gut"

There is powerful evidence that microorganisms create "leaky gut" syndrome. Microorganisms are associated with leaky gut in both animal and human models.

This comes as no surprise to the those who follow the SCD diet and have had it heal their gut. Many SCD veterans see their allergies resolve and can tolerate foods that they previously could not. Most of them who have never read research studies on the topic suspected microorganisms as the culprits. The positive changes can be attributed to SCD's elimination of pathogenic microorganisms.

Why then, hasn't the diet healed the leaky gut of every child who implements SCD? We now believe it us because parents frequently made the mistake of introducing advanced foods in the beginning stages of the diet. Such foods cannot be properly absorbed by a damaged gut and remain there undigested, providing nourishment for pathogenic microorganisnms Despite the fact that many improvements take place, the children's "leaky gut" did not heal completely when bad gut bacteria consumed the undigested food and were able to survive and reproduce.

We recently revised our website to caution about advanced foods. To that end, we also assembled the following collection of articles in order to prevent parents from making the mistake of introducing advanced foods too soon. These articles validate our concern over the role of microorganisms in "leaky gut" syndrome.


View this article in PubMed
* Riordan SM, * McIver CJ, * Thomas DH, * Duncombe VM, * Bolin TD, * Thomas MC.

Dept. of Gastroenterology, Prince of Wales Hospital, Sydney, Australia.

BACKGROUND: The influence of luminal bacteria on small-intestinal permeability has not been fully assessed. This study addressed this issue. METHODS: Thirty-four subjects (mean age 64 years; range 22-95 years) were investigated for possible small-intestinal bacterial overgrowth (SIBO) with culture of a small-intestinal aspirate. A lactulose/mannitol small-intestinal permeability test was performed, small-intestinal histology assessed and serum vitamin B12 concentrations measured in all subjects. Permeability was also assessed in a control group of 34 asymptomatic volunteers. RESULTS: Urinary lactulose/mannitol ratios were significantly increased in subjects with SIBO with colonic-type flora (P < 0.0005), even in the absence of villous atrophy. Urinary lactulose/mannitol ratios were increased in this group due to significantly increased urinary lactulose concentrations (P < 0.0005) rather than reduced urinary mannitol levels, after correcting for inter-subject variations in renal function. Counts of intraepithelial lymphocytes of CD8 phenotype were significantly increased in this group (P = 0.003). Although a significant correlation was found between intraepithelial lymphocyte counts and small-intestinal permeability overall (P < 0.002), these counts were not significantly different in subjects with SIBO with colonic-type flora whose permeability values were < or = > 0.028, the upper limit of normal in asymptomatic controls. Serum vitamin B12 concentrations did not differ significantly between groups (P > 0.5). Ageing did not independently influence small-intestinal permeability (P > 0.5). CONCLUSIONS: Small-intestinal permeability is increased in subjects with SIBO with colonic-type bacteria. This effect is independent of ageing and not mediated by vitamin B12 deficiency. Although counts of intraepithelial lymphocytes of CD8 phenotype are increased in this disorder, it is also unlikely that these cells play an important causative role in this process. Routine light microscopic assessment underestimates the prevalence of small-intestinal functional disturbance in this disorder.

PMID: 9200287 [PubMed - indexed for MEDLINE]


Brief explanation of the following research article:

Interleukin-10 gene-deficient mice are a special breed of mice that develop intestinal inflammation and a leaky gut. However, in a luminally sterile environment devoid of microorganisms, they will avoid getting a leaky gut or intestinal inflamation.

View this article in PubMed

1: Inflamm Bowel Dis. 1999 Nov;5(4):262-70.
Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora.

* Madsen KL, * Malfair D, * Gray D, * Doyle JS, * Jewell LD, * Fedorak RN.

Department of Medicine, University of Alberta, Edmonton, Canada.

The normal intestinal epithelium provides a barrier relatively impermeable to luminal constituents. However, patients with inflammatory bowel disease experience enhanced intestinal permeability that correlates with the degree of injury. IL-10 gene-deficient mice were studied to determine whether increased intestinal permeability occurs as a primary defect before the onset of mucosal inflammation or is secondary to mucosal injury. At 2 weeks of age, IL-10 gene-deficient mice show an increase in ileal and colonic permeability in the absence of any histological injury. This primary permeability defect is associated with increased mucosal secretion of interferon-gamma and tumor necrosis factor-alpha, and does not involve an increase in nitric oxide synthase activity. Colonic permeability remains elevated as inflammation progresses, while ileal permeability normalizes by 6 weeks of age. IL-10 gene-deficient mice raised under germ-free conditions have no inflammation, and demonstrate normal permeability and cytokine levels. This data suggests that the intestinal permeability defect in IL-10 gene-deficient mice occurs due to a dysregulated immune response to normal enteric microflora and, furthermore, this permeability defect exists prior to the development of mucosal inflammation.

PMID: 10579119 [PubMed - indexed for MEDLINE]


Below are several definitions to clarify the following research article:

Intestinal intraepithelial lymphocytes (IELs)
http://repository.upenn.edu/dissertations/AAI3031653/

Intestinal intraepithelial lymphocytes (IELs) make up a vast, but poorly understood population of lymphocytes. Located between epithelial cells that line the gut, they may provide a first line of defense against invading pathogens.

Campylobacter enteritis
http://www.nlm.nih.gov/medlineplus/ency/article/000224.htm

Campylobacter enteritis is an infection in the small intestine caused by Campylobacter jejuni, a type of bacteria.

Brief explanation of the following research article:

Patients who developed an acute case of Campylobacter enteritis were compared to people who did not have any digestive symptoms(asymptomatic controls). They had significantly higher levels of gut permeability, as assessed by the lactulose/mannitol ratio. This shows that bacterial infections are capable of increasing the gut permeability.

http://gut.bmj.com/cgi/content/abstract/47/6/804
Gut 2000;47:804-811 ( December )

Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome
GR C Spillera, D Jenkinsb, J P Thornleyb, J M Hebdena, T Wrighta, M Skinnerb, K R Nealc

a Division of Gastroenterology, University Hospital Nottingham, Nottingham, UK, b Department of Pathology, University Hospital Nottingham, Nottingham, UK, c Department of Public Health Medicine, University Hospital Nottingham, Nottingham, UK

Correspondence to: Dr R C Spiller, Division of Gastroenterology, C Floor, South Block, University Hospital, Nottingham NG7 2UH, UK. robin.spiller@nottingham.ac.uk

Accepted for publication 22 June 2000

BACKGROUND AND AIMS---Post-dysenteric irritable bowel syndrome (PD-IBS) develops in up to 25% of patients following Campylobacter enteritis. Our aim was to define the pathological basis of this subgroup of IBS. METHODS---Twenty one patients (group 1) underwent serial rectal biopsy and gut permeability testing following acute Campylobacter enteritis as did 10 PD-IBS patients (group 2) and 12 asymptomatic controls. RESULTS---In group 1, enteroendocrine cell (EC) numbers were markedly increased initially and at six and 12 weeks (p<0.001) compared with controls. Gut permeability, as assessed by the lactulose/mannitol ratio, was significantly elevated, initially and at 12 weeks (p<0.005). CD3, CD4, and CD8 lymphocyte counts in the lamina propria and intraepithelial lymphocytes (IEL) were significantly increased initially compared with controls. At visit 1, EC numbers were positively correlated with CD3 counts (r=0.6, p=0.01). At one year, seven subjects (five with persistent loose stools) had rectal biopsies which showed significantly elevated EC, CD3, and IEL counts. In group 2, EC and IEL counts were significantly increased compared with controls (p<0.001), as was gut permeability (p<0.01). CONCLUSION---Increased EC, T lymphocytes, and gut permeability are acute changes following Campylobacter enteritis which can persist for more than a year and may contribute to PD-IBS.


View this article in PubMed
1: Gastroenterology. 2002 Nov;123(5):1607-15.Click here to read Links

Erratum in: Gastroenterology 2003 Jan;124(1):275. El Asmar Rahzi [corrected to El Asmar Ramzi].

Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure.

* El Asmar R, * Panigrahi P, * Bamford P, * Berti I, * Not T, * Coppa GV, * Catassi C, * Fasano A.

Department of Pediatrics and Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

BACKGROUND & AIMS: Enteric infections have been implicated in the pathogenesis of both food intolerance and autoimmune diseases secondary to the impairment of the intestinal barrier. On the basis of our recent discovery of zonulin, a modulator of small-intestinal tight junctions, we asked whether microorganisms might induce zonulin secretion and increased small-intestinal permeability. METHODS: Both ex vivo mammalian small intestines and intestinal cell monolayers were exposed to either pathogenic or nonpathogenic enterobacteria. Zonulin production and changes in paracellular permeability were monitored in Ussing chambers and micro-snapwells. Zonula occludens 1 protein redistribution after bacteria colonization was evaluated on cell monolayers. RESULTS: Small intestines exposed to enteric bacteria secreted zonulin. This secretion was independent of either the species of the small intestines or the virulence of the microorganisms tested, occurred only on the luminal aspect of the bacteria-exposed small-intestinal mucosa, and was followed by a decrease in small-intestinal tissue resistance (transepithelial electrical resistance). The transepithelial electrical resistance decrement was secondary to the zonulin-induced tight junction disassembly, as also shown by the disengagement of the protein zonula occludens 1 protein from the tight junctional complex. CONCLUSIONS: This zonulin-driven opening of the paracellular pathway may represent a defensive mechanism, which flushes out microorganisms and contributes to the host response against bacterial colonization of the small intestine.

PMID: 12404235 [PubMed - indexed for MEDLINE]


LPS causes intestinal injuries that result in a leaky gut.

A research article that demonstrates that endotoxin (another name for LPS) causes intestinal mucosal permeability (another name for leaky gut) This article also uses the term lipopolysaccharide for LPS.

Click here to view this article on PubMed
The effect of endotoxin on intestinal mucosal permeability to bacteria in vitro.

* Go LL, * Healey PJ, * Watkins SC, * Simmons RL, * Rowe MI.

Department of Pediatric Surgery, Children's Hospital of Pittsburgh, Pa.

OBJECTIVE: To examine the role of the intestinal mucosa in bacterial translocation, in vitro bacterial passage across ileal mucosal segments mounted in Ussing chambers were studied in control and endotoxin (lipopolysaccharide)-treated rats. DESIGN: Experimental study. MATERIALS AND METHODS: Three groups of rats were studied. The experimental group received an intraperitoneal injection of lipopolysaccharide, while controls received an equivalent volume of saline solution; a third group received no treatment. Twenty-four hours later, all groups underwent laparotomy and organ culture to assess bacterial translocation. At the same time, a segment of mucosa from the terminal ileum of each animal was mounted in a Ussing chamber, and the transmucosal passage of labeled Escherichia coli from the luminal to serosal surface was assessed by results of serial cultures. RESULTS: In vivo bacterial translocation occurred in 100% of the lipopolysaccharide-treated animals, significantly higher than the incidence seen in controls (25%; P < .05). In vitro passage of labeled E coli across ileal mucosa in the Ussing chamber occurred in 78% of lipopolysaccharide-treated animals, while in controls transmucosal passage was seen in only 14% (P < .05). Histologic examination of mucosa from both groups using light and transmission electron microscopy demonstrated no structural differences between groups. CONCLUSIONS: Increased permeability to bacteria at the mucosal level contributes to the bacterial translocation seen in endotoxemia.

PMID: 7802577 [PubMed - indexed for MEDLINE]


The next article shows that LPS causes the tight junctions to widen and become disrupted. Please note that this alteration plays an important role in creating a leaky gut. The other changes induced by LPS include broken microvilli, a sign of celiac disease.

View this article in PubMed
1: Zhongguo Dang Dai Er Ke Za Zhi. 2006 Oct;8(5):425-8. Links
[Protective effects of recombinant intestinal trefoil factor against intestinal injuries induced by endotoxin in young rats]
[Article in Chinese]

* Li J, * Xu LF, * Sun M, * Li Q, * Gao H, * Jiang WG.

Department of Pediatrics, Second Affiliated Hospital of China Medical University, Shenyang 110004, China. lijun9524@126.com

OBJECTIVE: This study aimed to investigate the protective effects of recombinant intestinal trefoil factor (rITF) against intestinal injuries and the possible mechanism by examining the changes of diamine oxidase (DAO) and TNF-alpha and the intestinal ultrastructural changes in lipopolysaccharide (LPS) induced intestinal injuries. METHODS: Ninety-six ten-day-old Wistar rats were randomly injected with either normal saline (1 mL/kg, Control group), LPS (1 mL/kg) or LPS (1 mL/kg) + rITF (0.1 mL) intraperioneally. At 2, 6, 24 and 72 hrs after administration plasma DAO activity was determined using absorption spectrometry; and the intestinal protein and mRNA expression of TNF-alpha were measured using immunohistochemistry and RT-PCR methods. The intestinal ultrastructural changes were observed by electron microscopy. RESULTS: The plasma DAO activity in the LPS group began to increase at 2 hrs, peaked at 6 hrs and remained at significantly higher levels until 72 hrs after administration compared with the Control group (P < 0.01). The plasma DAO activity in the LPS + rITF group decreased noticeably compared with the LPS group at all time points (P < 0.01 or 0.05). A significant difference in the plasma DAO activity was only observed at 6 hrs after administration between the LPS + rITF and the Control group. The expression of TNF-alpha protein in the LPS group significantly increased at each time point, peaking at 6 hrs after LPS administration, with the IODT of TNF-alpha of 37,247.64 +/- 3,387.59 vs 6,191.02 +/- 482.32 (P < 0.01) compared with the Control group. rITF treatment decreased the expression of TNF-alpha protein although it remained significantly higher than in the Control group (P < 0.01). The TNF-alpha mRNA was weakly expressed in the Control group but strikingly increased after LPS injection (P < 0.01). Compared with the LPS group, the TNF-alpha mRNA expression in the LPS + rITF group decreased at all time points (P < 0.01 or 0.05). Vacuole changes of mitochodrium, cell nucleus condense, break and depletion of part of microvilli, and widen and disrupted tight junction were observed in the LPS group. The ultrastructural changes of intestinal tissues were improved in the LPS + rITF group. CONCLUSIONS: rITF can decrease the plasma DAO activity and inhibit the expression of TNF-alpha, resulting in a protective effect against intestinal injuries induced by LPS in young rats.

PMID: 17052407 [PubMed - indexed for MEDLINE]


Diet that is Easy to Digest may Heal the Leaky Gut

The elemental diet is a special medical diet that is esy to digest.

Click here to view this article on PubMed

1: Gastroenterology. 1991 Jul;101(1):84-9.
The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease. Teahon K, Smethurst P, Pearson M, Levi AJ, Bjarnason I.

Section of Gastroenterology, Medical Research Council Clinical Research Centre, Harrow, Middlesex, England.

This study examines whether treatment of acute Crohn's disease with an elemental diet improves intestinal integrity and inflammation as assessed by a 51Cr-labeled ethylenediaminetetraacetatic acid (EDTA) permeability test and the fecal excretion of 111In-labeled autologous leukocytes, respectively. Thirty-four patients with active Crohn's disease completed a 4-week treatment course with an elemental diet. Active disease was characterized by increased intestinal permeability [24-hour urine excretion of orally administered 51Cr-EDTA, 6.4% +/- 0.6% (mean +/- SE); normal, less than 3.0%] and by high fecal excretion of 111In-labeled leukocytes (14.2% +/- 1.1%; normal, less than 1.0%). Twenty-seven (80%) went into clinical remission, usually within a week of starting treatment. After 4 weeks of treatment, there was a significant decrease in both the urine excretion of 51Cr-EDTA (to 3.4% +/- 0.5%; P less than 0.01) and the fecal excretion of 111In (to 5.7% +/- 1.0%; P less than 0.001), indicating that such treatment is not just symptomatic. A framework for the mechanism by which elemental diet works, centering around the importance of the integrity of the intestinal barrier function, is proposed, and also appears to provide a logical explanation for some relapses of the disease.

PMID: 1904381 [PubMed - indexed for MEDLINE]


Yogurt May Heal the Leaky Gut

Yogurt is also very helpful for the leaky gut:

View this article in PubMed
1: Acta Paediatr Suppl. 2005 Oct;94(449):34-6.
Effects of specific lactic acid bacteria on the intestinal permeability to macromolecules and the inflammatory condition.

* Heyman M, * Terpend K, * Menard S.

INSERM EMI 0212, Faculte Necker-Enfants malades, Paris, France.

Non-live probiotic bacteria and their fermentation products can be used in milk-based formula intended for healthy infants. The effects of a milk formula fermented with Bifidobacterium breve and Streptococcus thermophilus and heated/dehydrated to inactivate the micro-organisms have been reported over the last few years to decrease the intestinal permeability to macromolecules in experimental animals in vivo and more recently to down-regulate inflammatory condition in vitro. Feeding guinea-pigs with such dehydrated fermented milk reinforced the intestinal barrier resistance to food proteins (HRP, beta-lactoglobulin). In addition, the products secreted by bacteria were capable of inhibiting the lipopolysaccharide (LPS)-induced TNF-alpha secretion by human peripheral mononuclear blood cells. The active secretion products were resistant to digestive enzymes and their anti-inflammatory properties were preserved after transepithelial transport across the filter-grown intestinal epithelial cell line, especially in inflammatory conditions. The binding of LPS to monocytes as well as NFkappaB nuclear translocation leading to pro-inflammatory cytokine transcription were inhibited by bacteria-culture supernatants. CONCLUSION: B. breve and S. thermophilus used as non-live micro-organisms in fermented infant formula seem to induce a reduction in macromolecular absorption and release metabolites exerting an anti-TNF-alpha effect, which persists after intestinal transport. Thus, specific lactic acid bacteria and their metabolites seem to affect positively the intestinal function.

PMID: 16214764 [PubMed - indexed for MEDLINE]