Autism - Antibiotics
Rapamycin & its observed impact on Autistic Children
(Vancomycin? -  Suramin?)
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mTOR pathways' impact on Autophagy via Antibiotic Dosing
Opposing metabolic drug interactions are based on dosing levels of antibiotic administration
Low Dose (0.1 ng/mL) vs High Dose (10 ng/mL)
 
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Key insight in understanding mechanism of action
Blocked Autophagy = Increase in Inflammation
Blocked mTOR = Diminished Inflammation

mTOR repeated signaling results in
Blocked Autophagy = Increased Inflammation = may contribute to neuronal death
 
   
AUTOPHAGY
DECREASED INFLAMMATION = NEURON SURVIVAL
 
mTOR constant signaling 
INCREASED INFLAMMATION = NEURON DEATH
   
 
Per Clinical Study Below
ANTIBIOTIC IMPACT ON INFLAMMATION
Rapamycin – (Vancomycin?) - (Suramin?}
Antibiotic induced 10–20% of the inflammatory cascade at a LOW dose of 0.1 ng/mL 
However, at
a HIGHER dose of 10 ng/mL., the antibiotic suppresses the inflammatory cascade by 60%
   
LOW LEVELS OF ANTIBIOTIC = INFLAMMATION = AUTOPHAGY BLOCKED
*Suggests that in study below, if Vancomycin was given at
LOW LEVELS it would have BLOCKED Autophagy.
HIGHER LEVELS OF ANTIBIOTIC = SUPPRESSED INFLAMMATION = AUTOPHAGY ACTIVATED
* Suggests that if they had given Vancomycin or Suramin at HIGHER LEVELS, inflammation
would have been diminished and Autophagy would have been ACTIVATED.
   
 
TAKEAWAY FROM THIS RESEARCH
Inflammation in the brain results in BLOCKED AUTOPHAGY
Reduction in Inflammation results in ACTIVATED AUTOPHAGY
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mTOR must be blocked to ensure diminished inflammation and activation of autophagy
 
 
Vancomycin Study
per N of  ONE Foundation Website
I went back to the medical literature. Bingo! I found a paper published in 2000 that documented a clinical trial at Chicago Rush Children's Hospital where 8 out 10 young children with severe autism experienced marked improvements in their autism when they were given a powerful antibiotic called vancomycin.
 
http://www.ncbi.nlm.nih.gov/pubmed/10921511
 
J Child Neurol. 2000 Jul;15(7):429-35.
 
Short-term benefit from oral vancomycin treatment of regressive-onset autism.
Sandler RH1, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Väisänen ML, Nelson MN, Wexler HM.
 
Abstract
 
In most cases symptoms of autism begin in early infancy. However, a subset of children appears to develop normally until a clear deterioration is observed. Many parents of children with "regressive"-onset autism have noted antecedent antibiotic exposure followed by chronic diarrhea. We speculated that, in a subgroup of children, disruption of indigenous gut flora might promote colonization by one or more neurotoxin-producing bacteria, contributing, at least in part, to their autistic symptomatology.

To help test this hypothesis, 11 children with regressive-onset autism were recruited for an intervention trial using a minimally absorbed oral antibiotic. Entry criteria included antecedent broad-spectrum antimicrobial exposure followed by chronic persistent diarrhea, deterioration of previously acquired skills, and then autistic features. Short-term improvement was noted using multiple pre- and post-therapy evaluations. These included coded, paired videotapes scored by a clinical psychologist blinded to treatment status; these noted improvement in 8 of 10 children studied. Unfortunately, these gains had largely waned at follow-up. Although the protocol used is not suggested as useful therapy, these results indicate that a possible gut flora-brain connection warrants further investigation, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism.
 
 
 
6 Clinical Studies
Abstracts from each study
 
 
 
http://www.nature.com/ja/journal/v68/n2/full/ja2014112a.html
J Antibiot (Tokyo). 2015 Feb;68(2):76-80. doi: 10.1038/ja.2014.112. Epub 2014 Aug 20.
 
Vancomycin blocks autophagy and induces interleukin-1β release in macrophages.
Ha YE1, Kong KH2, Cho MH2, Kim DH2, Song YS3, Yoon SY2.
 
Abstract
 
Systemic inflammatory response syndrome (SIRS) is a serious condition that can cause organ failure as an exaggerated immunoresponse to the infection or other causes. Recently, autophagy was reported as a key process that regulates inflammatory responses in macrophages. Vancomycin is one of the most commonly prescribed antibiotics for sepsis treatment or following surgery. However, there are no studies on how vancomycin affects autophagy or inflammation.
 
Here, we treated macrophage cell lines with vancomycin and lipopolysaccharides and found that vancomycin blocks autophagy and increases inflammatory responses. This finding suggests that vancomycin should be more cautiously administered in order to prevent unwanted SIRS during sepsis.
 
 
 
 
http://www.ncbi.nlm.nih.gov/pubmed/22155234
 
Biochem Biophys Res Commun. 2012 Jan 6;417(1):352-7. doi: 10.1016/j.bbrc.2011.11.114. Epub 2011 Dec 1.
 
Autophagy regulates inflammation in adipocytes.
Yoshizaki T1, Kusunoki C, Kondo M, Yasuda M, Kume S, Morino K, Sekine O, Ugi S, Uzu T, Nishio Y, Kashiwagi A, Maegawa H.
 
Abstract
 
Autophagy is an essential process for both the maintenance and the survival of cells, with homeostatic low levels of autophagy being critical for intracellular organelles and proteins. In insulin resistant adipocytes, various dysfunctional/damaged molecules, organelles, proteins, and end-products accumulate. However, the role of autophagy (in particular, whether autophagy is activated or not) is poorly understood.
 
In this study we found that in adipose tissue of insulin resistant mice and hypertrophic 3T3-L1 adipocytes autophagy was suppressed. Also in hypertrophic adipocytes, autophagy-related gene expression, such as LAMP1, LAMP2, and Atg5 was reduced, whereas gene expression in the inflammatory-related genes, such as MCP-1, IL-6, and IL-1β was increased.
 
To find out whether suppressed autophagy was linked to inflammation we used the autophagy inhibitor, 3-methyladenine, to inhibit autophagy.
 
Our results suggest that such inhibition leads to an increase in inflammatory gene expression and causes endoplasmic reticulum (ER) stress (which can be attenuated by treatment with the ER stress inhibitor, Tauroursodeoxycholic Acid).
 
Conversely, the levels of inflammatory gene expression were reduced by the activation of autophagy or by the inhibition of ER stress.
 
The results indicate that the suppression of autophagy increases inflammatory responses via ER stress, and also defines a novel role of autophagy as an important regulator of adipocyte inflammation in systemic insulin resistance.
 
Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR. When mTOR is overactive, they found, brain cells lose much of their “self-eating” ability. And without this ability, the brains of the mice were pruned poorly and contained excess synapses. “While people usually think of learning as requiring formation of new synapses,“ Dr. Sulzer says, “the removal of inappropriate synapses may be just as important.”
 
The researchers could restore normal autophagy and synaptic pruning—and reverse autistic-like behaviors in the mice—by administering rapamycin, a drug that inhibits mTOR. The drug was effective even when administered to the mice after they developed the behaviors, suggesting that such an approach may be used to treat patients even after the disorder has been diagnosed.
 
Because large amounts of overactive mTOR were also found in almost all of the brains of the autism patients, the same processes may occur in children with autism.
 
“What’s remarkable about the findings,” said Dr. Sulzer, “is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning. This says that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River. Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behavior, may be a unifying feature of autism.”
 
Alan Packer, PhD, senior scientist at the Simons Foundation, which funded the research, said the study is an important step forward in understanding what’s happening in the brains of people with autism.
 
“The current view is that autism is heterogeneous, with potentially hundreds of genes that can contribute. That’s a very wide spectrum, so the goal now is to understand how those hundreds of genes cluster together into a smaller number of pathways; that will give us better clues to potential treatments,” he said.
 
“The mTOR pathway certainly looks like one of these pathways. It is possible that screening for mTOR and autophagic activity will provide a means to diagnose some features of autism, and normalizing these pathways might help to treat synaptic dysfunction and treat the disease.”
 
 

 
 
Neurobiol Dis. 2015 Oct 9. pii: S0969-9961(15)30061-9. doi: 10.1016/j.nbd.2015.10.001.
 
mTOR Pathway Inhibition Prevents Neuroinflammation
and Neuronal Death in a Mouse Model of Cerebral Palsy.
 
Abstract
 
BACKGROUND AND PURPOSE:
 
Mammalian target of rapamycin (mTOR) pathway signaling governs cellular responses to hypoxia and inflammation including induction of autophagy and cell survival. Cerebral palsy (CP) is a neurodevelopmental disorder linked to hypoxic and inflammatory brain injury however, a role for mTOR modulation in CP has not been investigated. We hypothesized that mTOR pathway inhibition would diminish inflammation and prevent neuronal death in a mouse model of CP.
 
METHODS:
 
Mouse pups (P6) were subjected to hypoxia-ischemia and lipopolysaccharide-induced inflammation (HIL), a model of CP causing neuronal injury within the hippocampus, periventricular white matter, and neocortex. mTOR pathway inhibition was achieved with rapamycin (an mTOR inhibitor; 5mg/kg) or PF-4,708,671 (an inhibitor of the downstream p70S6kinase, S6K, 75mg/kg) immediately following HIL, and then for 3 subsequent days. Phospho-activation of the mTOR effectors p70S6kinase and ribosomal S6 protein and expression of hypoxia inducible factor 1 (HIF-1α) were assayed. Neuronal cell death was defined with Fluoro-Jade C (FJC) and autophagy was measured using Beclin-1 and LC3II expression. Iba-1 labeled, activated microglia were quantified.
 
RESULTS:
 
Neuronal death, enhanced HIF-1α expression, and numerous Iba-1 labeled, activated microglia were evident at 24 and 48h following HIL. Basal mTOR signaling, as evidenced by phosphorylated-S6 and -S6K levels, was unchanged by HIL. Rapamycin or PF-4,708,671 treatment significantly reduced mTOR signaling, neuronal death, HIF-1α expression, and microglial activation, coincident with enhanced expression of Beclin-1 and LC3II, markers of autophagy induction.
 
CONCLUSIONS:
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mTOR pathway inhibition prevented neuronal death and diminished neuroinflammation in this model of CP. Persistent mTOR signaling following HIL suggests a failure of autophagy induction, which may contribute to neuronal death in CP. These results suggest that mTOR signaling may be a novel therapeutic target to reduce neuronal cell death in CP.
 
 
Clin Hemorheol Microcirc. 2013;53(1-2):155-69. doi: 10.3233/CH-2012-1583.
 
Impact of antibiotics on the microcirculation in local and systemic inflammation.
Al-Banna NA1, Pavlovic D, Gründling M, Zhou J, Kelly M, Whynot S, Hung O, Johnston B, Issekutz TB, Kern H, Cerny V, Lehmann Ch.
  
Abstract
 
The main function of antibiotics is related to their capacity to eliminate a microorganism. In addition to the antimicrobial function of antibiotics, they are known to have anti-inflammatory and vasomodulatory effects on the microcirculation. The ability of non-antimicrobial derivatives of antibiotics to control inflammation illustrates the distinct anti-microbial and anti-inflammatory roles of antibiotics.
 
In this review, we discuss the impact of antibiotics on leukocyte recruitment and the state of the microcirculation. Literature reporting the effect of antibiotics in non-infectious inflammatory conditions is reviewed as well as the studies demonstrating the anti-inflammatory effects of antibiotics in animal models of infection. In addition, the effect of the antibiotics on the immune system is summarized in this review, in order to postulate some mechanisms of action for the pro and anti-inflammatory contribution of antibiotics.
 
Literature reported the effect of antibiotics on the production of cytokines, chemotaxis and recruitment of leukocytes, production of reactive oxygen species, process of phagocytosis and autophagy, and apoptosis of leukocytes.
 
Yet, all antibiotics may not necessarily exert an anti-inflammatory effect on the microcirculation.
 
Thus, we suggest a model for spectrum of anti-inflammatory and vasomodulatory effects of antibiotics in the microcirculation of animals in local and systemic inflammation. Although the literature suggests the ability of antibiotics to modulate leukocyte recruitment and microperfusion, the process and the mechanism of action are not fully characterized. Studying this process will expand the knowledge base that is required for the selection of antibiotic treatment based on its anti-inflammatory functions, which might be particularly important for critically ill patients.
 
 
 
 
International Journal of Inflammation - Volume 2014 (2014), Article ID 560790, 9 pages
 
Differential Role of Rapamycin and Torin/KU63794 in Inflammatory Response
of 264.7 RAW Macrophages Stimulated by CA-MRSA
Rebekah K. H. Shappley1 and Thomas Spentzas1,2
  
Abstract
 
Background. Rapamycin suppresses the RAW264.7 macrophage mediated inflammatory response but in lower doses induces it. In the present study, we tested the suppression of the inflammatory response in the presence of mTOR 1 and 2 inhibitors, Torin and KU63794. Methods. RAW264.7 cells were stimulated for 18 hrs with 106 to 107 CFU/mL inocula of community-acquired- (CA-) MRSA isolate, USA400 strain MW2, in the presence of Vancomycin.
 
Then, in sequential experiments, we added Torin(INHIBITOR), KU63794, and Rapamycin alone and in various combinations. Supernatants were collected and assayed for TNF, IL-1, IL-6, INF, and NO.
 
Results.
Rapamycin induces 10–20% of the inflammatory cascade at dose of 0.1 ng/mL and suppresses it by 60% at dose of 10 ng/mL.
 
The induction is abolished in the presence of Torin KU63794.
Torin and KU63794 are consistently suppressing cytokine production 50–60%.
 
Conclusions.
There is a differential response between Rapamycin (mTOR-1 inhibitor) and Torin KU63794 (mTOR 1 and 2 inhibitors). Torin and KU63794 exhibit a dose related suppression. Rapamycin exhibits a significant induction-suppression biphasic response. Knowledge of such response may allow manipulation of the septic inflammatory cascade for clinical advantages.
 
 
 
 
Nature 469, 323–335 (20 January 2011)
Autophagy in immunity and inflammation
Beth Levine,  Noboru Mizushima  & Herbert W. Virgin
 
Abstract
 
Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy — the 'autophagy proteins' — orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.
 
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