High Glutamate Levels – Low GABA caused by low bacteria levels?

Some CFS patients have been found to have high glutamate levels.  There are two possibilities:

  • Bacteria or infections producing too much
  • Bacteria that normally consumes it are missing — this I suspect is the more common cause of high levels in CFS.

Glutamate pathways are reported impacted in CFS [2017].

  • “These findings suggest that dietary glutamate may be contributing to FM symptoms in some patients.” [2012]
  • “patients with FM showed higher levels of glutamate/glutamine (Glx) compounds” [2010]
  • “CSF concentrations of substance P and glutamate have been repeatedly found to be increased in fibromyalgia patients [3234].” [2012]

Now we hit the interesting part of this issue:

  • “GI-tract-abundant Gram-positive facultative anaerobic or microaerophilic Lactobacillus, and other Bifidobacterium (Actinobacteria) species such as Lactobacillus brevis and Bifidobacterium dentium are capable of metabolizing glutamate to produce gamma-amino butyric acid (GABA),” [2014] [2012]
  • “The results revealed that 10 isolates, i.e., Lactobacillus buchneri (2 isolates), Lactobacillus brevis (6 isolates), and Weissella hellenica (2 isolates) had a high GABAproducing ability” out of 53 tested from Japanese foods: aburazushi, narezushi, konkazuke, and ishiru [2016]  10/53 or 19%
  • “In this paper, we screened our collection of 135 human-derived Lactobacillus and Bifidobacterium strains for their ability to produce GABA from its precursor monosodium glutamate. Fifty eight [58] strains were able to produce GABA. The most efficient GABA-producers were Bifidobacterium strains (up to 6 g/L)….The genes were found in the following genera of bacteria: Bacteroidetes (Bacteroides, Parabacteroides, Alistipes, Odoribacter, Prevotella), Proteobacterium (Esherichia), Firmicutes (Enterococcus), Actinobacteria (Bifidobacterium). These data indicate that gad genes as well as the ability to produce GABA are widely distributed among lactobacilli and bifidobacteria (mainly in L. plantarum, L. brevis, B. adolescentis, B. angulatum, B. dentium) and other gut-derived bacterial species.” [2016] 58/135 = 43% 

GABA Link

“GABA metabolism is dependent on the activity of three enzymes: glutamic acid decarboxylase, GABA-transaminase and succinic semialdehyde dehydrogenase. Decreased activity of these enzymes may cause many neurological syndromes, such as stiff-person syndrome, chronic fatigue syndrome, anxiety disorders and seizures.” [2007]

Bottom Line

Given any random bifidobacteria or lactobacillus strain, the possibility of it producing GABA from glutamate appears to be between 19% and 43%. The best odds are for

  • L. plantarum,
  • L. brevis,
  • B. adolescentis,
  • B. angulatum,
  • B. dentium

Given the low levels of bifidobacteria, lactobacillus and E.Coli seen in CFS patients, a high level of glutamate would be expected. It would not effect all because these are not the sole consumers of glutamate.

This model gives a concrete biological process accounting for this shifts seen.

Metformin – low dosages may help

I forwarded an article “Common diabetes drug may work by changing gut bacteria, study finds”  to a reader and he responded:

  • “This is fascinating Ken, thank you. I belong to untold numbers of CFS and Lyme Facebook groups, newsletters, forums, etc. Many of them talk of Metformin as being the biggest and best “new thing” out there for treatment. Once again it seems that all roads lead to the microbiome…”

I am opposed to trying random “new things” but very much in favor of trying “new things” that the model that you are using would predict to help.  With the microbiome model, I have had a very good batting average 🙂 .

What do we know about Metformin?

Bottom Line

The known shifts for metformin appear to be beneficial for CFS/Lyme patients with no reported negative shifts. I suspect that it will likely improve some subset of symptoms (which ones are unknown). It would be nice to see a formal study done and published for CFS/FM/IBS.

It is reported to have some side effects:

Metformin can rarely cause a serious (sometimes fatal) condition called lactic acidosis. Stop taking metformin and get medical help right away if you develop any of the following symptoms of lactic acidosis: unusual tiredness, dizziness, severe drowsiness, chills, blue/cold skin, muscle pain, fast/difficult breathing, slow/irregular heartbeat, stomach pain with nausea, vomiting, or diarrhea.” — of course, lactic acidosis is suspected to be a significant part of CFS…

On Facebook, a reader wrote ” I took metformin xr for my diabetes and it ripped me up!! Killed me with my IBS, to the point that I had to stop taking it.

VSL#3 A review

I have mentioned VSL#3 probiotic is passing but have not done an explicit review. I know that it is heavily promoted directly to MDs. In terms of readers’ experience…

  • taking VSL#3 (I hadn’t discovered your website yet).  I switched over to Prescript Assist, and it hasn’t even been a week yet, and yesterday, for the first time in 6 months I went for a 2 mile walk/jog around my neighborhood.  My mono symptoms have disappeared.” [2017]

So what is known about VSL#3 from clinical studies ideally. There are 250+ citations on PubMed, so it is well studied. It is helpful for some conditions and many MDs will suggest it blindly for any issue dealing with the microbiome or digestion.

Not Specific to CFS/IBS/FM

vsl

 

Relevant Studies

Research Double Speak:  “Improvement” – may mean that there is only a 2% improvement, shown by statistical analysis which is often indicated by the use of the word “significantly“.

  • Probiotics for Irritable Bowel Syndrome: Clinical Data in Children. ” concluded that Lactobacillus GG, Lactobacillus reuteri DSM 17938 and VSL#3 significantly increased treatment success. We recently showed that, in children with IBS, a mixture of Bifidobacterium infantis M-63®, breve M-16V® and longum BB536® is safe and is associated with better AP control and improved quality of life when compared to placebo.” –
  • ” clinical trials in children showed an improvement in abdominal pain for Lactobacillus GG, Lactobacillus reuteri DSM 17938, and the probiotic mixture VSL#3. The patients most benefiting from probiotics were those with predominant diarrhea or with a post-infectious IBS.” [2014]
  • “Before therapy, intestinal microbiota of IBS subjects differed significantly from that of healthy controls, with less diversity and evenness than controls (n = 9; P < 0.05), increased abundance of Bacteroidetes (P = 0.014) and Synegitestes (P = 0.017), and reduced abundance of Actinobacteria (P = 0.004). The classes Flavobacteria (P = 0.028) and Epsilonproteobacteria (P = 0.017) were less enriched in IBS. Abundance differences were largely consistent from the phylum to genus level. Probiotic treatment in IBS patients was associated with a significant reduction of the genus Bacteroides (all taxonomy levels; P < 0.05) to levels similar to that of controls.” [ [2013] The genus bacteroides improved, but not Actinobacteria, Synegistetes, or Epsilonproteobacteria. Flavobacteria was low, and article implies that it went lower.
  • Gut microbiota is not modified by Randomized, Double-blind, Placebo-controlled Trial of VSL#3 in Diarrhea-predominant Irritable Bowel Syndrome [2011].
  • Does VSL#3 really improve symptoms in children with IBS? [2012] – summarizes some major problems with how earlier studies were done.
  • A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating[2005]. “VSL# 3 reduces flatulence scores and retards colonic transit without altering bowel function in patients with IBS and bloating.”

No studies with SIBO, Chronic Fatigue Syndrome or Fibromyalgia.

Bottom Line

There is low value (and high costs) to taking VSL#3 for IBS/FM/CFS/SIBO.  While it does reduce one of the groups of bacteria — it does not impact other significant groups.  I greatly favor taking Prescript Assist or General Biotics Equilibrium as a better choice than VSL#3.

The use of retinoic acid with probiotics is an interesting aspect.

  • “Epithelial cells have also been shown to metabolize vitamin A into retinoic acid (RA) (2)”

On a naive level, it suggests that taking Vitamin A with probiotics may be beneficial — but this is strictly speculation.

 

 

Firmicutes/Bacteroidetes Ratio

The Firmicutes/Bacteroidetes ratio is a rough indicator of bacterial shifts.  The following are not included in these gtoups: BifidiobactiumEscherichia coli

Firmicutes: Includes Lactobacillus, Enterococcaceae, Bacillus. Usually Gram-Positive

firmi

Bacteroidetes usually gram-negative

bact

Not in either of the above: BifidiobactiumEscherichia coli

When the ratio increases then either

  • More firmicutes
  • Less bacteroidetes
  • or both with firmicutes increasing faster.

When the ratio decreases then either

  • Less firmicutes
  • More bacteroidetes
  • or both with firmicutes decreasing faster.

 

Lower Ratio

  • Systemic lupus erythematosus [2017]
  • Coeliac disease [2016]
  • Crohn’s Disease [2016]
  • Aging [2014]

Higher Ratio

  • Obese (higher BMI) [2017]
  • Gut dysbiosis in hypertension [2017] [2017]
  • Autism spectrum disorders [2017]
  • Chronic Fatigue Syndrome [2013]
  • Gulf War Illness [2017]
  • Irritable bowel syndrome [2016] [2016] 3x higher
  • Sjögren’s syndrome [2007]
  • Rheumatoid Arthritis  [2014] ” The signs of III degree dysbiosis, by reducing the concentration of Bacteroides spp., Bifidobacterium spp., Lactobacillus spp. populations, typical strain E. coli. But over growth of populations Klebsiella spp., Proteus spp., Staphylococcus spp., atypical forms of E. coli, Candida spp. ” Almost the identical pattern reported for CFS in 1998.

Changers:

I will add more to this page in the future.

  • Increases
  • Decreases –
    • Resveratrol [2014]
    • Lactobacillus Fermentum [2017]
    • Pea Fibre [2017]
    • Melatonin [2017]

 


Triphala – an ancient medicine

Triphala is a mixture from Ayurvedic medicine has been mentioned in context of reducing high Streptococcus [2017] as well as in a patient report. It is cheap ($22 for 454gm/ 1 pound on Amazon — Organic)) and traditionally taken as a tea (a bit bitter – but tolerable). It was used since the Roman Period in the west [2015]

It contains equal parts of three herbs:

On pubmed,

I have taken to adding some to tea regularly and several people have been impressed by changes it has made.

So what do we know about each?

Amalaki (Emblica officinalis)

 

Bibhitaki (Terminalia bellirica)

Haritaki (Terminalia chebula)

  • “The highest antibacterial potentiality was exhibited by the methanolic leaf extract of T. chebula, followed by the aqueous fruit extract of T. bellerica. The leaf extract of T. chebula can be considered to be as equally potent as the most effective antibiotics, such as ciprofloxacin, gentamycin, kanamycin, ofloxacin and cephalexin.” [2008]

See this prior post.

THIS IS NOT MEDICAL ADVICE — this post is an education summary of what has been reported on PubMed. Always consult with a knowledgeable medical professional before changing diet, supplements and prescription drugs.

uBiome’s Clinical Report “Smart Gut”

uBiome has been offering clinical reports to MDs of some uBiome people.

Hi there,

We wrote you recently to invite you to the pilot program for SmartGut.  We are writing to let you know you are still invited to participate in the SmartGut pilot program.

If ordered, we will send you a clinical report on over a dozen common pathogens and commensals found in the human gut that affect your health with a clinical kit that we’ll send your way.

All you have to do is answer a few questions about your current health, and we’ll coordinate with your physician to request the test for you for your archived baseline if you have one as well as a new kit. It’s even covered by insurance. (As part of our pilot, we will not balance bill you for any amounts not paid by your insurance company.)

A reader has gotten their results, the “SmartGut” test report, show below.

smart1

smart2

smart3

smart4

smart6

smart7

smart5

Smart8

smart9

smart10

Bottom Line

This report is designed to be typical physician friendly. Information is presented in a friendly (idiot) format. This is not my #1 choice for CFS patients, I believe GanzImmun Diagnostics AG report [GDs] that I reviewed in this recent post is better. Let us look at what is in these reports

  • Akkermansia muciniphila – both
  • Alistipes – both
  • Anaerotruncus colihominis – both
  • Bacteroides fragilis – both
  • Barnesiella – Smart Gut only
  • Bifidobacteria – Smart Gut: 1 measure. GD’s – 3 breakdowns
  • Butyrivibrio crossotus – both
  • Campylobacter Smart Gut only
  • Clostridium – both
  • Clostridium difficile – Smart Gut only
  • Collinsella aerofaciens – both
  • Desfulovibrio piger – both
  • Dialister – GD’s species, invisus Smart Gut
  • Escherichia spp – GD’s, Shigella Smart Gut
  • Fusobacterium – both
  • Fusobacterium nucleatum — GD’s
  • Lactobacillus – both
  • Odoribacter -both
  • Methanobrevibacter smithii – both
  • Oxalobacter formigenes – both
  • Prevotella – both
  • Roseburia – both
  • Ruminococcus – both
  • Ruminococcus albus – smart gut only
  • Salmonella enterica – smart gut only
  • Veillonella – smart gut only
  • Vibrio cholera  – smart gut only

I will refrain from listing the dozens other bacteria that GDs has. SmartGut gives a simple High, Low, Normal for each measure — perfect for a physician to look at and jump to conclusions (or dismissal — “you are fine! There are no microbiome problems!”). SmartGut does not provide treatment advice of any form. No pH is provided.

GD’s provide actual numbers and scales which provide a far more complete picture. Using the GD’s results and the information of what is significant in the Smart Gut report (which is based on studies cited at the bottom of their report)

Problem with both: There are no gender reference ranges.

This patient’s results

Recommendations are simple:

  • Bifidobacteria probiotics, no lactobacillus probiotics.
  • See increasing Akkermansia post (“pH 5.5–8.0, with optimum growth at 37 C and pH 6.5″ [2004]) – thus an alkaline environment would inhibit it some. This may be available as a probiotic in the coming months/years.
  • There was no report on E.Coli, just a report on “Escherichia-Shigella” which are overgrowths seen in Crohn’s disease.

 

 

 

A possible explanation of how CFS gets started

My model is that CFS is a persistent shift of bacteria following some event (typically infection or stress).  In doing a reader microbiome analysis I focused on their high pH (alkaline). This lead to the following addition to the model. Back in 2001, pH was discussed on the old group that I was the moderator on, CFSFMExperimental with intermittent results

A light bulb went on reading a paper dealing with weaning babies on to cow milk. The chart below shocked me — because it looked like the shift seen in CFS!!!! Bifidobacterium dropped, Lactobacillus dropped and Escherichia Coli dropped — just like CFS!

Milk

  • “An increase in the relative abundance of Bacteroides spp., Blautia spp., Parabacteroides spp., Coprococcus spp., Ruminococcus spp., and Oscillospira spp. and a decrease of Bifidobacterium spp., Lactobacillus spp., Escherichia spp., and Clostridium spp. were observed during weaning. The change in microbiome composition was accompanied by a gradual increase of fecal pH from 5.5 to 7.” [2016] That is, the result from going from human milk to cow milk in humans. Human milk have a pH of 7.4 [1986] while cow milk has a pH of 6.5 [source] and milk from different mammals are significantly different in composition [2004]

At this point I need to make a table to clarify the relationship between the pH of the food intake and the fecal pH. It is an inverse relationship. Low pH food causes the body to make more acid to digest it, this increased acid production is not confined to just the stomach but across the entire digestive system.

Food Food pH Fecal ph
Human Milk 7.4 (milk alkaline) 5.5
Cow Milk 6.5 (mild acid) 7.0

From a veterinary study [2013]

ph1

Hypothesis

“The onset of CFS was an event that resulted in the fecal pH increasing above the normal range (5.5-6.5) which resulted in bacteria composition changing [All bacteria are sensitivie to different pH ranes]. The shifted bacteria conspired to keep this more friendly-to-them pH value successfully.

Hypothesis Test

The above speculation means that we should find that believed triggering events for CFS may report in the literature a shift in fecal pH to a high (alkaline) value.

  • Giadia infections: see this post for literature on the outbreak with CFS seen in Norway.  ” infects the duodenum and upper intestine, which have a favorable alkaline pH, and gives rise to the clinical sequelae.” [2001]
  • Antibiotics Usage: “Stool with a high pH may mean inflammation in the intestine (colitis), cancer, or antibiotic use” [WebMd]
  • Lyme Disease: ” people with Lyme disease universally suffer from hyperammonemia [causing alkaline pH]” [source]
  • Virus:
    • ” Childhood episodes of hyperammonemia (high ammonia levels in the blood) may be brought on by viral illnesses including chicken pox, colds or flu, …. or even exhaustion.” [Source]

“Total organic acid was increased in acidic feces and decreased in alkaline feces. Lactic acid, succinic acid, and formic acid were the main contributors to acidity in acidic feces. In alkaline feces, acetic acid was significantly decreased. Propionic acid was markedly decreased in both acidic and alkaline feces compared with neutral feces” [2012]

Overall, there is little reported on PubMed (first choice of information) on Urine pH or Fecal pH or blood pH for the reported triggers of CFS.

Consequences:

“The following are some of the traditional causes of alkaline urine:

  1. urinary tract infections (Proteus and others)
  2. matabolic alkalosis (pyloric stenosis and ohters(
  3. failure of acidifications (renal tubular acidosis, chronic renal failure, or aldosterone abnormalities)
  4. ingestion (salicylate, sodium bicarbonate, acetazolamide, etc)
  5. respiratory alkalosis (hyperventilation)” [JAMA 1991]

Add in “acetazolamide, thiazide diuretics, potassium citrate, sodium acetate, sodium bicarbonate, sodium lactate” [Source]

  • “Infectious: Corynebacterium urealyticum, Klebsiella (rare), Proteus, Providencia, S. saprophyticus, Ureaplasma urealyticum” [2009]

Some drugs stay around in your system longer, which can result in adverse drug effects or hyper-sensitivity.

drugs

CFS Process

Once an alkaline environment has been established, alkaline friendly bacteria become established and attempt to maintain the alkaline state.  My original model assumed that the metabolites and natural antibiotics produced by different species helped to maintain the dysfunctional shift. This model may still be true, but a shift of pH is a simpler model that is consistent with the shift of bacteria seen.

Bottom Line

Assuming (moderate assumption) that alkaline urine/fecal plays a significant role in the dysfunctional shift seen in CFS/IBS/FM etc. then an alkaline shifted diet with probiotics and herbs would be a logical path.  Remember to reduce the alkaline urine, we want to eat alkaline foods — not acid foods! See the studies cited above.

What is an alkaline shifted diet? There are many sites on the web..  a few are below:

Many of the alkaline items match other recommendations on this site, for example

REMEMBER: there is a reversed relationship — to reduce acid, more acid food. to reduce alkaline, more alkaline food.

You do not want (because they are acid food): Cow Milk, Eggs, Cheese, Cream, Yogurt, Ices cream.

  • Goat milk is 6.4 – 6.7 [1921] — too acid
  • Soy and milk beverages at a constant pH of 6.5 or 5.5 — too acid again
  • Almond milk appears to be mildly alkaline and would be preferred.

THIS IS NOT MEDICAL ADVICE — this post is an education summary of what has been reported on PubMed. Always consult with a knowledgeable medical professional before changing diet, supplements and prescription drugs.