A big, successful trial of probiotics(theatlantic.com)
theatlantic.com
A big, successful trial of probiotics
https://www.theatlantic.com/science/archive/2017/08/at-last-a-big-successful-trial-of-probiotics/537093/?single_page=true
69 comments
Pediatric MD PhD. These are exciting results.
Sepsis among neonates is a major concern, even in the developed world. Babies new to the world have very weak immune systems, particularly with regard to antibody response which is initially almost entirely composed of waning amounts of transplacental IgA. This paper points out the the developing world has even higher rates of infant mortality from bacterial sepsis. So this is a big problem and impactful solutions have been tough to come by.
This is a large double-blind placebo controlled trial. They gave eligible babies 7 consecutive daily doses of either placebo or the study agent. Table 1 shows that both study groups are very similar, so we should not be too concerned with confounding variables. Table 2 shows the striking data re: sepsis death rates, with this "synbiotic" (probiotic bacteria + bacterial food) reducing death from sepsis by almost half(!). Table 3 looks at all causes of death and importantly, significant differences in other causes of death were not observed between the two groups--it wouldn't be all that helpful if this synbiotic group seemed to get some other serious problem as a side effect. It is a pretty straight-forward study and no major flaws in their methods or conclusions jump out at me.
While exciting overall, the authors point out some important points at the end. I think the most interesting is that they used this particular species of lactobacillus after studying babies in India about 20 years ago and finding differences in the rates of colonization with this and other probiotic species. In other words, they didn't just throw any sort of "good bacteria" at these babies--they had strong evidence to show that it actually colonized them and therefore could , in theory, have an effect on rates of sepsis. If they had used lactobacillus GG (one of the other species that they found had low rates of colonization), it would stand to reason that they wouldn't have gotten such an impressive effect or maybe none at all. Then the media would say, "probiotics don't save babies from sepsis." Basically I'm just applauding their careful selection of this bacterial species.
One final important note is that this result should not be generalized to other populations without future studies showing similar effects. The gut microbiome is influenced by geography and other environmental factors and interacts heavily with out immune systems, large parts of which vary by genetic background. To put it another way, just because this bacterial species works well in rural India does not mean it will work well in Peru or anywhere else.
Sepsis among neonates is a major concern, even in the developed world. Babies new to the world have very weak immune systems, particularly with regard to antibody response which is initially almost entirely composed of waning amounts of transplacental IgA. This paper points out the the developing world has even higher rates of infant mortality from bacterial sepsis. So this is a big problem and impactful solutions have been tough to come by.
This is a large double-blind placebo controlled trial. They gave eligible babies 7 consecutive daily doses of either placebo or the study agent. Table 1 shows that both study groups are very similar, so we should not be too concerned with confounding variables. Table 2 shows the striking data re: sepsis death rates, with this "synbiotic" (probiotic bacteria + bacterial food) reducing death from sepsis by almost half(!). Table 3 looks at all causes of death and importantly, significant differences in other causes of death were not observed between the two groups--it wouldn't be all that helpful if this synbiotic group seemed to get some other serious problem as a side effect. It is a pretty straight-forward study and no major flaws in their methods or conclusions jump out at me.
While exciting overall, the authors point out some important points at the end. I think the most interesting is that they used this particular species of lactobacillus after studying babies in India about 20 years ago and finding differences in the rates of colonization with this and other probiotic species. In other words, they didn't just throw any sort of "good bacteria" at these babies--they had strong evidence to show that it actually colonized them and therefore could , in theory, have an effect on rates of sepsis. If they had used lactobacillus GG (one of the other species that they found had low rates of colonization), it would stand to reason that they wouldn't have gotten such an impressive effect or maybe none at all. Then the media would say, "probiotics don't save babies from sepsis." Basically I'm just applauding their careful selection of this bacterial species.
One final important note is that this result should not be generalized to other populations without future studies showing similar effects. The gut microbiome is influenced by geography and other environmental factors and interacts heavily with out immune systems, large parts of which vary by genetic background. To put it another way, just because this bacterial species works well in rural India does not mean it will work well in Peru or anywhere else.
Outstanding comment. Thank you.
Not a GI specialist here, but I've read plenty of randomized controlled trials. The one-liner here might be "high quality[1] study shows substantial reduction in infant infections in rural India[2]." The biological mechanism makes sense, and as discussed in the article could be more than just good bacteria fighting off bad bacteria. A cynic may say the immunomodulation stuff is kind of hand-wavy and not being a GI specialist, pediatrician or immunologist myself I don't know. That would be an important point because all infections were reduced (not just GI infections), which may point to confounding variables. More on that later.
[2] As far as how the study applies to most of Europe and the US where infant mortality is 10x less, hard to say. The number of infants needed to treat to prevent a single infection was 27 which is low assuming these drugs are cheap and without side effects. Immediate side effects are unlikely given the low and comparable drop out rates among control and treatment groups. However, long-term effects are unknown given the timeframe of the study. Forming a recommendation for countries with more rigorous pasteurization/food preparation/etc, perhaps more access to care and well-child checkups, and much lower infant mortality in general isn't particularly easy here. I'm not up to date on other studies with probiotics. Again, not my specialty.
[1] The study quality looks sound and exclusions were reasonable, the control (placebo) and treatment groups matched up well in many ways and were sizable. There wasn't very much in the way of dropouts. The study looked at too small a population to determine differences in infant deaths, if there is one at all.
[2] As far as how the study applies to most of Europe and the US where infant mortality is 10x less, hard to say. The number of infants needed to treat to prevent a single infection was 27 which is low assuming these drugs are cheap and without side effects. Immediate side effects are unlikely given the low and comparable drop out rates among control and treatment groups. However, long-term effects are unknown given the timeframe of the study. Forming a recommendation for countries with more rigorous pasteurization/food preparation/etc, perhaps more access to care and well-child checkups, and much lower infant mortality in general isn't particularly easy here. I'm not up to date on other studies with probiotics. Again, not my specialty.
[1] The study quality looks sound and exclusions were reasonable, the control (placebo) and treatment groups matched up well in many ways and were sizable. There wasn't very much in the way of dropouts. The study looked at too small a population to determine differences in infant deaths, if there is one at all.
Problem solved http://sci-hub.io/10.1038/nature23480
Spasiba Russia.
Spasiba Russia.
If you want to try L. Plantarum yourself, get the strain 299v if you can. There's one by Jarrow (not affiliated, just made good experiences with it). AFAIK, most other strains of L. Plantarum produce D-lactic acid, while 299v produces L-lactic acid (I've even seen a paper where they used 299v to treat acidosis). D-lactic acid can be hard to metabolize and can lead to acidosis. Probiotics-induced acidosis is a thing - not good, most people with this end up in hospital and need infusions and some kind of intervention for the long term.
Acidophilus generally produces D-lactic acid, while e.g. L casei shirota (Yakult) does not. It pays to take a hard look at the strains in a probiotic.
Acidophilus generally produces D-lactic acid, while e.g. L casei shirota (Yakult) does not. It pays to take a hard look at the strains in a probiotic.
Just did a quick online search, and it seems that D-lactic acid might be responsible for Chronic Fatigue Syndrome too. This is something I'm going to read up more in the next few days.
Are there any good resources on this?
Are there any good resources on this?
I find the word probiotic to be inherently problematic. It includes any and all microorganisms that have a single positive health benefit, whether or not they're detrimental in other regards. That if a bacteria were to penerate gut epithelium (very bad), it would still be a probiotic if it reduced constupation.
Even if the research supporting the health benefits of a supplemental bacteria is sound, a single study always has a restricted scope.
It's saddening that 'probiotics' have found their way to products such as baby formula, while there is pretty much no regulation governing their sales and use (at least in Europe).
Even if the research supporting the health benefits of a supplemental bacteria is sound, a single study always has a restricted scope.
It's saddening that 'probiotics' have found their way to products such as baby formula, while there is pretty much no regulation governing their sales and use (at least in Europe).
In my opinion, the word antibiotic is even more problematic.
In a recent survey, 13% of practitioners admitted to having used sedatives or antibiotics as placebos:
https://www.sciencedaily.com/releases/2008/10/081023195216.h...
To me, antibiotics are an example of dangerous superstition rearing its nasty head right there smack in the middle an institution that prides itself as rational and superior.
I think pre-med and med school students should be required to take courses in chaos theory and ecology, as well as open minded primers on alternative and preventative medicines, not so much to advocate or practice them, but so they can have a better sense of medicine as an artform.
In a recent survey, 13% of practitioners admitted to having used sedatives or antibiotics as placebos:
https://www.sciencedaily.com/releases/2008/10/081023195216.h...
To me, antibiotics are an example of dangerous superstition rearing its nasty head right there smack in the middle an institution that prides itself as rational and superior.
I think pre-med and med school students should be required to take courses in chaos theory and ecology, as well as open minded primers on alternative and preventative medicines, not so much to advocate or practice them, but so they can have a better sense of medicine as an artform.
Or maybe just have Jeff Goldblum tell them that they're so preoccupied with whether they could that they didn't stop to think about whether they should. And that life finds a way.
Yeah they should be required to watch Jurassic Park (the original ONLY though the new one is garbage propaganda)
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The 9% placebo and even the 5% treatment sepsis rate seems very high. According to http://emedicine.medscape.com/article/978352-overview#a6 the US rate of neonatal sepsis is around 2/1000 live births so around 0.2%.
Given this, I wonder how applicable these results would be to neonates in the US.
Given this, I wonder how applicable these results would be to neonates in the US.
The US generally has clean water. The third world, and India in particular, frequently do not.
That said, the other immune boosts are interesting here. And what would be doubly interesting is to figure out probiotics that prevent allergies.
We've known for years that a child who is exposed to real illnesses in a dirty environment may die from that, but won't generally go on to develop asthma. In the developed world we have a lot of health problems coming from the immune system looking so hard for threats that it starts attacking your own body.
There is very, very good reason to believe that the right probiotics would solve this problem. However discovering what those probiotics are is not so simple...
That said, the other immune boosts are interesting here. And what would be doubly interesting is to figure out probiotics that prevent allergies.
We've known for years that a child who is exposed to real illnesses in a dirty environment may die from that, but won't generally go on to develop asthma. In the developed world we have a lot of health problems coming from the immune system looking so hard for threats that it starts attacking your own body.
There is very, very good reason to believe that the right probiotics would solve this problem. However discovering what those probiotics are is not so simple...
Hygiene hypothesis hasn't been proven yet.
It may not be conclusively proven, but there is strong supporting evidence. See, for example, http://www.jacionline.org/article/S0091-6749(15)01193-8/abst....
It may be that because of diet or other factors, this just wouldn't be as useful in the US.
No, it suggests something in the US is vastly more effective in preventing sepsis than this probiotic concoction.
Access to clean water...
They initially planned to include 8000 babies, but stopped early. With only a week of treatment they already found a significant decrease in sepsis rates. They stopped because they thought it'd be highly unethical to deprive the other babies of a life-saving treatment. This is a heartwarming example of when humanity and science conflict, but I'm glad humanity won
That's standard procedure for clinical trials.
Aside from preventing sepsis, it also reduced the risk of infections by both the major groups of bacteria: the Gram-positives, by 82 percent; and the Gram-negatives, which are harder to treat with antibiotics, by 75 percent. It even reduced the risk of pneumonia and other infections of the airways by 34 percent. That was “completely unexpected,” says Panigrahi, and it’s the result he’s especially excited about. It suggests that the synbiotic isn’t just acting within the gut, but also giving the infants’ immune systems a body-wide boost.
I don't know why they are so surprised. Given that some sources say the gut constitutes up to 70 percent of the immune system, it should be fairly obvious that improving gut health will have such effects.
Furthermore, you can infer a fairly direct relationship between gut health and lung health based on what happens in the body at altitude: You start urinating more to compensate for the thin air reducing your ability to exhale wastes. The body starts clearing them out of the blood by shunting them to the kidneys.
I don't know why they are so surprised. Given that some sources say the gut constitutes up to 70 percent of the immune system, it should be fairly obvious that improving gut health will have such effects.
Furthermore, you can infer a fairly direct relationship between gut health and lung health based on what happens in the body at altitude: You start urinating more to compensate for the thin air reducing your ability to exhale wastes. The body starts clearing them out of the blood by shunting them to the kidneys.
But a single strain of bacteria can do that? I would say that’s pretty surprising and if so a major discovery. I don’t currently have any such magic pills that I’m taking...
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The trial looks to be exceptionally rigorous and the sample size is very large. This is exciting science to say the least!
Interesting. I was skeptical of probiotics but the evidence seems to be suggesting otherwise.
This kind of builds on meta-analyses showing that probiotic use cuts rates of antibiotic-associated C. difficile infection.
Young children have very unstable microflora systems, so the results make sense from that perspective also.
This kind of builds on meta-analyses showing that probiotic use cuts rates of antibiotic-associated C. difficile infection.
Young children have very unstable microflora systems, so the results make sense from that perspective also.
I can recommend https://en.wikipedia.org/wiki/Lactobacillus_reuteri
"Similar results have been found in adults; those consuming L. reuteri daily end up falling ill 50% less often, as measured by their decrease use of sick leave."
"Similar results have been found in adults; those consuming L. reuteri daily end up falling ill 50% less often, as measured by their decrease use of sick leave."
Why the use of a placebo in a trial involving babies? Surely they would be immune to any placebo effect?
The researchers and their parents won't be though.
It's a double-blind study. The people conducting the study should not know who is in which group. They should be randomly administering either a probiotic or an identical looking placebo.
My issue isn't on the faith in probiotics side...the problem is which ones do I buy.
It's near impossible to know you're getting the good stuff so to speak.
It's near impossible to know you're getting the good stuff so to speak.
It really depends on what you need. I would be careful around soil based species, and avoid D-lactic acid producers (which eliminates a whole lot of probiotics), but apart from that you can just get what you need. E.g. if you have a problem with histamine intolerance you could go for strains that eat/reduce histamine. If you want better mood, you could try L Plantarum 299v or Bifidobacterium Longum or L casei shirota.
If you want to lose weight, Christensenella minuta is worth examining. The research[1,2] is preliminary, and I wouldn't trust any commercial preparations without validation, but it is compelling.
1. http://www.ctl.cornell.edu/events/celebration15/posters/Wate...
2. http://www.cell.com/abstract/S0092-8674(14)01241-0
1. http://www.ctl.cornell.edu/events/celebration15/posters/Wate...
2. http://www.cell.com/abstract/S0092-8674(14)01241-0
I'm intrigued by what mechanism this happens. Would be great if it changed the "fat set point" in the hypothalamus by reducing inflammation there (https://news.ycombinator.com/item?id=14932541).
Last time I tried a strain from the clostridia family (butyricum) I had an adverse reaction, so I might not be able to use this. But, everybody's different.
Last time I tried a strain from the clostridia family (butyricum) I had an adverse reaction, so I might not be able to use this. But, everybody's different.
Is there somewhere this is commercially available?
My point was rather that how do I know the bacteria aren't 100% dead?
Thanks for the details on strains though. :)
Thanks for the details on strains though. :)
Could you suggest some reliable sources of information on finding/comparing probiotics?
I've had a lot of luck with this brand: https://www.amazon.com/Dr-Mercola-Complete-Probiotics-Supple.... Take 2 each AM.
By "luck" I mean I haven't got the common cold in over 2 years since I started taking them. I'm sure there are other variables I'm not taking into account, e.g., exercise and healthy eating, my age (35), etc. but they're inexpensive and I don't see any reason not to take them.
EDIT: here are the strains that this brand includes (notably Lactobacillus plantarum, as mentioned in the study):
Lactobacillus acidophilus DDS-1, Bifidobacterium lactis, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus brevis, Bifidobacterium longum, Lactobacillus salivarius, streptococcus thermophilus, and Bifidobacterium bifidum
By "luck" I mean I haven't got the common cold in over 2 years since I started taking them. I'm sure there are other variables I'm not taking into account, e.g., exercise and healthy eating, my age (35), etc. but they're inexpensive and I don't see any reason not to take them.
EDIT: here are the strains that this brand includes (notably Lactobacillus plantarum, as mentioned in the study):
Lactobacillus acidophilus DDS-1, Bifidobacterium lactis, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus brevis, Bifidobacterium longum, Lactobacillus salivarius, streptococcus thermophilus, and Bifidobacterium bifidum
I can recommend https://en.wikipedia.org/wiki/Lactobacillus_reuteri . Try these ones: https://www.biogaia.com/
Does yoghurt have the good stuff?
The study was done on newborns just starting breastfeeding, but doesn't say whether only vaginal births or if C-sections were included.
99.8% and 99.7% of the births were vaginal for those receiving the placebo and the probiotics, respectively.
https://www.nature.com/articles/nature23480.epdf
https://www.nature.com/articles/nature23480.epdf
All the products containing Lactobacillus plantarum may see a boost in sales.
This strain is in milk kefir, no? Easy to cultivate at home.
See also: http://www.bbc.co.uk/news/health-38800977
Water kefir is also available :)
See also: http://www.bbc.co.uk/news/health-38800977
Water kefir is also available :)
Anecdotal: I recently started taking Milk Kefir and it has been a life changer. I never thought I had any problems till they were resolved by Kefir. Seen great improvements in energy levels and anxiety. It even fixed the minor IBS I had.
Factory produced Kefir has very few probiotics. They were removed intentionally. So maybe just placebo.
I actually make it at home as Kefir isn't sold in my country :). I couldn't yet take a call on whether its a placebo or not. My partner says its placebo effect too but I don't think so.
Can you please give some details on how you take it?
I bought the grains locally and use them to ferment milk for 24 hours (I live near equator so you might have to adjust for your climate). I strain the kefir - seperate out the grains - add some milk and store in the refrigerator for a week (so basically I make it once a week). I store the seperated kefir again in the refrigerator. I take one cup after lunch and one before sleeping (without any additives or even sugar).
> See also: http://www.bbc.co.uk/news/health-38800977
I don't see anything in the article about Lactobacillus plantarum, and there's quite a few strains of Lactobacillus out there.
I don't see anything in the article about Lactobacillus plantarum, and there's quite a few strains of Lactobacillus out there.
List of all the strains:
https://www.yemoos.com/pages/milk-kefir-strains
Depends on your kefir. Kefirs are unpredictable and they CAN go bad. Just be careful with that stuff, or even let a lab analyze yours if you can. Drinking up to 50 billion organisms (in one glass) every day has the potential to shift your microbiome for the better, or the worse.
When my son was born I did a bunch is research on probiotics with good scientific evidence of efficacy. I ended up getting him these which contain most of the promising/researched strains. It's also a liquid which helps in giving it to a baby. I'm pretty convinced that a good probiotic and Onega3 supliment are extremely beneficial.
https://www.amazon.com/BIOAMICUS-COMPLETE-Toddler-Probiotic-...
https://www.amazon.com/BIOAMICUS-COMPLETE-Toddler-Probiotic-...
I would have a hard time trusting amazon to sell the actual product here and not a knock off.
Good point. And certainly not trying to plug amazon, I think the product is available direct from the manufacturer for about the same price.
Probiotics are in general a bit iffy in terms of knowing what you are getting. Also makes a huge difference what kind of heat history it has seen in terms of actual live cell counts (i.e. Sitting in warehouse or hot UPS truck, etc)
Probiotics are in general a bit iffy in terms of knowing what you are getting. Also makes a huge difference what kind of heat history it has seen in terms of actual live cell counts (i.e. Sitting in warehouse or hot UPS truck, etc)
are there any though? From the article, it seems that they had to cultivate the colonies themselves.
VSL#3 has them (amongst others). Not sure whether it's the "ATCC strain 202195", though.
https://vsl3.com/about-vsl/
https://vsl3.com/about-vsl/
Streptococcus thermophilus
Bifidobacterium breve
Bifidobacterium longum
Bifidobacterium infantis
Lactobacillus acidophilus
Lactobacillus plantarum
Lactobacillus paracasei
Lactobacillus delbrueckii subsp. bulgaricusHaving had two major surgeries due to "unkillable" intestinal infection, I can advocate for the efficacy of VSL#3. My GI actually prescribed me a high-dose version post-op, and two years later i can say it has been life-changing. Other common "store shelf" probiotics are not the same for whatever reason (supply-chain refrigeration and cost might explain that somewhat).
Currently taking VSL#3 and it seems to be really helpful. How high was your dose?
My understanding is that Visbiome is also thought to be a comparable product that has the same formulation.
Yes, you can find it in some probiotic supplements.
https://www.gardenoflife.com/content/product/dr-formulated-p...
https://www.gardenoflife.com/content/product/dr-formulated-p...
Many brewers actually use lacto P to sour beer quickly. It's cheap and widely available.
Gotta be done:
https://xkcd.com/1471/
https://xkcd.com/1471/
I've been using General Biotics 115-strain pre- and probiotic product called Equilibrium [1]. You can find more info in the Science section [2].
[1]: https://www.generalbiotics.com/orders/new/
[2]: https://www.generalbiotics.com/science/
[1]: https://www.generalbiotics.com/orders/new/
[2]: https://www.generalbiotics.com/science/
But 115-strain is not the strain mentioned in this study, isn't it? So your point of bringing up this product is??!!
I meant, isn't one major point of this study is "not all probiotics are the same and finally someone found one is actually very helpful to new born babies"?
"The special mixture included a probiotic called Lactobacillus plantarum ATCC-202195 combined with fructo-oligosaccharide (FOS), an oral synbiotic preparation developed by Dr. Panigrahi." (from https://medicalxpress.com/news/2017-08-probiotics-sepsis-inf...)
Decrease in other infections (respiratory and nasal) is particularly interesting to see.
Now I want a HN MD to weigh in.