Gut microbiome alterations in children with AIS

[Dingo]

Have you checked that article for bias and statistical power? The results are probably false.

1) You are correct, the Yale team's results could be wrong.
2) This needs to replicated a few times for confirmation.

However they didn't simply show that a resistant starch diet ameliorated lupus. Although that would have been an interesting find it wouldn't necessarily explain the cause of the disease.
In this study the first thing they did was show that Lupus was a direct result of harmful stomach bacteria. After explaining the cause of the disease they modified its course with diet. That's what makes this stand out.

The Gut Microbiota Exacerbates Lupus-Related Mortality and Pathogenesis

The TLR7/IFN pathway is central in the pathogenesis of human SLE (Crow, 2014). Thus, we used a TLR7-dependent spontaneous and inducible mouse model to study the role of the microbiota in systemic autoimmunity. Lupus-prone TLR7.1 Tg C57BL/6 mice exhibit an 8- to 16-fold increase in TLR7 expression and spontaneously develop systemic signs of SLE starting at 6 weeks of age (Deane et al., 2007). To induce lupus-like disease in mice not genetically prone to excessive TLR7 signaling, we used topical imiquimod (IMQ), a TLR7 agonist, which was applied to the skin three times a week to 8-week-old wild-type (WT) C57BL/6 mice (Yokogawa et al., 2014). To assess the role of the gut microbiota, we suppressed its growth in both models using broad-spectrum antibiotics (ABX) or a GF state (Figure S1A). These interventions led to significantly increased survival (Figure 1A), decreased splenomegaly and hepatomegaly (Figure 1B), and decreased type I IFN gene expression in ileum and spleen as well as type I IFN secretion in the blood (Figures 1C and 1D). Consistent with systemic IFN levels, pDCs accumulated in spleen, mesenteric lymph nodes (MLN), and Peyer’s patches (PP) in both models and were also suppressed by antibiotics or a GF state (Figures 1E and 1F).

Blood disorders (anemia and leukocytosis) were normalized in antibiotic-treated mice and in the GF setting, suggesting that particularly these manifestations are microbiota dependent (Figure S1B). Antibiotics decreased bone marrow cellular depletion, and restored granulocyte-monocyte and megakaryocyte-erythrocyte progenitor populations (Figures S1C–S1E), thereby preventing IFN-dependent emergency myelopoiesis (Buechler et al., 2013). Finally, depletion of the gut microbiota decreased renal injury due to immune cell infiltration and nephritis (Figures 1G, 1H, and S1F) and improved renal physiology by decreasing proteinuria (Figure 1I).

These data indicate that the gut microbiota is needed for TLR7-dependent systemic autoimmunity. We next defined the gut microbial community structure in both models in order to identify potential pathobionts driving lupus pathogenesis.

If this finding is confirmed by other researchers it will prove that common diseases can be caused and cured by the Microbiome. That means any disease including maybe Scoliosis or anything else. It will change forever the way we look at common diseases.

[Pooka1]

https://www.tandfonline.com/doi/full...X.2018.1519395


Special Report
The role of gut microbiota in lupus: what we know in 2018?
Lorena Ruiz, Patricia López, Ana Suárez, Borja Sánchez & Abelardo Margolles
Pages 787-792 | Received 08 Jul 2018, Accepted 30 Aug 2018, Accepted author version posted online: 03 Sep 2018, Published online: 08 Sep 2018
Download citation https://doi.org/10.1080/1744666X.2018.1519395


ABSTRACT
Introduction: The role of the human intestinal microbiota in the maintenance of a healthy physiological condition, as well as its relation to the development of disease, remains to be clarified. Current evidence suggests that intestinal microbes could be involved in the initiation and amplification of autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus (SLE). Despite recent progress in understanding how these microbes influence the pathophysiology of lupus, studies are still limited.

Areas covered: In this review, we have tried to summarize the most relevant findings that have contributed to our understanding of the links between the human intestinal microbiota and the development of lupus. We also describe the potential role of individual microbial players in the physiology of lupus, and how they can shape relevant immune responses.

Expert commentary: Culture-independent techniques based on massive sequencing represent a powerful tool to unravel the biological activity of gut microbes. Current data demonstrates that, depending on the pattern of intestinal microorganisms or the presence of specific bacteria, different responses related to lupus physiology can be triggered. Fecal microbiota transplantation, live biotherapeutics, or dietary interventions targeting the microbiota will likely become a treatment for SLE.

KEYWORDS: Systemic lupus erythematosus, microbiota, microbiome, autoimmune diseases, dysbiosis
Additional information
Funding
This paper is not funded.

[Pooka1]

You mentioned Prevotella. This article mentions Prevotella and confounders.

Human gut microbiome: hopes, threats and promises
Patrice D Cani

Abstract
The microbiome has received increasing attention over
the last 15 years. Although gut microbes have been
explored for several decades, investigations of the role
of microorganisms that reside in the human gut has
attracted much attention beyond classical infectious
diseases. For example, numerous studies have reported
changes in the gut microbiota during not only obesity,
diabetes, and liver diseases but also cancer and even
neurodegenerative diseases. The human gut microbiota
is viewed as a potential source of novel therapeutics.
Between 2013 and 2017, the number of publications
focusing on the gut microbiota was, remarkably, 12
900, which represents four-fifths of the total number
of publications over the last 40 years that investigated
this topic. This review discusses recent evidence of the
impact of the gut microbiota on metabolic disorders
and focus on selected key mechanisms. This review
also aims to provide a critical analysis of the current
knowledge in this field, identify putative key issues or
problems and discuss misinterpretations. The abundance
of metagenomic data generated on comparing diseased
and healthy subjects can lead to the erroneous claim
that a bacterium is causally linked with the protection
or the onset of a disease. In fact, environmental factors
such as dietary habits, drug treatments, intestinal motility
and stool frequency and consistency are all factors that
influence the composition of the microbiota and should
be considered. The cases of the bacteria Prevotella copri
and Akkermansia muciniphila will be discussed as key
examples.

On top of that, at the level of our knowledge, it is still very
difficult to fully decipher the role of any microorganism in a
complex community such as the gut microbiota. This last point
is illustrated by two specific examples: the cases of two bacteria
that is Prevotella copri and Akkermansia muciniphila.

Conclusion and perspectives
We are living with a tremendous amount of microorganisms
in our guts, ranging from bacteria, archaea to virus and fungi.
There is no doubt about the fact that we have progressed in the
analysis of the composition of the microbiota and of the key
metabolites produced and even in the discovery and isolation
of novel bacteria. However, we must acknowledge that a large
number of the studies published the last couple of years have
reported differences in the microbiome under different conditions. Although most of them are very well performed, we still
need more work to go beyond the simple associations and we
need to provide as much as possible more complex analysis
(eg, multiomics and time series measurements) if we want to
finally approach the final causality. Indeed, simple associations
may lead to misinterpretation or overselling of expected results
when translated into the human context. Thus, both types of
approaches are important, that is, comparing diseased and
healthy conditions and then showing the causality as a proof
of concept. However, the general population as well as health
practitioners should be rigorous when drawing conclusions
from papers that assume that the discovery of differences in gut
microbiota composition is potentially strongly associated with a
specific disease or its overall evolution (box 1).

https://gut.bmj.com/content/gutjnl/67/9/1716.full.pdf

[Pooka1]

This article discusses one of the fundamental roadblocks in gut microbiome research which is the same roadblock in other bacterial studies in natural environments... only a small fraction of the species can be cultured yet genomic analysis yields a multitude of species but we don't know what they do because we can't culture them. Then there is the issue of how the bacteria operate in monoculture versus what they are really doing in the microbial consortium in the gut.

This is why the researchers in this area admit virtually nothing is known and we are decades away from real knowledge.

http://www.aaem.pl/Methods-of-analys...72200,0,2.html

[Pooka1]

1) You are correct, the Yale team's results could be wrong.
2) This needs to replicated a few times for confirmation.

However they didn't simply show that a resistant starch diet ameliorated lupus. Although that would have been an interesting find it wouldn't necessarily explain the cause of the disease.
In this study the first thing they did was show that Lupus was a direct result of harmful stomach bacteria. After explaining the cause of the disease they modified its course with diet. That's what makes this stand out.

You have cited a mouse study. Here is the deal with mouse studies in general...

https://www.realclearscience.com/blo...aningless.html

In 2006, a team of scientists from the University of Toronto reviewed 76 of the most highly cited animal studies published between 1980 and 2000, the vast majority published in prestigious journals like Cell, Science, and Nature. The reviewers found that only 37 percent of the works had been replicated in randomized trials on humans. Of the remaining 48 studies, 14 were contradicted in further trials and 34 remained untested more than a decade after being published.

The outlook for successfully translating cancer treatments from animals to humans is much worse. Only eight percent usually make the cut. The rate for stroke may be even more abysmal. When Malcolm Macleod, a Scottish neurologist at the University of Edinburgh, went hunting for new stroke therapies back in 2003, he and his colleagues found 603 drugs which had been tested on animals. Of those, only 97 ended up being tested in humans, and just one worked.

Ti Ed was correct about zebra fish studies probably being limited to zebrafish until they are shown to be correct in humans. I thought that one zebrafish study settled the matter of IS etiology but I see research is still going on in genetics so apparently it did not.

[titaniumed]

I have missed out due to Christmas related distractions......

In our quest for answers, clues are helpful and offer some hope. We cant help getting excited about finding some sort of pay dirt....But when it comes to finding gold, it takes a lot of miners in the search. If only it were that easy.....

I must say that this has been an excellent thread even though I feel like crying about this subject matter. (medical research)

All we can do is keep looking and trying...

Time for eggnog.
I will have to add more booze to kill off some the pathogenic microorganism's (smileyface) WARNING! These are NOT a probiotic smoothie's.
https://www.townandcountrymag.com/le...ggnog-recipes/

Merry Christmas everyone

Ed

[Pooka1]

Time for eggnog.
I will have to add more booze to kill off some the pathogenic microorganism's (smileyface) WARNING! These are NOT a probiotic smoothie's.
https://www.townandcountrymag.com/le...ggnog-recipes/

Merry Christmas everyone

Ed

Merry Christmas Ed! I looked at that link for a vegan recipe but did't find one. :-(

I truly hope that the solution to IS is NOT anything to do with the gut microbiome because it may not get more complex. At this point it is not just known unknowns but plenty of unknown unknowns. This field is not just in its infancy but in its premature infancy.

[Pooka1]

You take a look at a few of Dr Boachies extreme spine patients in Africa, and that kind of makes you wonder about diet, and its relationship to scoliosis.....

Despite the large differences in diet, contact with dirt, etc. the incidence of idiopathic sclerosis is nearly uniform around the world. This speaks to a very deep genetic reason that evolved early in human evolution and that an environmental trigger, if it exists, must also be uniform in distribution around the world.

[titaniumed]

I made it through the eggnog. No high speed ER room trips were required. (smiley face)

Here is a Scoliosis epidemiology study or studies from many countries....Interesting and loaded with various stats. Male/Female ratio is highest in Nigeria. Looks like Turkey has the lowest prevalence of scoliosis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957389/

Chongming Island (Near Shanghai) has a 2.52% figure....

On the subject of diet in Africa, I would imagine that not eating a balanced diet or simply starving one's self would weaken ones immune system resulting in some sort of disease, then the large scoliosis curves form. Not necessarily lack of diet directly resulting in a scoliosis.

In regards to longevity, do people live longer because of diet, or from prevention of diseases? Jean Calment was the longest lived human at 122, everyone looks at what the secret to her diet was....She was a smoker for 96 years. I guess she had good genes....
https://en.wikipedia.org/wiki/Jeanne_Calment
Ed

[Pooka1]

I made it through the eggnog. No high speed ER room trips were required. (smiley face)

Yay! One-Of-Two and Two-Of-Two are home from college/grad school and it is nice to be together.

Here is a Scoliosis epidemiology study or studies from many countries....Interesting and loaded with various stats. Male/Female ratio is highest in Nigeria. Looks like Turkey has the lowest prevalence of scoliosis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957389/

Chongming Island (Near Shanghai) has a 2.52% figure...

The claim is that the incidence of (I believe) adolescent idiopathic scolisois is 2-3%. Their result is 2.52% (too many significant figures there perhaps) but includes juvenile cases. I don't see the problem since AIS >> JIS in number. In re the other studies, I wonder if the study groups were well chosen and if they limited the results to AIS. There is some reason people keep citing 2-3% worldwide. I will try to find that reason. I am guessing they are culling the literature of incidence reports and just using the ones that were done correctly (large random groups, etc.).

Also the various studies cited apparently used different criteria for incidence. If they standardized on just AIS and ruled out non-idiopathic scoliosis and used large random groups, may be they would get to the 2-3% for all those studies

As an aside, they are claiming their r^2 of 0.18 for age driving Cobb angle is somehow meaningful. I don't make correlation claims unless the r^2 is >0.6. Big difference! Just sayin'. Also I think if they didn't left-censor the data at 10 degrees that might affect the r^2.

In regards to longevity, do people live longer because of diet, or from prevention of diseases? Jean Calment was the longest lived human at 122, everyone looks at what the secret to her diet was....She was a smoker for 96 years. I guess she had good genes....
https://en.wikipedia.org/wiki/Jeanne_Calment
Ed

Good genes no doubt!

[titaniumed]

Sounds like its time for Tea for Two.... My dad used to play that one on the Hammond organ. (Blast from the past)
https://www.youtube.com/watch?v=D0MtzQDltr0

Nice to have your daughters back for the holidays....We didn't get to have Crystal come home which creates this emptiness, void feeling even after all these years. Empty nest takes a long time, there is actually no recovery from this.

Cant comment on the study groups, but seeing more and more Chinese studies lately which is good to see.

Correction....It looks like India has a lower prevalence rate than Turkey. .13% in India is the lowest value.
and 43% of those found in India have polio which creates an even lower value.
https://www.ncbi.nlm.nih.gov/pubmed/3440651

The consensus might be adding in kyphosis patients to reach the 3% value.

Ed

[Pooka1]

So sorry Crystal could not make it back home. Easter is coming up...

The Indian study you cited may just prove that not doing radiographs underestimates the incidence of scoliosis. I continue to marvel at how some studies ever get published. I think we may be seeing an object lesson in why a majority of published research results are false unless the authors talk about correlating scoliometer indications with radiographic evidence for curves >10*.

[Pooka1]

Here is a recent article that selects a handful of articles to derive a prevalence of 0.47–5.2 % for AIS... all are school screenings...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566258/

Here they talk about the limitations of this approach...

Discussion
Present data show an overall prevalence of AIS of 0.47–5.2 %. The prevalence and severity of scoliosis is higher in girls than in boys. All data were obtained by school screening, and yet school screening is the most effective method for creating epidemiological data of adolescent scoliosis. However, school screening programs have many limitations which have been well described by Fong et al. [45]: The overall positive predictive value for detecting curves ≥10° and ≥20° were low, indicating that school screening has not been conducted effectively, and they showed a high heterogeneity of study designs across all screening programmes [45]. They also investigated the effectiveness of the Adams forward-bending test [46] and concluded that it was very low! If additional tests like angle of trunk rotation or Moiré topography were used, the effectiveness of screening could be improved, but so far no test could produce substantial benefit with a sufficient level of evidence [45].

Main individual limitations of the screening studies we cited:

Kamtsiuris [17] provided very good epidemiologic data, but they did not provide exact criteria of diagnosis of scoliosis. It also remains unclear who established the diagnosis of scoliosis: General practitioner or orthopedic surgeon.

Cilli [22] and Nery [19] only investigated children in the age range of 10–15 years, excluding important other age groups.

The lower prevalence of scoliosis in the study of Cilli [22] could be related to the age group investigated: They enrolled children from 10 to 15 years, whereas Daruwalla [20] showed that the highest prevalence of scoliosis is in girls that are older than 15 years. Kamtsiuris [17] also found highest prevalence in children of 14–17 years. Daruwalla [20] did only investigate age groups (6–7, 11–12 and 16–17 years) and they only enrolled females in the group of 16–17 years, and Suh [18] investigated only two age groups (10–12 and 13–14 years). Wong [21] also enrolled only children from 9 to 14 years and included curves <10°. The other epidemiologic studies mentioned above also did not explicitly exclude curves <10°.

Soucacos [23] conducted a very good study in Greece, describing his exact parameters for diagnosis of scoliosis. All listed epidemiologic studies used the Adams forward-bending test [46] for primary screening and performed radiologic diagnostics only when this test was positive, but Soucacos [23] was the only one who explicitly had the school screening tests performed by orthopedic surgeons, and not by nurses or other non-academic medical staff, diminishing the bias of his results.

However, the limitation of his study is again the investigated age group (9–14 years), excluding older adolescent children.

Investigation of comparable age groups is difficult because of differences in culture and school systems in the individual countries. In Singapore, for example, in the age group of 16–17 years there are only girls at school because the boys have to attend military service at that age [20].

Another bias mentioned in nearly all epidemiologic studies is that they do not consider the psychological impact of scoliosis on children, although it has been described extensively in current literature [47–49]. Young girls particularly, but also boys, that have deformities might feel embarrassed when being examined in school. When these children fall “ill” because of this embarrassment or beg their parents to refuse the examination and miss the school screening, a substantial bias is the consequence. Only one study [23] deals with that important potential bias and describes how the children are prepared psychologically for the examination and how fears and anxieties are dealt with.

-------------------

Here is the American Association of Neurological Surgeons repeating the 2-3% but don't list a reference...

https://www.aans.org/Patients/Neuros...ents/Scoliosis

Incidence and Prevalence
Scoliosis affects 2-3 percent of the population, or an estimated six to nine million people in the United States.

----------------

[Pooka1]

I found the reference for 2-3%... Weinstein (1988) but it is a course lecture and not the original references. I would have to find the references he uses to assess it. The truthiness of the 2-3% rate will rise or fall on the quality of those studies.

http://www.boneandjointburden.org/20...thic-scoliosis

-------------------

Here are four references in a paper that cites a rate of 2-4%... (https://www.aafp.org/afp/2014/0201/p193.html)

1. Lonstein JE. Adolescent idiopathic scoliosis. Lancet. 1994;344(8934):1407–1412.

2. Smith JR, Sciubba DM, Samdani AF. Scoliosis: a straightforward approach to diagnosis and management. JAAPA. 2008;21(11):40–45.

3. Reamy BV, Slakey JB. Adolescent idiopathic scoliosis: review and current concepts. Am Fam Physician. 2001;64(1):111–116.

4. Roach JW. Adolescent idiopathic scoliosis. Orthop Clin North Am. 1999;30(3):353–365, vii–viii.

I don't have the patience to chase these down. At this point I do not know how much ground the 2-3% figure stands on. Maybe very little despite the fact that it is bandied about so much.

I just listened to some POSNA videos and was mildly appalled at the credulity of some surgeons in regards the literature. Only one mentioned possible problems with published results. I feel like sending the paper showing most studies are false to those surgeons.

[Pooka1]

Idiopathic scoliosis is about 2-3% all over the world.

Upthread I had referred to this rate as "incidence". I see that it is actually the "prevalence" (percent) in the population.

I cannot find any mention of the incidence (new cases per time) of AIS in general. The incidence of AIS with one parent affected is generally stated to be 30% and is over 50% if both parents have AIS.

Assuming 90% of people have kids and 2.5% of those parents have AIS and there is a 30% chance the child will have AIS from one affected parent then the incidence is a very tiny number... 0.00675 or 0.675% if I did that correctly.