My eye caught a news story today Common food additive may impact gut bacteria, increase anxiety.

Earlier studies have shown that emulsifiers can alter the microbiome of mice, causing low-grade inflammation and increasing the risk of obesity and metabolic disorders.

A study in humans concluded that gut bacteria “can be directly impacted by these commonly used food additives, in a manner that subsequently drives intestinal inflammation.”

The scientists showed that the emulsifiers did impact gut bacteria, but in different ways for male and female mice. They also showed that the changes in behavior were different between the sexes.

Specifically, they saw an increase in anxious behavior, particularly in male mice. In female mice, there was a reduction in social behavior.

A common one is polysorbate 80, which I have a page on the bacteria that it is known to change, here. It is often found in ice cream and cottage cheese. It is also in some vaccines.

Another one, cited above is carboxymethylcellulose (CMC)

• The Role of Carrageenan and Carboxymethylcellulose in the Development of Intestinal Inflammation[2017].
• Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation [2017]
• Acute Exposure to Commonly Ingested Emulsifiers Alters Intestinal Mucus Structure and Transport Properties.[2018]
• Dietary Emulsifier-Induced Low-Grade Inflammation Promotes Colon Carcinogenesis. [2017]
• Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.[2015]
• Nonstarch polysaccharides modulate bacterial microbiota, pathways for butyrate production, and abundance of pathogenic Escherichia coli in the pig gastrointestinal tract.[2010]
• Bacterial overgrowth and inflammation of small intestine after carboxymethylcellulose ingestion in genetically susceptible mice.[2009]

Other emulsifers used in the US include [2017]:

• lecithin [phosphatidylcholine (PC)]  ,
• mono- and diglycerides (MDGs),
• stearoyl lactylates,
• sucrose esters, and
• polyglycerol polyricinoleate.

For lecithin, we read:

Dietary carnitine (present predominately in red meat) and lecithin (phosphatidyl choline) are shown to be metabolized by gut microbes to trimethylamine (TMA), which in turn is metabolized by liver flavin monoxygenases (especially FMO3 and FMO1) to form trimethylamine-N-oxide (TMAO). High levels of TMAO in the blood strongly correlate with cardiovascular disease and associated acute clinical events

Dietary modification of the microbiome affects risk for cardiovascular disease.[2013]

Bottom Line

Checking products for any emulsifiers before buying (and asking your waiter when eating out, which menu items contains no emulsifiers) is strongly recommended — especially if you have any gut or anxiety issues.

Foods commonly containing emulsifiers are:

• “almost every processed food, from ice cream, to low fat cookies and salad dressing contains a wide range of emulsifiers that keep ingredients from separating, improve the texture and taste especially of low-fat foods, and increase shelf life. ” [src]
• salad oils
• some cottage cheese, some cheese (especially processed) and many yogurts [src]
• ice cream
• bread
• chocolate
• margarine
• processed meat

Some of this list from an article entitled “The perfect mixture: emulsifiers make our food enjoyable” . IMHO, it needs a subtitle, “and do a number on your microbiome!’

A list of various names that may be on products [src]:

•  Soya Lecithin Granules G
• Soya Lecithin Powder P
• (Ultralec® P & G)
• Soya Lesithin-Powder,Granulate,Liquid
• Distilled Glycerin Monostearate(D…
• Potassium Stearate
• Calcium Stearoyl Lactylate(CSL)
• DATEM
• Glyceryl Monostearate
• Mono Propylene Glycol
• SPAN 80
• Sodium stearoyl lactylate(SSL)
• Tween
• Sodium Stearate
• Glycerol Triacetate
• Sugar Esters
• Polyglycerol Esters of Fatty Acid…
• Non dairy creamer
• Calcium Stearate
• Polyglycerol Polyricinoleate (PGPR)
• E No: E476
• Soya Lecithin Liquid (Yelkin® TS)

Bottom line: Use the raw ingredients to prepare meals. Beware of all processed foods.

What is Intrinsic Factor?

Intrinsic factor (IF), also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the ileum of the small intestine.^[5] In humans, the gastric intrinsic factor protein is encoded by the GIFgene.^[6]:989

Wikipedia

With CFS/ME, Lyme and other conditions being low in Vitamin B12, suggests that an issue with GIF could have developed. This may be due to an epigenetic event. The incidence of defects in the GIF Gene is very low.

However, wikipedia is incomplete, because it is not only parietal cells.

These findings demonstrate a potential for cellular expression of human intrinsic factor in nonparietal cells. Because such expression occurs normally at the margins of anatomical gastric regions, it suggests that local factors may influence expression of intrinsic factor.

Human gastric intrinsic factor expression is not restricted to parietal cells. [1996]

These data in humans with and without gastritis are consistent with the hypothesis that local factors influence ectopic gastric IF expression, arising from either the anatomical location, the focal inflammation, or both.

Production of ectopic gastric intrinsic factor in gastric mucosa of humans with chronic gastritis [2011]

The earliest recorded history of autoimmune gastritis can be traced to 1849 in London, when Thomas Addison described “a very remarkable form of anemia” later called pernicious (fatal) anemia (PA). This was followed by the recognition of a gastric mucosal defect suspected to have a nutritional basis, the discovery of the megaloblast that characterized the anemia, the insufficiency of a dietary extrinsic factor characterized as vitamin B12 (cobalamin), and a gastric-secreted intrinsic factor. Treatment with vitamin B12 proved curative. The link between PA and gastritis and atrophy was first confirmed histologically after immediate fixation of the stomach postmortem and later, in the 1940s, by peroral tube biopsy. The causes of gastritis remained enigmatic until the era of autoimmunity, when autoantibodies were detected first to gastric intrinsic factor and then to gastric parietal cells. Hints of a dichotomy in pathogenesis of gastritis were crystallized by the description in 1973 of Type A (Autoimmune) and Type B (later, Bacterial) gastritis.

Autoimmune gastritis: historical antecedents, outstanding discoveries, and unresolved problems. [2005]

Proton pump inhibitors also reduce the absorption of vitamin B(12) probably by inhibiting intragastric proteolysis 

Effect of proton pump inhibitors on vitamins and iron [2009]

 The results suggest that IF insufficiency may occur during cimetidine treatment in patients 

Effect of cimetidine on intrinsic factor secretion stimulated by different doses of pentagastrin in patients with impaired renal function. [1983]

Issues reported in the literature with low B12, includes:

• “The most common psychiatric symptoms were depression, mania, psychotic symptoms, cognitive impairment and obsessive compulsive disorder. Neurological involvement includes mainly combined spinal sclerosis, peripheral neuropathy and dementia. ” [2015]
• “These symptoms seem to fall into several clinically separate categories: slow cerebration; confusion; memory changes; delirium, with or without hallucinations and/or delusions; depression; acute psychotic states; and (more rarely) reversible manic and schizophreniform states. ” [1988]

Bottom Line

From the literature, it is well established that one bacteria influences GIF, Helicobacter pylori. In terms of drugs that reduces GIF, we see these drugs impact a lot of bacteria families (linked to from drug below):

• Cimetidine –
• Proton pump inhibitors
  • omeprazole
  • lansoprazole
  • rabeprazole

It appears that GIF production is influenced by the local environment/factors. An important factor for this is the microbiome – bacteria involved.

Treatment

First choice is always to stop drugs that reduces GIF. Second choice, is to eliminate any known bacteria that reduces GIF, explicitly, testing for
Helicobacter pylori (you may lack symptoms and still have it). Third choice is supplementing with Vitamin B12.

Fourth choice (which may also impact the 2nd choice), probiotics that produces or processes B12.

• Lactobacillus Reuteri and recommendations on how to take it
• What is the dosage (and type) of B12 that is best?
• B12 Deficiency: Correct with the proper probiotics
• The quest for a safe B-12 Supplement

A reader asked me to update my earlier posts (as well as

• Parkinson’s Disease and Gut Bacteria (2015)
• Neurology: Parkinson’s Disease (2018)

Blautia coccoides and Clostridium leptum produced the largest amount of hydrogen. Escherichia coli and Bacteroides fragilis constituted the second group that produced hydrogen 34- to 93-fold lower than B. coccoides. Bifidobacterium pseudocatenulatum and Atopobium parvulum constituted the third group that produced hydrogen 559- to 2164-fold lower than B. coccoides. Lactobacillus casei produced no detectable hydrogen. Assuming that taxonomically neighboring strains have similar hydrogen production, we simulated hydrogen production using intestinal microbiota that we previously reported, and found that PD patients produce a 2.2-fold lower amount of intestinal hydrogen compared to controls. 

Quantification of hydrogen production by intestinal bacteria that are specifically dysregulated in Parkinson’s disease [2018]

For what increases Blautia coccoides see this summary. In short:
arabinoxylan oligosaccharides (prebiotic) with rosemary, bernine, and cholic acid! No more red wine, smoking or walnuts!

Changes of Colonic Bacterial Composition in Parkinson’s Disease and Other Neurodegenerative Diseases. Several studies showed an increase of Lactobacillus, Bifidobacterium, Verrucomicrobiaceae and Akkermansia in PD. A decrease of Faecalibacterium spp., Coprococcusspp., Blautia spp., Prevotella spp. and Prevotellaceae was observed in PD. 

Changes of Colonic Bacterial Composition in Parkinson’s Disease and Other Neurodegenerative Diseases. [2018]

Chronic stress-induced gut dysfunction exacerbates Parkinson’s disease phenotype and pathology in a rotenone-induced mouse model of Parkinson’s disease[2018].

Gut microbiome-based secondary metabolite biosynthetic gene clusters detection in Parkinson’s disease.[2018]

Although most of these differences were associated with disease duration, lower abundance in Lachnospiraceae was the only difference between de novo PD and HC (remaining lower across almost all PD duration strata). Decreased Lachnospiraceae and increased Lactobacillaceae and Christensenellaceae were associated with a worse clinical profile, including higher frequencies of cognitive impairment, gait disturbances, and postural instability. When compared with HC, MSA and PSP patients shared the changes in PD, with a few exceptions: in MSA, Lachnospiraceae were not lower, and Prevotellaceae were reduced; in PSP, Lactobacillaceae were similar, and Streptococcaceae were reduced.

Unraveling gut microbiota in Parkinson’s disease and atypical parkinsonism.

The following genera were enriched in the blood of PD patients: Isoptericola, Cloacibacterium, Enhydrobacter and Microbacterium; whereas genus Limnobacter was enriched in the healthy controls after adjusting for age, gender, body mass index (BMI) and constipation. Additionally, the findings regarding these genera were validated in another independent group of 58 PD patients and 57 healthy controls using real-time PCR targeting genus-specific 16S rRNA genes. Furthermore, not only the genera Cloacibacterium and Isoptericola (which were identified as enriched in PD patients) but also the genera Paludibacter and Saccharofermentans were positively associated with disease duration. Some specific genera in the blood were related to mood disorders. We believe this is the first report to provide direct evidence to support the hypothesis that the identified microbiota in the blood are associated with PD. 

Detection of Microbial 16S rRNA Gene in the Blood of Patients With Parkinson’s Disease. [2018]

 In conclusion, the present meta-analysis revealed a higher prevalence of H. pylori infection in PD patients suggesting that H. pylori may contribute to PD pathophysiology. In addition, the significantly lower UPDRS scores in non-infected PD patients and in patients after H. pylori eradication therapy demonstrate that the infection may deteriorate the clinical severity of the disease.

H. pylori and Parkinson’s disease: Meta-analyses including clinical severity. [2018]

Caution: The treatment for H. pylori will also impact the microbiome and the changes may be due to side-effects on other bacteria.

• Helicobacter pylori infection is associated with an increased risk of Parkinson’s disease: A population-based retrospective cohort study.[2018]
• Eradication of Helicobacter pylori infection might improve clinical status of patients with Parkinson’s disease, especially on bradykinesia.[2017]
• Association of Helicobacter pylori with Parkinson’s Disease [2017].
  • ” H. pylori infection was present in 50% of Indian PD patients. H. pylori seropositivity was associated with a poor response to levodopa and increased medication usage, while eradication therapy was associated with better patient outcomes. “

Side Note on Suggestions from MicrobiomePrescription site vs Literature

However, it is not yet clear whether a specific dietary concept or the effects of the intestinal microbiota on the human metabolism could play a role in the course of the disease. Given the lack of prospective nutrition studies, only general recommendations can be given: a “balanced” seasonal regional diet with emphasis on vegetables, fruits, nuts, fish, low amount of red meat, and non-processed foods with a low level of simple carbohydrates may be helpful. 

[Nutritional aspects in Parkinson’s disease: disease risk, dietary therapy and treatment of digestive tract dysfunction] 2018.

From MicrobiomePrescription, based on bacteria shifts alone, we have very similar results, even on non-processed food:

Adherence to the Mediterranean diet is associated with lower probability of prodromal PD in older people. Further studies are needed to elucidate the potential causality of this association, potential relation of the Mediterranean diet to delayed onset or lower incidence of PD, as well as the underlying neurobiological mechanisms

Mediterranean diet adherence is related to reduced probability of prodromal Parkinson’s disease.

In terms of the analysis site, the Mediterranean diet has many plus and many minus. See Explaining Suggestions post for understanding why this may have occurred.

Bottom Line

Microbiome dysfunction and Parkinson’s is getting better and better established. There is a bit of a chicken and the egg situation between infections such as H. pylori or fungus [2017]. Did those pathogens triggered the microbiome dysfunction that lead to Parkinson’s OR did the Parkinson’s microbiome make it easier for those pathogen to occur?

Blind use of antibiotics or other drugs may make things worst. The following ones adversely impacts at least 50% of the microbiome shifts reported:

• metformin
• rifaximin antibiotics
• risperidone (prescription)
• streptomycin antibiotics
• amoxicillin
• kanamycin a sulfate antibiotic
• gentamicine sulfate antibiotic

With literally dozens of drugs of antibiotics impacting 35% of the microbiome shifts adversely.

At the supplement level, we find that B vitamins adversely impact more microbiome shifts than they help:

• Vitamin B3: Adverse 9, Helps 6
• Vitamin B1: Adverse 9, Helps 5
• Vitamin B7: Adverse 7, helps 4
• Vitamin B6: Adverse 7, helps 4
• Vitamin B9: Adverse 7, Helps 4

There was not a single clear “you should take” in the list of vitamins generated. At the amino acid and similar, melatonin had a 11 Adverse to 4 Helps. Proline was the exception: 4 increases and 1 adverse.

In terms of food: Whey, sesame cakemeal, red meat all were clean avoids, having adverse shifts for 25% of the known shifts and nothing known to help. (i.e. in the low protein diet above — exclude red meat)

Harsh bottomline: It seems that most of the things that helps CFS and many other conditions — may actually make Parkinson’s worst. “Cook book recipe for healthy living” may make things worst.

Suggestions on based on PubMed studies. I try to keep to the terms used in the study as much as possible.

When you go to the suggestions page, you may see for diet something like:

First, note that there ate SIXTEEN shifts that we are trying to correct. None of the diets impact more than 5. A lot of the suggestions appear to disagree with each other. The reason is simple – one impacts 3 of the 16 bacteria, another impacts 5 of the 16 bacteria. We do not have sufficient studies published to know more.

For the above, a little common sense and reasoning helps:

• A low animal protein diet would appear to combining the first two items (plus hits the 5th item dead on) and actually agrees with the last one NOT a high animal protein diet.
• Similarly, increase dietary fiber, decrease low fiber diet and decrease high processed food diet also work together nicely.

We do not know exactly what is a “low animal protein diet” – does it include eggs and milk product only, does it include fish? pork? beef? Are the sources organic or commercial? To answer that question, you need to read the actual studies, and in some cases, contact the authors.

How are suggestions computed?

Suppose you have 4 shifts (A and B is too high, Y and Z is too low). And we have a study on apples. This study found that it increases A, decreases B, Z (nothing about Y)

We would report it as Increase Apples: 2, Decrease Apples: 1. Why, because it improves 2 items and makes 1 item worst.

We find a study for peaches, but it only mentions A decreases. We would report it as Increase Peaches: 1, Decrease Peaches:0Because B,Y,Z are not mentioned — we really have no idea if it impacts them.

We discover another study on apples, and it mentions that Y and Z decreases. This study by itself, would be Increase Apples: 2

When we go to the net effect, we end up adding each study together:

• Increase Apples: 2, Decrease Apples: 1
• Increase Apples: 2

The net result is: Increase Apples: 4, Decrease Apples:1. (I do not actually add the numbers, I use a fuzzy logic aggregation). The value for increase apples is higher — because we have greater confidence. Studies often disagree, and this is how we handle the disagreement.

We are working with studies that are often vague and may be silent about things that were either not tested for, or had no impact. We are in the world of fuzzy logic.

It has been some 18 months since my last posts on autism

• Autism Microbiome
• Impacting Autism bacteria
• BPA, Autism and the Microbiome

An update on new studies since then:

• ” we found an increased hazard ratio of autism associated with otitis media[inflammation of the middle ear] (1.83 95% CI 1.71-1.95) and antibiotics usage (1.29 95% CI 1.17-1.43).  ” [2018]
• “In the sibling-stratified Cox model, only broader spectrum antibiotics were associated with increased risk of autism: hazard ratio (HR) = 1.16 ” [2019]
• ” Among 3253 children with ASD, 37.0% had a GI-related diagnosis during the last 2 years of their 5-year health coverage enrollment period, compared to 20.0% of 278,370 children from the general population without an ASD diagnosis. Greater numbers of oral antibiotic fills during the first 3 years of enrollment were found to significantly increase the hazard rate of having a later GI-related diagnosis (adjusted hazard ratio 1.48; 95% confidence interval 1.34, 1.63) in children both with and without ASD. ” [2018]
• Alteration of gut microbiota-associated epitopes in children with autism spectrum disorders[2019].
• The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders [2018].
• The role of microbiota in autism spectrum disorders[2018].
• Gut Microbial Dysbiosis in Indian Children with Autism Spectrum Disorders [2018].
• ” we demonstrate a molecular basis for how the host microbiome is crucial for a normal behavioural response during social interaction. Our data further suggest that social behaviour is correlated with the gene-expression response in the amygdala, established during neurodevelopment as a result of host-microbe interactions.  ” [2018]
• ” In this review, the latest evidence linking mitochondrial dysfunction and abnormalities in mitochondrial DNA (mtDNA) to the pathogenesis of autism will be presented.  ” [2018] – Ouch, it’s associated with the mother’s DNA, or mutations from it.
  • ” we uncovered elevated common polygenic risk, …and a maternally inherited X-linked deletion ” [2018]
• “in the results found in this review, the highest prevalence of the C. albicans in children with ASD stands out. However, little is still known about the involvement of Candida spp., and other types of fungi, on gastrointestinal symptoms and ASD symptoms, in children with ASD. ” [2019]
  • Anti-Candida albicans IgG Antibodies in Children With Autism Spectrum Disorders[2018].
  • “ASD children had a higher rate of high-positive values compared to typically developed children with an unadjusted odds ratio of 3.45”
• Reduced microbiome alpha diversity in young patients with ADHD. [2018]
• The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism [2018].
  • ” In conclusion, our data on the gut microbial community of the 400-E12 rats in response to prenatal VPA exposure indicate that this model, in addition to demonstrating behavioral and anatomical similarities to autism, also mimics the microbiota features of autism, making it one of the best-suited rodent models for the study of autism. “
  • Alteration of gut microbiota-associated epitopes in children with autism spectrum disorders[2019].
• ” In this review, the latest evidence linking mitochondrial dysfunction and abnormalities in mitochondrial DNA (mtDNA) to the pathogenesis of autism will be presented.  ” [2018] – Ouch, it’s associated with the mother’s DNA, or mutations from it.
  • ” we uncovered elevated common polygenic risk, …and a maternally inherited X-linked deletion ” [2018]
• “in the results found in this review, the highest prevalence of the C. albicans in children with ASD stands out. However, little is still known about the involvement of Candida spp., and other types of fungi, on gastrointestinal symptoms and ASD symptoms, in children with ASD. ” [2019]
  • Anti-Candida albicans IgG Antibodies in Children With Autism Spectrum Disorders[2018].
  • “ASD children had a higher rate of high-positive values compared to typically developed children with an unadjusted odds ratio of 3.45”
• “At the genus level, we found that the relative abundance of Sutterella, Odoribacter and Butyricimonas was much more abundant in the ASD group whereas the abundance of Veillonella and Streptococcus was decreased significantly compared to the control group.  ” [2018]
• The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism [2018].
  • ” In conclusion, our data on the gut microbial community of the 400-E12 rats in response to prenatal VPA exposure indicate that this model, in addition to demonstrating behavioral and anatomical similarities to autism, also mimics the microbiota features of autism, making it one of the best-suited rodent models for the study of autism. “

Treatment Implications

• Diet Can Impact Microbiota Composition in Children With Autism Spectrum Disorder.[2018]
• Probiotic treatment reduces the autistic-like excitation/inhibition imbalance in juvenile hamsters induced by orally administered propionic acid and clindamycin [2018].

” we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host’s gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction. ”

Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder.

There is promising evidence to suggest that probiotic therapy may improve gastrointestinal dysfunction, beneficially alter fecal microbiota, and reduce the severity of ASD symptoms in children with ASD. Future research is still warranted in this area because there are methodologic flaws in the available literature and optimal species, strains, dosages, and duration of treatment have not been identified.

Role of Probiotics in Managing Gastrointestinal Dysfunction in Children with Autism Spectrum Disorder: An Update for Practitioners. [2018]

The results showed that children on exclusion diets reported significantly lower scores of abdominal pain and bowel movement, as well as lower abundance of Bifidobacterium spp. and Veillonellaceae family, but higher presence of Faecalibacterium prausnitzii and Bacteroides spp. In addition, significant correlations were found between bacterial populations and faecal amino acids in this group, compared to children following an unrestricted diet. Following B-GOS® intervention, we observed improvements in anti-social behaviour, significant increase of Lachnospiraceae family, and significant changes in faecal and urine metabolites.

A prebiotic intervention study in children with autism spectrum disorders (ASDs). [2018]

Bottom Line

Autism appears to be associated with two major factors: mutations in the DNA, especially in mtDNA. and microbiome. DNA and the microbiome have intense interplay with microbiome shifts likely causing epigenetic changes in DNA in some cases.

Altering the microbiome (although complex to do), promises the greatest hope in moderating the symptoms of Autism and ASD.

I have updated my microbiome analysis site with additional information taken from the various articles cited above for those who have had microbiome done by ubiome.com or others.

For those that have not, there is a Apriori Adjustment page located here.