Is the cause of gluten sensitivity drinking water?

If you look at my 2018 post “What is the best diet in your opinion?” [repost in 2022], you will find a logic that is simple: your microbiome adapts over generations to the food available. When food choices quickly, issues arise in the microbiome. One known issues:

The other day I spotted a non-alcoholic Imperial Pale Ale at Costco and picked up a dozen. During the summer when I am working outside, I like having a cold one when I come inside. Health Canada in 2023 updated their guidance to restrict alcohol use to standard drinks or less per week  with discussion about putting health labels (like tobacco labels) on all drinks. This product tastes like a good IPA, but has no significant alcohol — likely close to the common beer that my ancestors had for breakfast, lunch and dinner.

The light went on! Up until around 1900, beer and ales were common daily drinks –including for children. The reason was simple, water was often deadly due to bacteria in it. Clean drinking water was scarce or unreliable. Milk was fine. Coffee and Tea was fine. Water was not. The beer was not the typical 8% alcohol often seen in American Beers, but 2% or less.

This leads to the speculation that removing regular gluten exposure during childhood — via weak beers and plain-old-school porridge (oats, barley etc.) is the cause of the exploding gluten sensitivity!

It is very likely that gluten sensitivity is connected to diet changes – most of our wheat was breed for specific things, like yield per acre — those changes may contribute too. It is impossible to find clear evidence — but blaming drinking water is an amusing suggestion!

When SIBO Treatment Fails

SIBO or Small Intestinal Bacterial Overgrowth was first proposed as a medical condition in 1970. The first use of breath tests for it was around 1974. The key things to remember is that this condition was the naming of a collection of symptoms. The name reflected the speculation on the general cause without any specifics. Over the years, this condition has been broken down in 6 general subsets depending on the results of breath test (and a potential 7th, if the symptoms are there but no positive breath test results).

Assuming that it is a bacteria overgrowth — which bacteria is overgrown? The breath test does not provide evidence on which specific bacteria a person has.

Based on Kyoto Encyclopedia of Genes and Genomes, we see many suspect bacteria. Worse still, it may not be a single species overgrowth but several.

  • Hydrogen Levels (H2) – 595 species
  • Methane Levels (CH4) – 622 species
  • hydrogen sulfide (H2S) – 3817 species

The clinical practice is often applying a simple logic “If it is an overgrowth, we just toss the appropriate antibiotic at it and it is solved!”. Experience has shown that some are generally effective, i.e.

  • Rifaximin was 78% effective [2023]
  • Amoxicillin (500 mg 3 times a day per, during the first month), followed by ciprofloxacin (500 mg twice a day per, during the second month) and metronidazole (500 mg 3 times a day per, during the third month) about 56% effective [2023]

With effective usually being defined as symptom improvement not remission. Reporting adverse reaction is poorly done.

The reality that using herbs, oil of.. , tinctures, etc. have the same problem as antibiotics. With the evidence above there is not way to determine which ones will be effective for the individual.

There is a recognized and accepted way to better determine the bacteria involved: Small Intestine Aspirate. This is a quasi-surgical procedure to take a sample from the Small Intestine.

Small-bowel aspiration during upper esophagogastroduodenoscopy: Rao technique [2020]

The gotcha is the handling of the sample, the treating physician or the lab may do one of several possible things:

  • Just report the quantity (confirming an overgrowth) — most common
  • Classic culturing of the sample — which will report on the culturable bacteria (most are NOT culturable)
  • 16s testing of the sample – better resolution
  • Shotgun testing of the sample — best resolution

Cost issues can be complicated by insurance companies not covering the costs in most situations.

The Downstream Proposal

Whatever is in the small bowel or intestine eventually makes it way thru the entire system and ends up in a stool. The amount will likely differ because of passages through multiple environments.

The motivation for this post was a reader telling me that his hydrogen sulfide levels have become a problem. His latest sample had a significant amount of them. This suggests that 16s sampling can be helpful for detecting the species involved and thus treatment suggestions based on the bacteria that appear to be in overgrowth (by virtue of the breath test elements).

The video below takes you through the process.

A Walkthru

Note that the top antibiotics suggested from Microbiome Prescription are those used for treating SIBO.

Suggested Readings

Many older articles have stale information, the following are very recent publications.

ME/CFS Patient – First Microbiome Sample

The Ask

I’ve been reading the cfsremission.com site for a few years now and respect and appreciate your work very much! Today I received results from my first test with Biomesight and have uploaded to microbiomeprescription.com, however I’m struggling to know where to go from here.

It looks like I have high F. prausnitzii which goes against some of the CFS research. I can also see zero E. coli (I think) and low bifidobacteria/lactobacillus, but not sure there are strep/staph/klebsiella/other pathogens which I was expecting to see, owing to my issues with histamine/bloating, am I correct?

I’m reluctant to go ahead with taking herbal antimicrobials as I’m not sure exactly what I should be trying to kill off. The suggestions that come up mostly seem to be fibres/prebiotics which I haven’t typically responded well to in the past (worsened bloating and oily skin).

My backstory:

My issues started with the persistent abdominal bloating and sneezing/nasal congestion about 5 years ago. The bloating never goes away, and now I’ve progressed into a state of moderate but unrelenting fatigue, muscle pain and inflammatory issues (dry eyes, etc.), made worse by COVID and then the Pfizer jab last year which pushed my ’steady state’ in terms of energy to a lower level than it ever has been. I know that the root cause of this all is my gut. For example, I can eat regular yoghurt and the next day I will wake up with a back ache, 50% more tiredness and very sneezy. I did test positive for SIBO around 3 years ago but multiple rounds of rifaximin did nothing to help, neither did herbal antimicrobials. The bloating seems to be inflammatory/mast cell related rather than actual gas.

Symptoms:

  • – Crushing fatigue/muscle weakness/PEM (do not have a CFS diagnosis but the symptoms fit)
  • – General inflammation/muscle pain
  • – Freezing cold hands/feet all the time
  • – Sneezing/nasal congestion/itchy throat especially after histamine containing foods
  • – Persistant abdominal bloating which never goes away 
  • – Brain fog
  • – Acne/very oily skin
  • – Dry eyes

For other analysis of the microbiome of people with ME/CFS, see this index.

First Questions Researched

Low Faecalibacterium prausnitzii is seen in several studies for ME/CFS. This person’s level is at a huge 23.7% of the microbiome — the 93%ile. However, for ME/CFS sibling (Long COVID) we have two studies reporting high levels for Long COVID (with 4 reporting Low) and three for COVID being high and one being low. In other words — atypical levels are to be expected. Note that he had COVID and then the Pfizer jab – so Long COVID is likely a better diagnosis than ME/CFS (at this point). The two tend to merge over time.

Usual Analysis Approach

The percentile x percentage breakdown shows the typical pattern for ME/CFS and Long COVID: Over representation on the low percentiles and under representation of the high percentiles.

PercentileGenusSpecies
0 – 92122
10 – 192225
20 – 291822
30 – 391718
40 – 49919
50 – 591623
60 – 691214
70 – 791016
80 – 8997
90 – 9959

The likely causes suggested are: Faecalibacterium prausnitzii, Phocaeicola coprocola and Bacteroides stercoris. The top one was already flagged by the reader.

Going over to Dr. Jason Hawrelak Recommendations, we see a lot out of range.

TaxonomyRankLowHighYour ValueStatus
Bacteroidiaclass03537.029Not Ideal
Akkermansiagenus130.003Not Ideal
Bacteroidesgenus02033.827Not Ideal
Bifidobacteriumgenus2.550.349Not Ideal
Blautiagenus5104.049Not Ideal
Desulfovibriogenus00.250.002Ideal
Eubacteriumgenus0150Ideal
Lactobacillusgenus0.0110.002Not Ideal
Methanobrevibactergenus0.00010.020Not Ideal
Roseburiagenus5102.658Not Ideal
Ruminococcusgenus0158.32Ideal
Proteobacteriaphylum043.705Ideal
Bilophila wadsworthiaspecies00.250.265Not Ideal
Escherichia colispecies00.010Ideal
Faecalibacterium prausnitziispecies101523.71Not Ideal
Overall Percentile Ranking56.5% 

Looking at PubMed matches we see that he is somewhere between these two siblings

  • Long COVID   (45 %ile) 10 of 204
  • COVID-19   (18 %ile) 3 of 118
  • Chronic Fatigue Syndrome   (66 %ile) 4 of 64

Going Forward

He wrote “For example, I can eat regular yoghurt and the next day I will wake up with a back ache, 50% more tiredness and very sneezy. ” Most yogurt contains large amount lactobacillus acidophilus (probiotics) which is high on his to avoid list. In general lactobacillus should be avoided with brain fog because many species produces d-lactic acid (See my 2019 post Reminder of D-Lactic acidosis and ME/CFS – which contains the name of bacteria that may contribute to the issue). If you cannot find a yogurt free of these bacteria, you may wish to give yogurt up. I would suggest the following probiotics as likely being good choices:

He wrote ” multiple rounds of rifaximin did nothing to help, neither did herbal antimicrobials.” Well, that antibiotic is a negative, and like the lactobacillus yogurt above is likely to contribute to the microbiome issues. He did not specify the herbs that he tried.

-75.8rifaximin (antibiotic)s

Typical herbs used for SIBO [Src] are below. Having no results (or negative results) is not surprising.

  • Allicin – positive
  • Oregano – positive
  • Neem – negative
  • Berberine –  negative
  • Peppermint – negative

The top herbs suggested

He wrote “The suggestions that come up mostly seem to be fibres/prebiotics which I haven’t typically responded well to in the past (worsened bloating and oily skin).’ We see that almost all of the prebiotics are below 100 priority (item #170), so they would not make it into my preferred list (I prefer to keep to the to 100 or less). 25% of these are actually below a -200 priority. We also see low fiber diet is high priority. So his experience and the computations are in agreement

Other Items

In terms of common antibiotics for ME/CFS, near the top we see metronidazole (see this 2017 post) and erythromycin (See Azithromycin in Chronic Fatigue Syndrome (CFS), an analysis of clinical data [2006], where 58% improved). If you can persuade your MD to prescribe.

Supplements of note: Taxifolin (See 2021 post dealing with histamine), glutamine (The Role of Glutamine in the Aetiology of the Chronic Fatigue Syndrome [2011] ). Nothing in the flavonoids, polyphenols list stand out. In terms of prefer sugars: chitosan,(sugar),sucralose, raffinose(sugar beet) – most sugars are marginal or negatives. In terms of Vitamins: Iron and magnesium.

Bottom Line

In my years of reviewing literature on ME/CFS, the typical results are similar to the Azithromycin study above: it works for X% of the people and has no or negative effect for the rest. It is my hypothesis/belief that the microbiome determines if a substance works or not.

Above, you see my preferred approach — look at the top 5-10% of suggestions and then cross reference the literature to see which are known to help some. The alternative of working from studies (without reviewing the microbiome) has failed to produce consistent positive results over the decades that it has been tried. The other key item is to look at the bottom 20% of suggestions and eliminate as many of them that you can.

For “Just give me suggestions”, I prefer the priority to be over 150 if possible for takes, and below 0 for avoids.

Remember this is a multiple path journey. Keep on the suggestions for 6-12 weeks and then retest. The suggestions may shift a bit with each course correction.

Postscript – and Reminder

I am not a licensed medical professional and there are strict laws where I live about “appearing to practice medicine”.  I am safe when it is “academic models” and I keep to the language of science, especially statistics. I am not safe when the explanations have possible overtones of advising a patient instead of presenting data to be evaluated by a medical professional before implementing.

I cannot tell people what they should take or not take. I can inform people items that have better odds of improving their microbiome as a results on numeric calculations. I am a trained experienced statistician with appropriate degrees and professional memberships. All suggestions should be reviewed by your medical professional before starting.

The answers above describe my logic and thinking and is not intended to give advice to this person or any one. Always review with your knowledgeable medical professional.

Post COVID with Digestive Pain – is it Long COVID?

Backstory

Backstory – 48 male. Very healthy and fit 

Covid infection last year.  Little to no symptoms. Some stomach issues but nothing big. Then got vaccinated. Then got Covid again, January of this year and has been off since. Burping. Pressure. IBS. Gerd. Pain. 

I am sure I have SIBO due to lots of PPI’s and ibuprofen during Covid. Also did a round of antibiotics a few months ago also. Looking for guidance to correct.

Greatest Concern: Is it Long Covid?

Comment on Concern

A May 2023 article states “1 in 10 People Get Long COVID After Omicron“. Since Long COVID often results in an inability to work or do fun things — most well read people that I know (including myself) continues to wear masks (in my case, a 3M P100, 99% better than a N95). This is much better than earlier versions: “Earlier this month, he reported in the British Journal of Haematology that his patients’ risk of Long Covid symptoms 3 months after infection had dropped from 46% with the original coronavirus strain and another called Alpha, to 35% with the Delta variant, to 14% with Omicron.” The strains are getting milder — but still a 10% risk with its severe financial (and fun) impact should be respected.

Analysis

The initial good news is that we do not have the typical pattern for Long COVID and/or ME/CFS. Those conditions typically have over representation of 0-9%ile count. We have under representation. There is always the chance that it could cascade in that direction, but taking action now will likely decrease those odds.

PercentileGenusSpecies
0 – 946
10 – 191726
20 – 292026
30 – 392024
40 – 492446
50 – 592948
60 – 693127
70 – 792135
80 – 892536
90 – 992140

There was no matches to patterns from the US National Library of Medicine nor to our own citizen science patterns.

Going over to Dr. Jason Hawrelak recommended levels, we have the following of greatest concern. FYI: Lactobacillus was at desired ranges.

TaxonomyRankLowHighYour ValueStatus
Bacteroidiaclass03558.608Not Ideal
Bifidobacteriumgenus2.550.024Not Ideal
Blautiagenus5101.57Not Ideal
Roseburiagenus5100.079Not Ideal
Proteobacteriaphylum044.558Not Ideal
Escherichia colispecies00.010.031Not Ideal

Looking at Proteobacteria, we have the high count coming from the species Aestuariispira insulae (95%ile) with just two likely candidates to decrease it: berberine and azithromycin,(antibiotic)s.

Going Forward

Going over to “Just give Me Suggestions”, the canned simple suggestions include

There is a faint echo of suggestions seen with Long COVID and ME/CFS.

Going over to technical details, we find that berberine (from looking at one bacteria only) is not a recommended from the consensus. The top priorities are (skipping prescription items) are (in decreasing priority):

My usual suggestion is having barley porridge for breakfast each day. For probiotics (in decreasing priority):

Keep to it for 6 weeks and then retest.

Postscript – and Reminder

I am not a licensed medical professional and there are strict laws where I live about “appearing to practice medicine”.  I am safe when it is “academic models” and I keep to the language of science, especially statistics. I am not safe when the explanations have possible overtones of advising a patient instead of presenting data to be evaluated by a medical professional before implementing.

I cannot tell people what they should take or not take. I can inform people items that have better odds of improving their microbiome as a results on numeric calculations. I am a trained experienced statistician with appropriate degrees and professional memberships. All suggestions should be reviewed by your medical professional before starting.

The answers above describe my logic and thinking and is not intended to give advice to this person or any one. Always review with your knowledgeable medical professional.

Addendum

You can see below how much he failed to match studies from the US National Library of Medicine.

  •  Acne   (17 %ile) 6 of 16
  •  ADHD   (4 %ile) 14 of 53
  •  Allergic Rhinitis (Hay Fever)   (2 %ile) 4 of 39
  •  Allergies   (1 %ile) 6 of 51
  •  Alopecia (Hair Loss)   (2 %ile) 1 of 20
  •  Alzheimer’s disease   (20 %ile) 44 of 88
  •  Amyotrophic lateral sclerosis (ALS) Motor Neuron   (8 %ile) 11 of 41
  •  Ankylosing spondylitis   (1 %ile) 10 of 503
  •  Anorexia Nervosa   (24 %ile) 8 of 24
  •  Antiphospholipid syndrome (APS)   (0 %ile) 0 of 22
  •  Asthma   (5 %ile) 12 of 36
  •  Atherosclerosis   (7 %ile) 3 of 519
  •  Autism   (1 %ile) 39 of 97
  •  Autoimmune Disease   (0 %ile) 0 of 2
  •  Barrett esophagus cancer   (10 %ile) 2 of 16
  •  Bipolar Disorder   (1 %ile) 5 of 50
  •  Brain Trauma   (3 %ile) 3 of 23
  •  Carcinoma   (1 %ile) 7 of 32
  •  Celiac Disease   (1 %ile) 8 of 70
  •  Cerebral Palsy   (29 %ile) 5 of 16
  •  Chronic Fatigue Syndrome   (2 %ile) 12 of 64
  •  Chronic Kidney Disease   (34 %ile) 9 of 35
  •  Chronic Lyme   (32 %ile) 1 of 3
  •  Chronic Obstructive Pulmonary Disease (COPD)   (27 %ile) 5 of 30
  •  Chronic Urticaria (Hives)   (3 %ile) 3 of 23
  •  Coagulation / Micro clot triggering bacteria   (30 %ile) 4 of 37
  •  Colorectal Cancer   (1 %ile) 4 of 310
  •  Constipation   (45 %ile) 2 of 8
  •  Coronary artery disease   (41 %ile) 4 of 18
  •  COVID-19   (1 %ile) 28 of 118
  •  Crohn’s Disease   (1 %ile) 32 of 113
  •  cystic fibrosis   (50 %ile) 2 of 16
  •  deep vein thrombosis   (57 %ile) 3 of 25
  •  Depression   (1 %ile) 38 of 194
  •  Dermatomyositis   (19 %ile) 2 of 9
  •  Eczema   (4 %ile) 5 of 26
  •  Endometriosis   (56 %ile) 9 of 45
  •  Eosinophilic Esophagitis   (45 %ile) 5 of 19
  •  Epilepsy   (4 %ile) 18 of 51
  •  Fibromyalgia   (7 %ile) 13 of 35
  •  Functional constipation / chronic idiopathic constipation   (2 %ile) 11 of 37
  •  gallstone disease (gsd)   (20 %ile) 6 of 23
  •  Gastroesophageal reflux disease (Gerd) including Barrett’s esophagus   (8 %ile) 3 of 23
  •  Generalized anxiety disorder   (28 %ile) 2 of 16
  •  Gout   (8 %ile) 2 of 21
  •  Graves’ disease   (22 %ile) 15 of 41
  •  Hashimoto’s thyroiditis   (1 %ile) 2 of 23
  •  Hidradenitis Suppurativa   (35 %ile) 3 of 13
  •  Histamine Issues From Ubiome   (21 %ile) 1 of 5
  •  Histamine Issues,Mast Cell Issue, DAO Insufficiency   (13 %ile) 3 of 43
  •  hypercholesterolemia (High Cholesterol)   (5 %ile) 2 of 26
  •  Hyperlipidemia (High Blood Fats)   (9 %ile) 4 of 24
  •  hypersomnia   (11 %ile) 1 of 12
  •  hypertension (High Blood Pressure   (17 %ile) 20 of 78
  •  IgA nephropathy (IgAN)   (1 %ile) 2 of 29
  •  Inflammatory Bowel Disease   (8 %ile) 17 of 60
  •  Insomnia   (30 %ile) 9 of 26
  •  Irritable Bowel Syndrome   (3 %ile) 24 of 68
  •  Juvenile idiopathic arthritis   (19 %ile) 1 of 85
  •  Liver Cirrhosis   (1 %ile) 13 of 638
  •  Long COVID   (1 %ile) 41 of 204
  •  Lung Cancer   (40 %ile) 6 of 19
  •  ME/CFS with IBS   (9 %ile) 4 of 18
  •  ME/CFS without IBS   (11 %ile) 5 of 25
  •  Menopause   (0 %ile) 0 of 14
  •  Metabolic Syndrome   (21 %ile) 54 of 276
  •  Mood Disorders   (9 %ile) 57 of 249
  •  Multiple Sclerosis   (1 %ile) 20 of 93
  •  Multiple system atrophy (MSA)   (30 %ile) 4 of 20
  •  Neuropathy (all types)   (16 %ile) 5 of 20
  •  neuropsychiatric disorders (PANDAS, PANS)   (37 %ile) 5 of 15
  •  Nonalcoholic Fatty Liver Disease (nafld) Nonalcoholic   (1 %ile) 12 of 72
  •  NonCeliac Gluten Sensitivity   (0 %ile) 0 of 5
  •  Obesity   (1 %ile) 28 of 148
  •  obsessive-compulsive disorder   (1 %ile) 10 of 61
  •  Osteoarthritis   (18 %ile) 3 of 15
  •  Osteoporosis   (4 %ile) 6 of 28
  •  Parkinson’s Disease   (28 %ile) 60 of 96
  •  Postural orthostatic tachycardia syndrome   (14 %ile) 1 of 6
  •  Premenstrual dysphoric disorder   (13 %ile) 1 of 10
  •  Psoriasis   (1 %ile) 8 of 47
  •  rheumatoid arthritis (RA),Spondyloarthritis (SpA)   (1 %ile) 28 of 125
  •  Rosacea   (17 %ile) 4 of 25
  •  Schizophrenia   (1 %ile) 13 of 92
  •  Sjögren syndrome   (3 %ile) 9 of 35
  •  Sleep Apnea   (6 %ile) 3 of 24
  •  Small Intestinal Bacterial Overgrowth (SIBO)   (7 %ile) 2 of 21
  •  Stress / posttraumatic stress disorder   (1 %ile) 7 of 57
  •  Systemic Lupus Erythematosus   (2 %ile) 15 of 71
  •  Type 1 Diabetes   (2 %ile) 12 of 51
  •  Type 2 Diabetes   (1 %ile) 31 of 227
  •  Ulcerative colitis   (1 %ile) 16 of 110
  •  Unhealthy Ageing   (1 %ile) 1 of 40

The Microbiome and Stress – Most people do nothing!

The three episodes of ME/CFS that I have had were all caused by stress:

  • In University days — Doing triple honors and a life threatening condition hit my father
  • At Microsoft — Assigned to a bad boss that created endless non-productive stress (he was “asked” to leave shortly after I went off sick — co-workers also has issues)
  • At Amazon — similar to the above, except no co-operation from fellow employees — everyone was trying to have other team members be who was cut on the next review cycle.

This week’s New Scientist article: We may finally know why psychological stress worsens gut inflammation (26 May 2023) which cited from The enteric nervous system relays psychological stress to intestinal inflammation (May 25, 2023) motivated me to cite my own experience.

Society and family often expects you to put up with stress. In some cases, it may be needing a job and stress is “just a normal aspect of that“. In other cases, there may be “drama queens”, “gas lighters” and other personality types that uses stress to manipulate people.

There have been many studies finding that ME/CFS is associated with prior stress. Some literature:

One study is particularly interesting: Distinctive personality profiles of fibromyalgia and chronic fatigue syndrome patients. [2016] and likely applies to many people with microbiome dysfunctions. For many years, “Personality Type A are more prone to get ME/CFS” that is people with a pattern of behavior and personality associated with high achievement, competitiveness, and impatience. This study refines that paint brush more. Please read this study.

“Well, I can’t do anything about it”

Most people can do many things. For myself, I have (finally) accepted this simple rule: “If the stress cannot be resolved in X weeks, promptly exit stage left/abandon ship”. In terms of work, if I quit a job, take a financial hit for a while, and get a less stressful job — that is a better alternative than risking a ME/CFS relapse and being unable to work at all. In terms of family, decline contact with stressful members of the family. The latter often require a smoke screen so you agree to come to family gathering and then car troubles, work emergency, prevents you attending.

In other cases, it may take help from others to identify and unlearn habits/conditionings from childhood or prior relationships.

Society and friends can be a major source of stress. This can come from many sources “high expectations of you” to “keeping up with the Jones” to “you are not doing your duty”.

IMHO, your first duty is for your own health. How can you support and care for others when your health is blocking things.

Stress is a co-factor

Other factors are involved, diet, past virus, DNA. Stress is a significant factor and for many people it is the hardest to change because people often resign to their current stress level. For myself, I often surprise my wife by being hyper-reactive to issues. I avoid procrastination and attempt to deal with issues promptly — it is an effective way of reducing stress. Procrastination on the grounds of having to think thing over (or hoping things will resolve themselves) adds to your stress queue in small amounts. If you can’t do anything about it, then accept that reality and don’t worry about it.

Bottom Line

Take a hard look at stress in your life and then resolve them. Your health is the cost of not resolving them.

ME/CFS Patient- Ongoing Samples

This is a series of samples from a long time suffer from Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In looking at the samples, we must keep in mind two factors:

  • Lab Read Quality. A low read quality reports much fewer bacteria than a high read quality.
    • 1.8 reports 300, a high read quality can triple the bacteria counts selected.in a category
    • This usually does not impact the broad stroke criteria such as Dr. Jason Hawrelak (JasonH)
  • A sickness (COVID, Flu) or even vaccination will alter the microbiome and create the appearance of lost ground. This was seen and covered in the post below

My usual practice is compare the latest with the prior only. Trying to weave a dialog covering all prior tests is contra productive with going forward. What is past, is water under the bridge.

This reader had one major question — the suggestions seem to have changed a lot. That is the focus of this post. Have there been a dramatic change, or are the changes likely connected to a few bacteria dropping off the list and a few new ones being added.

Earlier post for this person

Person’s Subjective Report: “Symptom-wise and treatment-wise, I don’t have much to report that is new or an outlier to previous years of samples and treatments.”

Review over Multiple Samples

Data from the same lab (using Ombre data, Biomesight version is also available).

Compared to the prior sample, we see:

  • Less extreme percentiles than prior sample
  • Less rarely seen bacteria
  • Less pathogens
  • Less outside of:
    • Outside Lab Range (+/- 1.96SD)
    • Outside Box-Plot-Whiskers
    • Outside Kaltoft-Moldrup
  • No change using a multitude of 3rd party criteria.
  • Less compounds at high levels, more compounds at low levels

General impression, there has been objective improvement

Criteria4/18/20232/2/202311/1/20224/11/20221/11/202203/09/20215/27/2020
Lab Read Quality4.85.38.615.31.82.94.3
Bacteria Reported By Lab638734800750312394544
Bacteria Over 99%ile414123934
Bacteria Over 95%ile36422421301012
Bacteria Over 90%ile56794649462536
Bacteria Under 10%ile2546154329162632
Bacteria Under 5%ile102154287101511
Bacteria Under 1%ile21784150
Lab: Thryve
Rarely Seen 1%101578029
Rarely Seen 5%366158702418
Pathogens27343230212630
Outside Range from JasonH4444777
Outside Range from Medivere13131919141414
Outside Range from Metagenomics101077999
Outside Range from MyBioma13131010888
Outside Range from Nirvana/CosmosId22222222171717
Outside Range from XenoGene51514848424242
Outside Lab Range (+/- 1.96SD)18241417855
Outside Box-Plot-Whiskers67976363582845
Outside Kaltoft-Moldrup14321829040089102141
Condition Est. Over 99%ile0005210
Condition Est. Over 95%ile00224651
Condition Est. Over 90%ile073381192
Enzymes Over 99%ile134744414156
Enzymes Over 95%ile11417999727311465
Enzymes Over 90%ile46926624215254683512
Enzymes Under 10%ile13312321943070141106
Enzymes Under 5%ile5847108310478853
Enzymes Under 1%ile711646145
Compounds Over 99%ile113122312753
Compounds Over 95%ile3712267469305276
Compounds Over 90%ile1461902319338488365
Compounds Under 10%ile954809823998530617800
Compounds Under 5%ile906789788961521599787
Compounds Under 1%ile872783757892515582776

Comparing Suggestions

The reader noticed a significant change of suggestions between the samples. So I am going to document out how to verify or see the results. Also, remember that you can merge consensus from two different samples. Minor items like taking samples at different time of days, unusual food, significant dosages of herbs, probiotics or supplements within 48 hours of taking a sample can cause temporal shifts.

Step by step:

  • Do “Just Give Me Suggestions” for 1st sample
    • Click “For more technical details”
    • Click Download, save the file
  • Repeat for 2nd sample
  • Open Excel or equivalent on the .csv file downloads
    • Each sample will be in a difference instance of Excel
  • Add a new work sheet to one
    • Copy one set of data to the other
    • Rename worksheets as “Current Consensus” and “Prior Consensus”
  • Copy the Mid2 column to the first column in the Prior Consensus”
  • Insert a blank column after the Mid2 column,
  • Insert into this new blank column: =VLOOKUP(I2,’Prior Consensus’!A:J,2,FALSE)
    • This brings the net value over.
    • You can brink other values over by changing “2”

I have done a video below of the process.

Wait! This is more for your mobile phone users

Go to Multiple samples, then pick your samples as shown below

You will now see a summary at the top

In this case we have 80% agreement on suggestions between samples

Bottom Line

I have not done further analysis etc. The reader has acquired those skills already. I have address only the issue of shifting suggestions. My best advice is simple: Do an uber consensus between the present and the last sample. The logic is simple — samples has some volatility based on time of day that the sample was taken as well as substances consumed in the prior 48 hours. Remember we are dealing with a lot of fuzzy data — both in what is reported from your sample, and what changes what from the literature.

The result of an uber consensus is a continuation of the prior suggestions (with a little pruning) and incorporation of the current suggestions.

Exploration in Picking Critical Bacteria

This is a continuation of a nerdy technical series with Predicting Conditions from PubMed Studies earlier. I continue using depression as my canary. We use two data sets from two different retail providers: Ombre Labs (USA) and Biomesight (UK).

Means, T-Scores – Walking Two Paths

There are two paths available, with no clear best choice:

  • Compare averages from samples that reported some amount (thus excluding zero values)
    • Lower degree of freedom and thus T-Scores
  • Compare averages from samples with a zero being used when an item is not reported.
    • Higher degrees of freedom and higher T-Scores

Picking one or the other of these paths seems to be done a priori by most researchers. To get a feel for the differences, I processed data from Ombre Labs and Biome Sight by both methods. Ombre Labs is almost solely from American Samples. BiomeSight is from around the world. The data suggests that Americans are more prone to depression.

MeasureBiomesightOmbre Labs
Bacteria Taxon Seen1,8782,586
With Depression87101
Without Depression639343
Percentage with Depression Reported12%23%
Highest T-Score with reported only (No Zero values)9560
ABs(T-Score) over 3.2 (No Zero values)11351185
Highest T-Score with Zero if missing282176
Abs(T-Score) over 3.2 (with Zero if missing)13911492
Highest Composite T-Score (Sqrt of the above t-score multiple by each other)15892
Composite T-Score over 3.2 ( < 0.001)11931306
Percentage of Bacteria with T-Score over 3.263%50%
Larger total sample size results in higher t-scores

We then did a composite T-Score between the two labs by bacteria to see the best indicators (in decreasing order of significance). We then compared to results from studies on the US National Library of Medicine

BacteriaDepressionPubMed
Blautia wexleraeIncreasedGenus has 50% high and 50% low
CatonellaIncreased
Catonella morbiIncreased
PseudobutyrivibrioIncreased
ClostridiaceaeDecreased
Sutterella wadsworthensisDecreasedMatch (genus)
SlackiaIncreasedMatch
AnaerobrancaDecreased
ActinobacillusDecreased
Haemophilus parainfluenzaeDecreasedMatch (genus)
ProteinivoraceaeDecreased
Bacteroides ovatusDecreased
ThermoclostridiumDecreased
EggerthellalesIncreasedMatch
EggerthellaceaeIncreased
ThermoanaerobacteralesIncreased
PrevotellaDecreasedGeneral Match at genus
Veillonella disparDecreasedMatch (genus)
Blautia gluceraseaIncreasedGenus has 50% high and 50% low
Blautia hanseniiIncreasedGenus has 50% high and 50% low
LachnospiraDecreasedGeneral Match at genus
AlphaproteobacteriaIncreased
[Ruminococcus] torquesIncreasedDisagree
Desulfallaceae Watanabe et al. 2020Increased
Bifidobacterium bifidumDecreasedDisagrees, but the genus was a match

Where there was a study available, we had our results in good agreement. Note that our sample sizes far exceed those of any of the studies we found.

We had about 20% less significant bacteria by eliminating those samples with no/zero counts. By requiring both methods to be significant reduces the risk of false positives. In this case, we have an abundance of significant bacteria and such a criteria is viable.

Many of the items deemed very significant were of low frequency of being seen in samples

  • Erwinia tasmaniensis: seen in 7.2% of Biomesight samples, not reported in Ombre.
    • With Condition: Seen in 3% of samples with count of 353 /million
    • Without Condition: Seen in 7.7% of samples with count of 128 / million
    • Significant with excluding (11.2), significant with deeming zero (23)

This takes us to the phrase of the analysis: Given a random sample, what is the probability of correctly predicting depression. The end goal is to determine the most influential bacteria responsible for depression. One approach is using random forest on the data trimmed to those bacteria deemed significant or very significant. Another approach is use splines mixed with logistic regression. We must be careful not to shove this problem into an existing square or round hole, instead we need to allow the data to speak to us.

Remember, bacteria do not operate independent of each other. They are highly dependent on the metabolites of each other. Some of my earlier explorations found the KEGG Enzymes estimators were better predictors than bacteria. To be continued.

A Nurse with ME/CFS

Backstory

It all started in February 2018, I am a nurse by profession and after having worked in various cities in my country. I finally got a stable job in my birthplace , my work always caused me stress, and I always thought that sooner or later stress would affect me. I would go to work and notice how the anxiety was going to my digestive system but when my working day ended it was as if a deep sensation of peace would come to me as if a valve opened and let out the gas from a pot..

I have seen that stress is one of the factors that can cause a change in the intestinal microbiota. I was finally diagnosed with a Generalized Anxiety Disorder and Major Depression in September 2018. In September of that year I was also diagnosed with ME/CFS since my fatigue was palpable (non-refreshing sleep). My wisdom teeth were extracted since I was diagnosed with temporomandibular joint dysfunction and I have to say that my instability problems dissipated over the months but everything else remained. Throughout these years I have been struggling with this, without knowing what I really had: CFS/ME, depression, generalized anxiety disorder, irritable bowel syndrome…

But what I do know for sure is that I was a happy person, with a partner, with economic stability, without any debt problem, nor work problems and from one day to the next my life changes to such an extent that I end up with depression and suicidal ideas.

Analysis

This person did the results with Xenogene which gives more information than 16s tests. Unfortunately, they do not provide percentile rankings so we have to borrow those estimates from elsewhere.

The pattern matches that of most people with ME/CFS: over representation of the 0-9%ile. An ideal microbiome should have the number in each 10%ile range being the same.

PercentileGenusSpecies
0 – 92370
10 – 19413
20 – 29816
30 – 391017
40 – 4979
50 – 59413
60 – 69616
70 – 79612
80 – 89217
90 – 9985

Looking at other health issues:

  • Dr. Jason Hawrelak Recommendations is at 89%ile, with the following of most concern:
    • Faecalibacterium prausnitzii – too low (lab agrees)
    • E.Coli — is too high, (lab agrees)
    • Roseburia – too low (Lab identifies one species too low, but two normal)
    • Blautia – too high (lab agrees)
  • Bacteria deemed unhealthy

IMHO – See MD for Antibiotics!

These levels of Salmonella and Shigella are of conventional medical concern. Potentially, you could negotiate with the MD for antibiotics that are effective for them and which will also help your microbiome.

Going Forward

As is becoming my norm, “Just give me Suggestions” button runs 4 sets of suggestion that will usually produce good suggestions.

After doing this, we will hand pick the bacteria of concerns:

This is done using Microbiome Tree on my Profile

And add this to make 4 sets of suggestion. While these may already be selected in the other suggestions, this additional run will emphasis those suggestions more.

Consensus – antibiotics

The topic antibiotics suggested (considering everything) are:

Cross checking with Special Reports (which computes a different way), we find that both lists have many in agreement. This list is full of the antibiotics often prescribed by ME/CFS specialists.

AntibioticConfidence
tetracycline (antibiotic)s0.98
ciprofloxacin (antibiotic)s0.939
metronidazole (antibiotic)s0.93
amoxicillin (antibiotic)s0.721
rifaximin (antibiotic)s0.623
minocycline (antibiotic)s0.548
ceftazidime (antibiotic)s0.505
vancomycin (antibiotic)0.439
intesti-bacteriophage0.418
imipenem (antibiotic)s0.353

There are many antibiotics that are listed in the avoid list. If the MD is willing, I would suggest following the Cecile Jadin’s approach for antibiotics, single course of one antibiotic, a break, then a different antibiotic (preferable a different family).

Consensus – Other

The top ones of the non-antibiotics list are also familiar supplements to many ME/CFS patients. In decreasing priority:

Vitamin B12 and B2 are high priority.

Probiotic Rotation

I would suggest 2 weeks on one of these and then move onto the next one. Repeat at the end:

I would suggest (after discussing with your medical profession) to keep to the above for 2-3 months and then do a retest.  You are sailing your microbiome to safer waters though an archipelago. The winds and the charts will often require many course corrections.

Reader Feedback

From what I have seen of your recommendations, the conventional antibiotic treatment would be shorter than that of products such as oregano, thyme…

There is no doubt that I will talk to my doctor, precisely in a few days I have an appointment with my internal medicine doctor (infections) and I will take my test result so that if he wishes he can prescribe antibiotics, although I am afraid that taking them will further imbalance my microbiota but there is no doubt that possibly my digestive problems (abdominal pain) do not have their origin in irritable bowel syndrome or irritable colon and are produced by these bacteria that I may infect myself having worked in an infectious unit before falling ill .

I know of several MDs that specialized in treating ME/CFS patients who after a few years also came down with ME/CFS. Bacteria is easily transferred by skin contact, inhalation – in most cases, each exposure compound the very low odds of contagion from a single contact. Over time, the risk increases.

  • “Is CFS contagious? Because the cause of CFS remains unknown, it is impossible to answer this question with certainty. However, there is no convincing evidence” Wisconsin Department of Health
  • ” The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients’ immune responses, suggesting exposure to the same antigen (a pathogen).” [2015]

Postscript – and Reminder

I am not a licensed medical professional and there are strict laws where I live about “appearing to practice medicine”.  I am safe when it is “academic models” and I keep to the language of science, especially statistics. I am not safe when the explanations have possible overtones of advising a patient instead of presenting data to be evaluated by a medical professional before implementing.

I cannot tell people what they should take or not take. I can inform people items that have better odds of improving their microbiome as a results on numeric calculations. I am a trained experienced statistician with appropriate degrees and professional memberships. All suggestions should be reviewed by your medical professional before starting.

The answers above describe my logic and thinking and is not intended to give advice to this person or any one. Always review with your knowledgeable medical professional.

Multiple COVID leading to Heart Issues?

Back Story

We’ve had COVID over half a dozen times since early 2020. My primary symptoms are fatigue, brain fog, and breathlessness/lack of endurance. But the full list of symptoms is long… It’s gotten so bad that I’m out of work. 

I felt brief but significant improvement with low-dose naltrexone, and with low-dose nicotine patches (wasn’t a fan of using that, but it was a successful experiment). 

We’re on a ton of supplements with the guidance of our doctors, but our symptoms are worse than ever, and getting worse with time. We think our microbiomes have been damaged, which the Biomesight results seem to agree with. 

Looking at what is reported for Long COVID, we have few matches:  (5 %ile) 24 of 212, but wtih   Coronary artery disease (93 %ile) 6 of 18. This hints at a different direction which the literature indicating that it is possible.

Patients with COVID-19 were at increased risk of a broad range of cardiovascular disorders including cerebrovascular disorders, dysrhythmias, ischemic and non–ischemic heart disease, pericarditis, myocarditis, heart failure, and thromboembolic disease.

The COVID Heart—One Year After SARS-CoV-2 Infection, Patients Have an Array of Increased Cardiovascular Risks [2022]

As well as Long-term cardiovascular outcomes of COVID-19 [2022].

Review

  • Potential Medical Conditions Detected has nothing of concern
  • Prevotella copri is at 88%ile indicating a significant risk of mycotoxin (from fungi) being present. We also have:
    • ”As with ongoing symptomatic COVID-19, multiple Prevotella species (38) are associated with long COVID. Prevotella species are overrepresented in patients with COVID-19 and are thought to produce proteins that can promote SARS-CoV-2 infection and increase clinical severity of COVID-19 (42).” which may account for the multiple COVID.
  • Dr. Jason Hawrelak Recommendations is at 99.9%ile with low Akkermansia and Bifidobacterium being main item of concern.

We have the typical over representation of bacteria in the 0-9%ile.

PercentileGenusSpecies
0 – 95373
10 – 191618
20 – 291122
30 – 391521
40 – 491523
50 – 591116
60 – 691522
70 – 792417
80 – 891317
90 – 9975

With the following being flagged of concern:

  • Roseburia – 99%ile and 17% of the microbiome
  • Ruminococcus bromii – 96%ile and 5.9% of the microbiome

Roseburia is reported to be decreased in several COVID studies [2021] [2022] [2023] hence the shifts are unlikely to be strongly COVID associated. Similarly a decrease of Ruminococcus is seen after COVID vaccination [2022]. Increases in Ruminococcus is reported in chronic heart failure patients [2018] and atrial fibrillation[2019]

Going Forward

Doing the “Just give Me Suggestions” and then looking at the consensus, we see diet changes at the top of the list:

In other words, lean meat diet.

The top probiotics are:

Going over to KEGG Derived: We see Escherichia coli on the top, with Lacticaseibacillus rhamnosus, Bifidobacterium bifidum, and lactobacillus salivarius being on the positive list (agreement on suggestions with two different algorithms)

I am inclined to suggest diet changes with rotating probiotics every 2 weeks (making sure that you have therapeutic dosages). Retest after 8 weeks and see where we moved to.

Bottom Line

The assumption of typical long COVID or ME/CFS were reasonable assumptions with no microbiome data. You may wish to review other reviews of Long COVID patients. see Analysis Posts on Long COVID and ME/CFS. However, when we add in microbiome data we do not find a match — instead we have indicators of possible cardiac issues arising out of COVID. I would suggest asking for an in depth analysis by your medical professional in this direction.

Microbiome and Vitamin D

For the last decade I have been citing literature for the appropriate dosage levels of Vitamin D. The RDA level is not sufficient for a healthy microbiome — it is sufficient only to stop rickets from occurring.

Some old citations from 2015 Post

  • “Several diseases have been linked to vitamin D deficiency, such as hypertension, diabetes, depression, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and chronic pain syndromes such as fibromyalgia. ” [2013]
  • “Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D concentrations ≤20 ng/mL (50 nmol/L). The overall prevalence rate of vitamin D deficiency was 41.6%,” [2011]
  • “Older adults are advised to maintain serum 25(OH)D concentrations >75 nmol/L.” [2006]
    • Dr. Mercola recommends 45-50 ng/ml or 115-128 nmol/l [source]
  • “Vitamin D intakes required to maintain serum 25(OH)D concentrations of  >80 nmol/L in 97.5% of the sample[of men and women aged 20-40 y] were … 41.1μg/d (1640 IU), respectively.” [2008]
  • “The clinical trial evidence shows that a prolonged intake of 250 mug (10,000 IU)/d of vitamin D(3) is likely to pose no risk of adverse effects in almost all individuals in the general population; this meets the criteria for a tolerable upper intake level.” [2007]
  • “Evidence from clinical trials shows, with a wide margin of confidence, that a prolonged intake of 10,000 IU/d of vitamin D(3) poses no risk of adverse effects for adults,” [2009]
    • NOTE: there was no evidence going 50% higher has any risks. The studies just tested the 10,000IU level.
  • “Vitamin D, important for maintaining bone health in Crohn Disease[CD], may have potential as a treatment for the core inflammatory disease process. There is plausible evidence in favour of vitamin D as an anti-inflammatory from animal models, epidemiological and cross sectional studies of CD.”[2015]
    • “Active Crohn’s disease was associated with low serum 25-OH vitamin D.”[2013]
    • “In addition, low vitamin D has been associated with disease activity in CD patients, and supplementation appears to be beneficial in improving clinical scores and reducing inflammation.” [2014]
    • “Vitamin D is an inexpensive supplement which has been shown to improve IBD outcomes.”[2014]
    • “people with IBD may remain in remission longer when treated with oral vitamin D…suggest that vitamin D may modify the immune response in IBD.” [2015]

And from my 2017 post:

  • “This study demonstrates for the first time a direct antiviral effect of vitamin D in an in vitro infectious virus production system.”[2011]
  • “vitamin D is the environmental factor that most strongly influences autoimmune disease development.”[2015]
  • “A significant negative correlation between vitamin D level and widespread pain index was found.”[2012] i.e. FM
  • Serum 25-Hydroxyvitamin D3 and BAFF Levels Are Associated with Disease Activity in Primary Sjogren’s Syndrome [2017].  “Female SS patients had significantly lower vit D levels  than controls” [2015]
  • “Our findings showed that the high-dose supplementation of vitamin D[9 of 50000 IU cholecalciferol capsules for 3 months taken at weekly intervals] affects measures of systemic inflammation: reductions in High-Sensitivity C-Reactive Protein level and Neutrophil-to-lymphocyte ratio (NLR) distribution.” [2017]
    • “The results of the meta-analysis of 10 trials involving a total of 924 participants showed that vitamin D supplementation significantly decreased the circulating hs-CRP level by 1.08 mg/L” [2014]

This is a good technical discussion: Vitamin D3 Deficiency Results in Dysfunctions of Immunity with Severe Fatigue and Depression in a Variety of Diseases [2014]

I mentioned a formula from 2010 in the first post. Fortunately, there are several Vitamin D calculator available. I put in the numbers from the above post below

Use: https://www.grassrootshealth.net/project/dcalculator/

The numbers agree with my 2015 calculated example. 10,000 IU/day over 3 months

The factor not considered is age. Vitamin D absorption decreases with age;

In addition to classic role of vitamin D in musculoskeletal health over the last decade it was shown that low blood serum concentrations of 25(OH)D are associated with a number of non-skeletal disorders including cancer, high blood pressure, age-related cognitive decline, disorders of the immune and reproductive systems, etc. The prevention of the development of these diseases is reached under considerably higher concentrations of the vitamin in the blood serum, than is necessary to maintain the normal state of the bone tissue, to regulate calcium absorption and homeostasis

[Physiological needs and effective doses of vitamin D for deficiency correction. Current state of the problem [2017]

“Vitamin D was first discovered as the curative agent for nutritional c, and its classical actions are associated with calcium absorption and bone health. However, vitamin D exhibits a number of extra-skeletal effects, particularly in innate immunity. Notably, it stimulates production of pattern recognition receptors, anti-microbial peptides, and cytokines, which are at the forefront of innate immune responses. They play a role in sensing the microbiota, in preventing excessive bacterial overgrowth, and complement the actions of vitamin D signaling in enhancing intestinal barrier function. Vitamin D also favours tolerogenic rather than inflammogenic T cell differentiation and function. Compromised innate immune function and overactive adaptive immunity, as well as defective intestinal barrier function, have been associated with IBD. Importantly, observational and intervention studies support a beneficial role of vitamin D supplementation in patients with Crohn’s disease, a form of IBD. This review summarizes the effects of vitamin D signaling on barrier integrity and innate and adaptive immunity in the gut, as well as on microbial load and composition. Collectively, studies to date reveal that vitamin D signaling has widespread effects on gut homeostasis, and provide a mechanistic basis for potential therapeutic benefit of vitamin D supplementation in IBD.”

Vitamin D signaling in intestinal innate immunity and homeostasis [2017]

There is no appropriate dosage to take without lab results. I know females over 50 that freaked out their physician when they stated that they were taking 20,000 IU of vitamin D3 daily for the last 2 years. Lab tests were quickly ordered!! The lab tests showed her just above the middle of the normal range. The ability to absorb is significantly reduced with IBS, IBD, UC, Crohn’s disease, etc. It’s a matter of getting the labs, take an aggressive dosage for 6 months, retest and then adjust the dosage according to the new results.

“The biggest problem is that MDs are often behind the times and do not work from the latest literature.  For example a single dosage of 600,000 IU of vitamin D is deemed safe on medscape, or 10,000 IU/day for months [source]. One of the studies above cited an average of 60,000 IU/day for 3 months!  [2017]”

From my 2017 post

Target Dosages?

At least 128 nmol/l or 50 ng/mL. You want to be at the TOP of the normal range. You will get push back from MD with higher level because of medical myth that above this is toxic. I say myth because there is no evidence in the literature. There were issues with Vitamin D2 supplements which was sold for a while because it was cheap to produce and is chemically different.

Of 20,308 measurements, 8 percent of the people who had their vitamin D measured had levels greater than 50 ng/mL, and less than 1 percent had levels over 100 ng/mL.

“We found that even in those with high levels of vitamin D over 50 ng/mL, there was not an increased risk of hypercalcemia, or elevated serum calcium, with increasing levels of vitamin D,” says study co-author Thomas D. Thacher, M.D., a family medicine expert at Mayo Clinic. [2015]

Of course, there are some rare DNA mutations that could cause problems with that level. One person’s experience with the details. If you have adverse reaction — get the additional tests described below.

Vitamin D Is Not as Toxic as Was Once Thought: A Historical and an Up-to-Date Perspective [2015]

“(Obese adults require doses 2-3 times higher.)”

“The evidence is clear that vitamin D toxicity is one of the rarest medical conditions and is typically due to intentional or inadvertent intake of extremely high doses of vitamin D (usually in the range of >50,000-100,000 IU/d for months to years).”