Pondering Probiotics

Author: Amy Proal

What if, rather than conferring a benefit to the digestive tract, probiotics worked by slowing the pace of bacterial die-off in organs near the gut, or even in other areas of the gut itself?

Many people go out of there way to buy probiotics, which can be purchased in myriad forms.There’s been some discussion on the Marshall Protocol study site about how probiotics, or bacteria that are believed to beneficially improve bacterial composition in the gut, may be palliating symptoms but not improving overall health. This probably seems ludicrous to people who go out of their way to buy yogurt with “friendly” bacteria such as acidophilis, or people who dig into their savings to buy probiotics in numerous forms including little silver pearls.

And yet consider this hypothesis. Whereas it used to be believed that the adaptive immune system dictated the immune response in the gut, recent research has made it clear that the innate immune system - which is active inside the villi of the intestines and stomach - is actually largely responsible for keeping gut bacteria in check.

The innate immune system mounts a response to every pathogen that enters the body, whether “friendly” or harmful.So when bacteria enter the body – whether described as “friendly” or pathogenic – the innate immune system mounts a response to their presence. That’s its job. It’s as if the innate immune system is a bouncer at a club who must check the ID of each person who wishes to enter.

The response or challenge that the innate immune system mounts towards every bacterium entering the GI track causes the production of inflammatory cytokines and chemokines. According to Marshall, part of this inflammatory response may cause a migration of white blood cells called monocytes from nearby organs of the body, or other parts of the gut, to the area of the GI track where they can face incoming probiotics.

Think about how this response might affect the liver, the pancreas, the kidneys, or even different areas of the gut. Since monocytes engulf bacteria and play an important role in killing the chronic intraphagocytic bacteria that cause inflammatory disease (collectively called the Th1 pathogens), if the white blood cells leave these organs in order to face probiotic bacteria entering the gut, the rate of bacterial die-off in these nearby organs should tone down or subside.

Monocytes may migrate from other organs near the gut in order to face incoming probiotics.Since we now understand that it is the death of the Th1 pathogens that cause the bulk of a person’s symptoms (inflammatory cytokines and toxins are released when they die), the result of this reduced bacterial die-off should generate a feeling of temporary wellness in these other organs, organs that also affect digestion and detoxfication.

In the same sense, if a patient’s immune system is working to target a pocket of bacteria in one area of the gut, new probiotic bacteria may divert its attention from that area of infection to a different area of the gut, diminishing bacterial die-off in the original area.

Besides slowing the body’s response to bacterial death (known as immunopathology) in organs near the gut or areas of the gut itself, the above scenario unfortunately places an extra load on the innate immune system, which is the same branch of the immune system that works to try to keep the Th1 pathogens under control.

As previously discussed, in cases where patients are infected with Th1 pathogens, the innate immune system is constantly working hard in an attempt to kill them. But because the system must work to mount an inflammatory response each time probiotics enter the body, the ingestion of probiotic bacteria gives the already over-worked system another task, which at the same time diverts its attention away from killing the Th1 pathogens.

If the innate immune system is forced to manage incoming probiotics, then the rate of bacterial die-off in organs near the gut, or other areas of the gut, may slow.Even in people considered healthy, overloading the innate immune system is still a problem, since if its focus is diverted to dealing with probiotics, it may be less effective at targeting other pathogens that enter the body. Also, since people often begin to harbor the Th1 pathogens well before becoming symptomatic, any feelings of “wellness” they experience after taking probiotics may be due to the same mechanisms described above.

“We now know that the GI tract relies on the innate (Th1) immune system, and the VDR, to deal with intestinal flora,” states Marshall. “A decade ago it was thought that antibodies (the Th2 adaptive immune system) were involved. So it is certain that ingesting probiotics will place a load on the very part of the immune system already weakened by fighting Th1 inflammation in the major organs. Whether this is good or bad is open to interpretation.”

According to chronic disease physician Dr. Greg Blaney, concentrated probiotics, especially if they contain the artificial sugar Fructooligosaccharides (FOS), are most likely to affect the GI tract and surrounding organs in the manner described above. New probiotic blends with extra ingredients added may also be particularly unhelpful.

Indeed, a recent study by researchers at the University of Newcastle in Australia found that treatment with probiotics doubles levels of the inflammatory cytokine Interferon-gamma,^[1] confirming that the bacteria do create a Th1 inflammatory reaction upon their entry into the gut.

“ We now know that the GI tract relies on the innate (Th1) immune system, and the VDR, to deal with intestinal flora.”Interferon-gamma also catalyses (by the action of the enzyme CYP27B1) the production of the 1,25-D – the active form of vitamin D that functions as both a hormone and a cytokine. Since the Th1 pathogens create ligands that block the VDR and subsequently dysregulate the pathway that controls CYP27B1,^[2] this implies that healthy people might react differently to probiotics than people with Th1 disease, or at least be more negatively impacted by their ability to produce an inflammatory response.

This is because when enzymes such as CYP27B1 are dysregulated by VDR blockage, the body is unable to keep 1,25-D levels in the correct range. As the hormone starts to rise to unnaturally high levels, it binds many of the nuclear receptors – including the glucocorticoid receptor, the alpha/beta thyroid receptors, and the adrenal receptors - displacing the metabolites that are meant to be in the receptors under normal conditions.^[3] This upsets the balance of several critical hormonal feedback pathways.

Here at Bacteriality our favorite hormone to scrutinize goes by the name of 1,25-D. So, you can understand our disappointment when we relate that, yet another group of researchers, these from U. of Newcastle, didn’t measure the 1,25-D levels of their subjects. It would have been quite interesting to note if the levels of the hormone/cytokine was higher among those subjects taking probiotics.

The above hypothesis would explain why Dutch researchers recently published a study in the Lancet which found that among patients with predicted acute pancreatitis, more than twice as many patients given probiotic supplements to prevent infection died compared to those who received placebos.^[4]

The Lancet study found that among patients with predicted acute pancreatitis, more than twice as many patients given probiotic supplements to prevent infection died compared to those who received placebos.

“The adverse effects of probiotics noted here were unexpected,” Hein Gooszen and colleagues at the University Medical Centre Utrecht in the Netherlands wrote.

In the study of 296 people with similarly acute forms of pancreatitis, one group received a placebo and the other a mixture of probiotic supplements, some commonly available (the probiotics were administered via the mouth by a tube headed directly into the bowels). The number of people who developed infections was similar, but 24 volunteers died in the probiotic group compared to nine in the placebo group. 8 of the subjects in the group given probiotics died from bowel ischaemia, while the others succumbed to pancreatitis.

One must admit that a logical explanation for the deaths described above could be that in the case of the patients given probiotics, macrophages were diverted from areas of the bowel or pancreas where they were striving desperately to fight infection (let’s assume here that bowel ischaemia and pancreatitis are bacterial diseases). Furthermore, when the probiotics reached the GI tract, they may have put such a load on the patients’ innate immune systems that it was otherwise unable to keep their disease states under control. This study at least causes one to raise an eyebrow about the possibility that an alternate hypothesis for probiotics isn’t far fetched.

One must also consider that other explanations for how probiotics improve health remain largely speculative. For the most part, probiotics are assumed to be helpful because they offer some people temporary symptomatic relief – but as high levels of vitamin D or corticosteroids demonstrate, palliation does not always indicate improvement.

Elie MetchnikoffThe first researcher to hypothesize that certain bacteria might play a positive role in the gut was Russian scientist and Nobel laureate Elie Metchnikoff, who, in the beginning of the 20th century, suggested that it might be possible to replace harmful microbes in the gut with useful microbes. He hypothesized that bacteria such as clostridia, which are part of the normal gut flora, produce toxic substances from the digestion of proteins. He believed these compounds were responsible for what he called “intestinal auto-intoxication”, which he linked to physical changes associated with old age.

This led him to propose that milk fermented with lactic-acid bacteria could inhibit the growth of these “toxic” bacteria because of the low pH produced by the fermentation of lactose. Soon, he introduced the idea that a diet high in sour milk fermented with the bacteria he called “Bulgarian Bacillus” could improve digestive health. Friends in Paris soon followed his example and physicians began prescribing the sour milk diet for their patients.

But in 1920, Rettger demonstrated that Metchnikoff’s “Bulgarian Bacillus”, later called Lactobacillus bulgaricus, is actually unable to live in the human intestine. Naturally, the fermented food hypothesis petered out.

After that point, research on probiotics focused on the idea that scientists could isolate bacteria that seemed to be involved in a positive process and add extra amounts to the gut, with the hope of displacing other less desirable pathogens.

For example, Henry Tissier, a researcher at the Pasteur Institute, isolated a bacterium from breast-fed infants and named it Bacillus bifidus communis. He recommended that doctors give bifidus communis to babies suffering from diarrhea in the hopes that it would displace other species that might be causing the problem in the first place. Yet benefit from the treatment remained dubious.

The benefits of giving Bacillus bifidus communis to infants remains dubious.Later, it was reasoned that “helpful” bacteria should be isolated directly from the gut, and in 1935, certain strains of Lactobacillus acidophilus were found to be very active when implanted in the human digestive tract. Trials were carried out using this organism, and encouraging results were obtained, especially in the relief of chronic constipation. Yet since the liver, kidneys, and parts of the gut not affected by probiotics are involved in the constipation process, one could argue that such benefits are also explained by Marshall’s hypothesis.

In these and other cases, one must question – how can we assume that bacterial species such as those isolated from breast-fed infants or from the digestive tract are necessarily “good”? Can we simply assume that a bacterial species is beneficial because it appears at face value not to be causing any harm?

It’s true that certain bacterial species are competitive, meaning that one species may be able to kill another. Take, for example, Streptococcus, which has been shown to effectively kill Staphylococcus bacteria. In fact, the antibiotic demeclocycline, which was derived from a strain of Streptococcus bacteria, is particularly effective at quelling Staphylococcus infections.

Yet do the bacterial species in common probiotic products possess such competitive properties? To date, there has simply been no evidence or laboratory studies showing that they do. Plus, if probiotic strains are indeed killing other more virulent pathogens, wouldn’t the death of such strains cause a rise in immunopathology rather than a feeling of relief?

“Can we simply assume that a bacterial species is beneficial because it appears at face value not to be causing any harm?”Another reality that probiotic enthusiasists often fail to consider is how horizontal gene transfer affects probiotic bacteria in the gut. Horizontal gene transfer is a process in which organisms swap genetic material by trading plasmids, or circular molecules of DNA that can replicate independently of a pathogen’s other genetic material.

This means that even if a species of bacteria considered to be “helpful” enters the gut, it can easily trade plasmids with other disease causing pathogens – quickly changing it from a potentially harmless organism to yet another pathogen contributing to disease.

This may be especially true for people with high loads of Th1 bacteria in the gut that can all too easily swap their genetic material with probiotic bacteria, rendering them part of the disease process rather than the “cure.”

Horizontal gene transfer allows bacteria to share genetic material“Increasingly, studies of genes and genomes are indicating that considerable horizontal gene transfer has occurred between bacteria,” states James Lake of the Molecular Biology Institute at the University of California. In fact, due to increasing evidence suggesting the importance of the phenomenon in organisms that cause disease, molecular biologists such as Peter Gogarten at the University of Connecticut have described horizontal gene transfer as “a new paradigm for biology.”

Gorgarten insists that horizontal gene transfer is “more frequent than most biologists could even imagine a decade ago.” In the face of such statements, we may want to reconsider ingesting large loads of extra bacteria that inevitably become part of a pool of pathogens trading genetic material when they actually enter the body.

Indeed, one of the largest meta-analysis studies on probiotics, published in the American Journal of Clinical Nutrition by researchers at the Wageningen Centre for Food Sciences in the Netherlands, reviewed 49 studies on probiotics with lackluster results.^[5] 26 of the studies dealt with the prevention or treatment of diarrheal disease, 9 with the prevention of cancer or of the formation of carcinogens, 7 with the lowering of serum cholesterol, and 7 with the stimulation of the immune system. The most widely studied probiotic bacteria were Lactobacillus GG (22 studies), Lactobacillus acidophilus (16 studies), Bifidobacterium bifidum (6 studies), and Enterococcus faecium (7 studies). The team concluded that intake of Lactobacillus GG did shorten the diarrheal phase of rotavirus infection, but that “evidence for the prevention by Lactobacillus GG and other probiotics of diarrhea due to viral or bacterial infections was less strong.” The effects of probiotics on the immune system were “inconclusive” because of the variety of outcome variables reported.

The largest meta-analysis on probiotics reviewed 49 studies on the bacteria with lackluster results.The team also reported that cholesterol-lowering abilities of probiotics “seem to be transient”, and found that production of mutagens after a meal might be reduced by intake of probiotics, but the relevance of the finding “was unclear”. The study finally concluded that while probiotics may have some effect on rotavirus infection, “other health effects of probiotic bacteria have not been well established.”

A 2005 study by the Food Standards Agency on 11 different types of probiotic bacteria attempted to determine where the pathogens break down as they pass through the digestive system. While the researchers were able to determine that most strains of probiotics survive past entry into the stomach, the data failed to show “if or where probiotics might have an effect,” meaning that mainstream researchers aren’t even sure where probiotics take effect, let alone what they do when they get to their target destination.

Despite doubt cast on the benefits of probiotics, it’s doubtful that Marshall’s hypothesis will gain any credence in the near future. There’s simply too much money at stake, and according to the Associated Press, “the market is ahead of the science. It’s all part of a burgeoning effort to capitalize on an obsession with health foods.” Over 150 food products that have probiotics have been introduced in the market this year - compared to about 100 last year and just 40 the year before that.

In fact, probiotics are a multibillion-dollar global industry. In the United States alone, retail sales of probiotic-containing foods and supplements totaled an estimated $764 million in 2005 and are projected to reach $1 billion in 2010, according to market research firm BCC Research.

Dannon’s Activia yogurt, introduced last year, is among the best known U.S. products. Its first-year U.S. sales totaled more than $100 million. General Mills introduced its competitor, Yo-Plus, under the Yoplait yogurt brand this year.

Other 2007 products include: Kraft Foods Inc.’s LiveActive prebiotic cottage cheese and probiotic cheddar cheese; Nestle’s probiotic Good Start Natural Cultures baby formula; Beech-Nut Nutrition Corp.’s Good Evening prebiotic baby food; and the Swiss firm Barry Callebaut’s probiotic chocolate.

Probiotics have been added to a vast array of productsProbiotic manufacturer Nutraceutics just targeted $100 million in probiotic sales. Meanwhile, New Zealand oral probiotics developer BLIS Technologies is planning to issue new shares to fund an expansion of its business into new international markets in order to boost development efforts that will benefit shareholders if the products take off.

A continent away, dietary supplements with Probi’s healthy bacteria Lp299v will be launched in China in conjunction with the leading domestic health food company Biostime Inc. The list goes on as probiotics continue to be added to a mind-blowing number of new foods and products. As with vitamin D and most other supplements available in dietary form, the mistaken notion that “more is always better” seems to reign supreme.

As stated in a recent article on probiotics in Time Magazine, “Whether or not you’ve ever developed a taste - or even a tolerance - for living things in your lunch, more are on the way. Food companies have been coming to the conclusion that if a few of these superstar bacteria are good for you, then more will be even better.”

Also unnerving is that the FDA hasn’t set any upper limit for probiotic consumption, largely because nobody really knows exactly what they do upon entering the body, so recommending a “desirable” dose is impossible. This means that a person can guzzle tremendous loads of probiotic supplements without ever consulting the advice of a doctor.

When it comes to probiotics, the mistaken notion that “more is always better” seems to reign supreme.At least, according to Time, the U.S. Food and Drug Administration is “relatively neutral, using the growing popularity of probiotics to caution manufacturers not to pitch the foods as some sort of panacea for any specific disease.” Whether food companies actually follow such advice remains to be seen.

The NIH has declared the study of gastrointestinal bacteria and probiotics a major research initiative. “The fact that there are a number of health implications and a lack of understanding associated with the use of probiotics makes this a very interesting subject to study,” said Crystal McDade-Ngutter, who heads an NIH working group on the topic.

The skeptic in me can’t help thinking that a lot of companies are making a pretty penny off simple palliation. At the very least, the fact that probiotics possess the ability to modulate where and when the innate immune system is activated should give one pause. In the meantime, Marshall prefers not to give advice about probiotics.

“I haven’t stated a position on probiotics,” states Marshall. “There are many on the [Marshall] protocol who are convinced they are helpful, and I would prefer to concentrate on the key issues that folk really need to solve – no vitamin D, plenty of Benicar, and a supportive family/medical environment. Probiotics are a second-order effect, I think (less important).”

“So I tend to leave it to the individual. Most Th1 patients have severe GI tract involvement, and dealing with that takes just about every tool in their arsenal. If probiotics seem to help, then who am I to say no? On the other hand, they do not form part of the base protocol, as any benefit is not obvious to me, whether based on personal experience, or biological knowledge.”

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