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Are Probiotics Useless? Here’s a Microbiome Researcher’s Perspective

An altered gut microbiome is associated with a number of different chronic diseases, including obesity, diabetes, metabolic syndrome, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), skin conditions, anxiety, depression, and multiple sclerosis, to name a few. (1) Animal studies have confirmed that many of these relationships are causal—in other words, gut dysbiosis in and of itself is sufficient to cause disease. (2)

Recent media coverage is painting probiotics as anything from completely purposeless to potentially harmful. So, are probiotics useless? Check out this article to find out what the research really says.

With all of this emerging research, it’s no surprise that there is increasing interest in ways to alter the gut microbiota to improve our health.

According to a 2012 survey, 3.9 million Americans regularly take probiotics or consume them in yogurts, smoothies, or other foods, and 61 percent of physicians regularly prescribe probiotics to their patients. (3)

While probiotics are largely unregulated and their use has always been controversial, there are now hundreds of peer-reviewed, randomized, placebo-controlled trials that have demonstrated the safety and efficacy of a variety of probiotic strains. (4)

So yesterday, I was surprised to find that my inbox was inundated with emails asking for my opinion on the latest media headlines:

“Probiotics are mostly useless and can actually hurt you”

“Probiotics: don’t believe the hype?”

“There’s really not much proof probiotics work”

These media articles appeared in the wake of two new papers published in the prestigious journal Cell, authored by scientists at the Weizmann Institute of Science in Tel Aviv, Israel:

Study #1: Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features

Study #2: Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT

As I scanned through the full text of the studies, it didn’t take long to realize that the media had shrouded any real discussion of the study findings in favor of scare tactics and click-bait titles.

If you want the real evidence, I’ll break it down here, including a nuanced discussion of the fecal vs. gut microbiome and the evidence for and against probiotics. If you want to skip the scientific details and just hear my take on this research, feel free to skip to the “Takeaways and Implications” section at the end.

Finding #1: The Fecal Microbiome Isn’t Really the Gut Microbiome (But We’ve Actually Known That for a While)

Many clinicians, researchers, and citizen scientists alike use stool samples as a relatively inexpensive and noninvasive way to sample the gut microbiome. I use them regularly in my own research. Unfortunately, stool samples may not be reflective of the microbes that are actually present in the gut.

The gut can be divided into the upper GI tract (small intestine) and the lower GI tract (large intestine, or colon). It can also be divided cross-sectionally into the gut lumen and the gut mucosa. If you think of the gut as a hollow tube, the lumen is the innermost (center) part of the tube, while the mucosa is like a sticky gel-like substance coating the wall of the tube.

In the first study, researchers took samples from the feces, gut lumen, and gut mucosa of mice and humans. They found that each sample type harbored a distinct community of microbes and that fecal samples were a far cry from accurately predicting abundance of bacteria from even the most distal part of the GI tract. In humans, more than 10 bacterial taxa were significantly over- or underrepresented in stool samples compared to the lower GI tract lumen and mucosa.

My take: While certainly interesting, this finding is not all that novel. We’ve known for quite some time that the gut microbes associated with the mucus layer are not the same as those found in the lumen and stool samples. (7)

Finding #2: Probiotic Colonization Is Largely Transient in Mice (But We’ve Known That for a While, Too)

Next, the researchers investigated whether probiotic supplementation would result in effective colonization of the mouse gut. For four weeks, they gave mice a cellulose placebo or a probiotic supplement containing a total of 5 billion colony-forming units (CFU) from 11 different human-associated strains, including:

Lactobacillus acidophilus

Lactobacillus casei

Lactobacillus casei subsp. paracasei

Lactobacillus plantarum

Lactobacillus rhamnosus

Bifidobacterium longum

Bifidobacterium bifidum

Bifidobacterium breve

Bifidobacterium longum subsp. infantis

Lactococcus lactis

Streptococcus thermophilus

Analysis of the upper and lower GI tract lumen and mucosa found no evidence of probiotic colonization. However, probiotics did significantly alter the the lower GI tract microbiome. Altogether, 21 bacterial taxa differed between the probiotic and control groups in the lower GI mucosa.

My take: this finding is also not too surprising. Researchers have theorized for quite some time that probiotics do not actually colonize the gut; instead, their effects are due to their ability to shift gut community dynamics and modulate the immune system whilst in transit. (8)

Finding #3: The Normal Microbiome Inhibits Probiotic Colonization

The authors hypothesized that the mice were not colonized by the probiotics because their normal, commensal microbiome was resistant to the supplemented strains.

To test this, they used germ-free mice, which are raised in sterile incubators with no exposure to microbes. These previously sterile mice were given the same 11-strain probiotic supplement for 14 days.

In the absence of a normal microbiome, the mice had massive colonization of the probiotic strains. This confirmed that commensal microbes were inhibiting the colonization of the probiotic strains.

The authors summarized their findings:

Taken together, these findings suggest that despite daily administration, human-targeted probiotics feature low-level murine mucosal colonization, mediated by resistance exerted by the indigenous murine gut microbiome.

Finding #4: Probiotic Colonization in Humans Is Individualized

While inbred lab mice allow for reduced variability microbiome research, they are not necessarily indicative of what happens in genetically diverse human populations. Thus, the researchers next recruited 15 healthy volunteers to receive the 11-strain probiotic or a cellulose placebo twice daily for four weeks.

Unlike in mice, they found that nine out of 11 probiotic species were significantly enriched in the mucosa of the probiotic-supplemented group after four weeks. The effect was most pronounced in the ascending and descending colon of the lower GI tract.

Interestingly, there was significant variability between participants in terms of how receptive they were to probiotic colonization:

Six of the 15 volunteers had significant elevation in the absolute abundance of probiotic strains in the gut mucosa and were deemed “permissive” probiotic colonizers.

Nine of the 15 volunteers did not have significant enrichment of these strains and were termed “resistant” to probiotic colonization.

Despite clear evidence of colonization, the researchers found no alterations in the gut microbiome in any region of the lower or upper GI tract when all 15 individuals were considered. Only when “permissive” probiotic colonizers were analyzed separately did they find significant shifts in the gut microbiome.

This doesn’t mean that the probiotics had no effect, though. The authors write:

Nonetheless, when all probiotic-consumers were considered together, probiotics consumption led to transcriptional changes in the ileum, with 19 downregulated and 194 upregulated genes noted, many of which related to the immune system including B cells.

My take: this data supports previous findings that, even in transit, probiotics are able to influence host gene expression and immune function. (9) Furthermore, it suggests that, at least in some individuals, probiotics may be able to colonize the gut.

Finding #5: Probiotics Slow Recovery of the Normal Microbiome after Antibiotics

As though the first four findings weren’t enough, the researchers then sought to determine how probiotic colonization might differ after broad-spectrum antibiotic treatment. (This begins the second paper.)

It’s well known that the human microbiome can take many months to recover from a single course of broad-spectrum antibiotics, and even then, recovery may be incomplete. (10, 11)

Moreover, antibiotic exposure, especially during the early years of life, is associated with an increased risk of developing allergies, asthma, autoimmunity, obesity, IBD, and skin conditions. (12, 13)

Thus, probiotics are widely used and prescribed during or after antibiotics, with the idea that flooding the system with good bacteria can help prevent the adverse effects of antibiotic-induced gut dysbiosis. Indeed, several short-term studies have suggested that probiotics might be helpful in preventing antibiotic-associated diarrhea. (14)

However, the impact of probiotics on the long-term restoration of the gut microbiota after antibiotics had not been studied—until now.

The Israeli researchers first treated both mice and a cohort of 21 healthy human volunteers with a single course of the broad-spectrum antibiotics ciprofloxacin and metronidazole (14 days in mice, seven days in humans). They then split the mice and humans into three groups:

Group 1 was allowed to spontaneously recover over time.

Group 2 was supplemented with an 11-strain probiotic (in the same formulation as above) for four weeks following antibiotics.

Group 3 underwent autologous fecal microbiota transplant (aFMT), where their own fecal samples before antibiotics were frozen and used to re-inoculate their gut a day after the antibiotics finished.

So, what did they find? Antibiotic perturbation of the gut microbiome only mildly improved probiotic colonization in mice, but it significantly enhanced probiotic colonization in the human gut mucosa, particularly in the distal small intestine and lower GI tract.

More importantly, they found that treating the gut with probiotics actually delayed the normal recovery process of the gut microbiome.

To be honest, I wasn’t sure what to make of this at first. I first read the mouse data, which suggested that probiotic supplementation significantly delayed the return to baseline microbiome richness, even compared to spontaneous recovery, and that several taxa were slower to return to baseline.

My initial reaction was, “Okay, does species richness matter, though?” What if the interim microbiota has less richness but is in some way protecting the host? Perhaps the gut mucosa is selecting for certain microbes to take up some extra space within the gut environment, providing protection until the ecosystem can recover?

But then I reviewed the human data. The authors write:

“…probiotics-consuming individuals did not return to their baseline stool microbiome configuration by the end of the intervention period (day 28), and dysbiosis was maintained even 5 months after probiotics cessation, with all stool samples collected through day 180 remaining significantly different from baseline. [emphasis added]

The lower GI mucosa of the probiotics group experienced a significant bloom of Blautia, Akkermansia, Enterococcus, and Bifidobacterium spp. and maintained low alpha diversity for several months. Meanwhile, in the spontaneous recovery group, significant differences in stool composition from baseline had vanished within 21 days after antibiotics.

My take: These findings certainly call into question the use of probiotics after antibiotic exposure. Competition is a key feature of any ecosystem, and all microbes, probiotic or not, are simply trying to occupy as much of that ecosystem as they can. A mass extinction, such as that caused by broad-spectrum antibiotics, can significantly alter community dynamics and, as clearly shown here, response to probiotic supplementation.

The authors did note a few limitations:

No clinical symptoms were measured during or after antibiotic treatment.

They tested a single combination of broad-spectrum antibiotics and a single oral probiotic supplement mixture: “Other combinations of antibiotics, probiotics, and treatment routes and timings merit further studies.”

The study was also conducted in healthy adults, so these results can’t necessarily be extrapolated to children, the elderly, or those with gut pathologies.

One experiment I wish they had performed: I would have LOVED to see them “challenge” the mice with Salmonella or some other enteropathogen in the aftermath of the antibiotics. This would help determine if there is any potential trade-off; for instance, perhaps normal restoration of the gut microbiome is delayed, but the probiotic-colonized gut confers greater protection against pathogens until the ecosystem recovers. I’ll discuss what data we do have in this regard in the “Takeaways and Implications” section at the end.

Finding #6: Lactobacillus in Particular Prevented Microbiota Recovery

Perhaps the coolest part of this study was the culture-based experiments that the researchers performed last. They took the probiotic pill and cultured it in five different growth conditions that differentially supported the growth of each of the four genera (Lactobacillus, Bifidobacterium, Lactococcus, Streptococcus).

After 24 hours of culture, they collected the biochemical “soups” surrounding the probiotics on the dish and added each to an anaerobic culture of fresh human fecal microbiota. They found that the “soups” that had come from the plate with lots of Lactobacillus showed the strongest inhibition of the native human fecal microbiome.

Specifically, Lactobacillus significantly reduced the diversity and altered the gut community structure. Abundance of Prevotella and Clostridiales were particularly affected, in line with what the researchers saw in the live mice and human experiments.

Finding #7: A Personal Poop Transplant Results in Rapid Recovery After Antibiotics

By this point you should be asking: what about Group 3, the ones that received their own fecal samples to reinoculate their gut?

In stark contrast to the probiotic-supplemented group, both mice and humans in the aFMT group “achieved a rapid and near-complete gut mucosal microbiome recolonization.” In mice, fecal microbial diversity was back to normal within eight days after aFMT, and fecal microbiota composition was indistinguishable from baseline at four weeks post-antibiotics. Similar results were seen in the lower GI tract and upper GI tract.

In humans, the fecal microbiota had recovered to baseline composition as early as one day after aFMT! Unlike the probiotic-supplemented and spontaneous recovery groups, aFMT was also capable of restoring several key species, including Alistipes shahii, Roseburia intestinalis, and Coprococcus spp. Notably, these are all microbes that produce butyrate, an essential metabolite for the health of the gut barrier.

Importantly, aFMT also restored native host gene expression profiles along the GI tract.

My take: This is absolutely brilliant, and I hope it leads to greater awareness about the merits of self-FMT. I’ll discuss this in detail below in the “Takeaways and Implications” section.

Takeaways and Implications

That was quite a lot of information for just two studies! If you got bogged down in the details, here are the major takeaways and implications of this research and how it will affect my thinking about the gut microbiome going forward.

The Fecal Microbiome Is Not the Same as the Gut Microbiome

Study #1 is aligned with prior findings that suggest fecal samples are a poor indicator of gut microbial composition. This is why I don’t put too much stock in uBiome results, as much as I find them fascinating. I still believe comprehensive stool analysis is useful, as it can help screen for potential pathogens, parasites, and yeast, among other important markers.

However, I take any bacterial abundance information with a grain of salt and recognize that it is not directly representative of community dynamics in the gut environment. I am increasingly using a combination of comprehensive stool analysis, PCR-based stool testing, organic acids testing, and SIBO breath testing with my clients to provide a better overall picture of what’s going on in the gut.

Probiotics May Not Always Colonize the Gut, but They Are NOT Useless

Study #1 showed that probiotic colonization is very individualized and likely depends on the state of your gut and the probiotic strains used. In mice, the normal commensal gut microbiome inhibited colonization of probiotic strains.

Still, hundreds of randomized, placebo-controlled human clinical trials have shown that probiotics have efficacy for IBS, IBD, skin conditions, anxiety, depression, and more. (15, 16, 17)

Even when probiotics do not colonize the gut, they may impact host gene expression and the host immune system.

Not All Probiotics Are Created Equal, and It IS Possible That They Could Cause Harm

Probiotics are largely unregulated, and some studies have reported probiotic-associated deaths. (18, 19) Several meta-analyses also suggest that probiotic-associated adverse events may be underreported in clinical trials. (20)

There is likely a huge difference between the probiotic strains tested and validated in human clinical trials and the ones found on the average grocery store shelf.

This is part of the reason I’ve spent over 50 hours putting together an extensive analysis of the most popular soil-based probiotics on the market, to determine which strains have shown clinical efficacy and have been shown to be safe in clinical trials. (You can subscribe to my newsletter to be notified when it is released next week.) I also plan to do a similar analysis of Lactobacillus- and Bifidobacterium-based probiotics in the near future.

Probiotic Use Delays Restoration of the Gut Microbiota, Which May Represent a Trade-Off for Protection against Infection

Study #2 clearly showed that probiotic use after antibiotics can delay restoration of the normal gut microbiota for at least five months. Lactobacillus strains, in particular, appeared to inhibit the “normal” commensal microbiota. However, several studies suggest that probiotic use during antibiotics does confer protection to the host.

A 2012 meta-analysis of RCTs published in the Journal of the American Medical Association found that probiotic use was associated with a significantly lower risk of developing antibiotic-associated diarrhea. (21) However, the reduction in absolute risk was only 0.07. This means that 13 people would need to be treated and potentially delay normal restoration of their gut microbiome for one person to avoid diarrhea.

Subgroup analyses revealed a trend for an increased relative risk of antibiotic-associated diarrhea in those receiving Lactobacillus- (p=0.09) and Bifidobacterium- (p=0.16) containing probiotics. Saccharomyces and Bacillus spp., on the other hand, showed a numerical (non-significant) reduction in absolute risk.

A 2017 meta-analysis of RCTs published in Gastroenterology found that probiotic use reduced the risk of Clostridium difficile (since renamed Clostridioides difficile) infection in hospitalized adults taking antibiotics. (22, 23)

Probiotics given within two days of antibiotic initiation were the most effective in preventing C. diff infection.

Again, the reduction in absolute risk was small. This time, 43 people would need to be treated with probiotics and potentially delay normal restoration of their gut microbiome for one person to avoid C. diff. This was also performed in hospitalized patients, who are at much higher risk of C. diff. infection than individuals taking antibiotics in an outpatient setting.

Based on the current human data that we have, I do not think the benefits of probiotic use during or after antibiotics outweigh the long-term delay in native microbiome restoration (in most cases). However, I certainly encourage everyone to weigh the potential costs and benefits for themselves and with their physician and make an educated decision about whether to take probiotics based on their individual circumstances.

I eagerly await future studies that may help determine whether other types of probiotics (such as Bacillus spp. or S. boulardii) can confer protection to the host without delaying restoration of the gut ecosystem, and when they should be initiated in relation to the course of antibiotics.

Diet and Lifestyle Are Still the Most Potent Modulators of Gut Microbial Composition

Probiotics are NOT a replacement for a nutrient-dense diet, and diet is still the primary determinant of microbiota composition. Data from my lab shows that exercise may help promote a healthy gut microbiota as well.

aFMT Is the Best Solution for Rapid Recovery after Antibiotics (And Maybe We Should All Be Banking Poo for Later!)

Study #2 showed that aFMT, or infusing the gut with your individual stored, frozen pre-antibiotic fecal material, leads to the most rapid reconstitution of the normal microbiome after taking antibiotics.

You can imagine doctor’s offices in the future having large bio-banks of stool, ready to reinoculate a patient with their own personal fecal microbiota should they ever acquire a harmful pathogen or have to take antibiotics. I certainly know that I’m planning to create my own personal bio-bank after seeing this research!

Which brings me to another somewhat crazy, but related, thought: could we save stool samples from when we’re young, and reinoculate ourselves later in life with a younger microbiome? In controlled studies, FMTs from younger animals have been shown to reduce aging-associated chronic inflammation and increase lifespan in mice and fish, after all, and frozen stool can be stored for many years without major changes in microbial composition. (24, 25, 26)

If you have to take antibiotics and don’t have the ability to do aFMT (i.e., have a pathogenic infection or have no stored healthy fecal samples), allowing the gut to recover on its own and supporting it with a nutrient-dense diet may be the best course of action.

Hope you enjoyed this article! Be sure to let me know what you thought in the comments below. You can also subscribe to my weekly newsletter for more great content and get exclusive access to my definitive gut–skin axis guide.

About Lucy: Lucy is a fourth-year MD-PhD student in Nutritional Sciences at the University of Illinois. Her research focuses on understanding how diet and exercise can beneficially modulate the gut microbiota and gut barrier function in states of health and disease.

Lucy is also a staff research associate for Kresser Institute and writes weekly on her blog at NGmedicine.com. She strives to be a resource for unbiased, non-sensationalist information and hopes to use her degrees to create a world where functional, integrative, and preventive medicine is not only accepted by conventional doctors, but is the norm.

Lucy consults regularly with clients that have gut, skin, and autoimmune conditions. You can find out more about her at NGmedicine.com or subscribe to her weekly newsletter here!

The post Are Probiotics Useless? Here’s a Microbiome Researcher’s Perspective appeared first on Chris Kresser.

Source: http://chriskresser.com September 18, 2018 at 06:46PM

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