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In the future, giving specific microbes or entire microbial communities may be part of some cancer treatments! This is because the composition of a person's gut microbiome (the community of bacteria, fungi, and viruses) influences whether a person responds to immunotherapy drugs. This means that the mixture and variety of microbial species living in your intestines may determine whether you respond to cancer immunotherapy drugs. Wow!

One recent study found benefits from fecal microbial transplants (FMT) - that is, transplanting the stool (which contains an entire microbial community of bacteria, fungi, viruses) from a donor who had responded well to immunotherapy drugs to a person with advanced melanoma who had not responded to immunotherapy drugs. In total, 15 persons received stool transplants, and 6 of them had changes to the gut microbiome (becoming more like the donor's gut microbiome) so that the immunotherapy drug now worked against melanoma.

Now studies are needed to identify which specific microbes are the ones that were critical for overcoming a tumor's resistance to immunotherapy drugs.

This is very exciting research because the best treatments for advanced melanoma (metastatic melanoma) are immunotherapy drugs, but it only works for a minority of patients at this point. Microbial manipulation (in this case with fecal transplants) could be a game changer!

Excerpts from Science Daily: Fecal microbiota transplants help patients with advanced melanoma respond to immunotherapy

For patients with cancers that do not respond to immunotherapy drugs, adjusting the composition of microorganisms in the intestines -- known as the gut microbiome -- through the use of stool, or fecal, transplants may help some of these individuals respond to the immunotherapy drugs, a new study suggests. Researchers at the National Cancer Institute (NCI) Center for Cancer Research, part of the National Institutes of Health, conducted the study in collaboration with investigators from UPMC Hillman Cancer Center at the University of Pittsburgh.  ...continue reading "Microbes and Advanced Melanoma Treatment"


People assume that taking probiotics results in the beneficial probiotic bacteria colonizing and living in the gut (or sinuses when using L. sakei). It is common to hear the phrase "take probiotics to repopulate the gut" or "improve the gut microbes". The human gut microbiota (human gut microbiome) refers to all the microbes that reside inside the gut (hundreds of species). Probiotics are live bacteria, that when taken or administered, result in a health benefit. But what does the evidence say?

First, it is important to realize that currently supplements and foods contain only a small variety of probiotic species, with some Lactobacillus and Bifidobacterium species among the most common. But they are not the most common bacteria found in the gut. And very important bacteria such as Faecalibacterium prausnitzii (a reduction of which is associated with a number of diseases) are not available at all in supplements. One problem is the F. prausnitzii are "oxygen sensitive" and they die within minutes upon exposure to air, a big problem when trying to produce supplements.

The evidence from the last 4 years  of L. sakei use for sinusitis treatment is that for some reason, the L. sakei is not sticking around long-term and permanently colonizing in the sinuses. My family's experiences and the experience of other people contacting me is that every time a person becomes sick with a cold or sore throat, it once again results in sinusitis, and then another treatment with a L. sakei product is needed to treat the sinusitis, even though less is needed over time. And of course this has been a surprise and a big disappointment. [See Dec. 2020 update below.]

The same appears to be true for probiotics (whether added to a food or in a supplement) that are taken for other reasons, including intestinal health. Study after study, and a review article, finds that the beneficial bacteria do not colonize in the gut even if there are health benefits from the probiotics. That is, there may be definite health benefits from the bacteria, but within days of stopping the probiotic (whether in a food or a supplement) it is no longer found in the gut. Researchers know this because they can see what bacteria are in the gut by analyzing (using modern genetic sequencing tests) what is in the fecal matter (the stool).

However, the one exception to all of the above is a fecal microbiota transplant (FMT) - which is transfer of fecal matter from one person to another. There the transplanted microbes of the donor do colonize the recipient's gut, referred to as "engraftment of microbes". Some researchers found that viruses in the fecal matter helped with the engraftment. So it looks like more than just some bacterial strains are involved. Another thing to remember is that study after study finds that dietary changes result in microbial changes in the gut, and these changes can occur very quickly.

[Dec. 2020 update: A few recent studies are now suggesting that if a person takes or uses a bacterial species that naturally occurs in the body and is depleted, than it may stick around for a while - this is colonization, even if only short-term. We also find this occurring with L. sakei - while we may need to use it now and then, this is occurring less frequently over time, and we need to use a much smaller amount when needed. Colonization! Overall, there has been major improvement of our sinuses over time - and yes, they feel great.]

From Gut Microbiota News Watch: Learning what happens between a probiotic input and a health output

What scientists know is that probiotics in healthy individuals are associated with a number of benefits. Meta-analyses of randomized, controlled trials show that probiotics help prevent upper respiratory tract infections, urinary tract infections, allergy, and cardiovascular disease risk in adults. But between the input and the output, what happens? A common assumption is that probiotics work by influencing the gut microbe community, leading to an increase in the diversity of bacterial species in the gut ecosystem and measurable excretion in the stool.

But this theory doesn’t seem to be true, according to a recently published systematic review by Kristensen and colleagues in Genome Medicine. Authors of the review analyzed seven studies and found no evidence that probiotics have the ability to change fecal microbiota composition. So even though individuals in the different studies were ingesting live bacterial species, the bacteria didn’t stick around to increase the diversity of the gut fecal microbiota.

Do probiotics alter the fecal composition of healthy adults? The answer seems to be no,” says Dr. Mary Ellen Sanders, Executive Science Officer for the International Scientific Association for Probiotics and Prebiotics (ISAPP)....Dr. Dan Merenstein, Research Division Director and Associate Professor of Family Medicine at Georgetown University Medical Center in Washington, DC (USA), agrees. “Initially when probiotics were studied, some people expected to see permanent colonization. We now realize that is unlikely to occur,” he says. “This study shows that the probiotics tested to date do not result in overarching bacterial community structure changes in healthy subjects. But clinical effects are clearly demonstrated for probiotics, and likely some are mediated by microbiome changes.

At issue, then, is not what probiotics do for healthy individuals, but exactly how they work: the so-called ‘mechanism’. Sanders, who described some alternative mechanisms in her BMC Medicine commentary about the Kristensen review, points out a logical error in news stories worldwide that covered the article: the assumption that if probiotics fail to change the microbiota composition, they fail to have any health effects. Sanders emphasizes that probiotics might work in many possible ways. “Probiotics may act through changing the function of the resident microbes, not their composition. They may interact with host immune cells,” she says. “They may inhibit opportunistic pathogens that are not dominant members of the microbiota. They may promote microbiota stability… .” 

For years it has been known that most children with autism spectrum disorder (ASD) have all sorts of gastrointestinal (GI) problems (e.g., constipation, diarrhea, stomach pain, food intolerance), and the more severe the autism, the more severe the GI problems. Recent studies suggested that a major factor in this are abnormal gut bacteria, with the gut microbial community out of whack (dysbiosis). Previous studies looking at the gut microbiome of children with autism have shown lower diversity and lower amounts (abundances) of certain bacteria in children with autism compared to neurologically normal (neurotypical) children.

A recent study of children with autism spectrum disorder found that giving the children a fecal microbiota transplant (FMT) led to significant and lasting improvements in both gastrointestinal (GI) symptoms and autism-related behaviors and symptoms. A fecal microbiota transplant (FMT) is a transplant of fecal matter from a healthy donor to the recipient. A fecal microbial transplant contains approximately a thousand bacterial species that live in a healthy gut, as well as other microbes such as viruses and fungi. FMTs have so far been an amazingly successful treatment for recurrent Clostridium difficile infections, and are now being looked at as promising treatments of chronic inflammatory diseases such as inflammatory bowel disease.

The researchers were surprised to see an 80% improvement in gastrointestinal symptoms, especially abdominal pain, indigestion, diarrhea, and constipation. They also saw about a 25% improvement in autism related behaviors and symptoms which persisted for 8 weeks after treatment stopped, which is when the study ended. One measurement of adaptive behaviors (such as communication, daily living skills, and socialization) found that the average developmental age increased by 1.4 years after treatment. The researchers also found that there was a "rebalancing" of the gut microbes following treatment. They found evidence of "successful partial engraftment of donor microbiota and beneficial changes in the gut environment" - meaning they could see that donor microbes were living in the gut. Also, overall bacterial diversity increased (which is good) and the abundance of certain bacteria increased (including Bifidobacterium, Prevotella, and Desulfovibrio), and these changes persisted until the end of the study.

The researchers caution that this was a small trial, that there could be placebo effects, and so the results should be "cautiously interpreted and viewed as preliminary." But nonetheless, the results are exciting. Really exciting. From Science Daily:

Autism symptoms improve after fecal transplant, small study finds

Children with autism may benefit from fecal transplants -- a method of introducing donated healthy microbes into people with gastrointestinal disease to rebalance the gut, a new study has found. Behavioral symptoms of autism and gastrointestinal distress often go hand-in-hand, and both improved when a small group of children with the disorder underwent fecal transplant and subsequent treatment. In the study of 18 children with autism and moderate to severe gastrointestinal problems, parents and doctors said they saw positive changes that lasted at least eight weeks after the treatment. Children without autism were included for comparison of bacterial and viral gut composition prior to the study.

Previous research has established that children with autism typically have fewer types of some important bacteria in their guts and less bacterial diversity overall -- a difference that held true in this study. That could be because many of them are prescribed a lot of antibiotics in the first three years of life, the research team wrote in the study.

Parents of the children not only reported a decrease in gut woes including diarrhea and stomach pain in the eight weeks following the end of treatment: They also said they saw significant changes for the better when it came to behavioral autism symptoms in their sons and daughters, who ranged from 7 to 16 years old....One of those tools showed the average developmental age increased by 1.4 years after treatment. 

Researchers also were able to document a rebalancing of the gut following treatment. At the end of the study, the bacterial diversity in the children with autism was indistinguishable from their healthy peers. The study also included a unique viral analysis by Ohio State scientists, made possible because of previous work in the world's oceans. Gregory, who is particularly interested in the interplay between viruses and bacteria, used genetic testing to examine the viral diversity in the guts of the treated children. It rebounded quickly, and became more similar to the donor's microbiome. "Those donor viruses seemed to help," she said.

Fecal transplantation is done by processing donor feces and screening it for disease-causing viruses and bacteria before introducing it into another person's gastrointestinal tract. In this study, the researchers used a method called microbiota transfer therapy, which started with the children receiving a two-week course of antibiotics to wipe out much of their existing gut flora. Then, doctors gave them an initial high-dose fecal transplant in liquid form. In the seven to eight weeks that followed, the children drank smoothies blended with a lower-dose powder[Original study.]

The latest development in treating stubborn cases of Clostridium difficile infections (CDI) are "poop pills" - pills that patients can easily swallow rather than having to go through a fecal microbiota transplant (FMT). The "poop pills" are filled with blenderized fecal matter from healthy donors, are much easier for patients to swallow, and they successfully treat C. difficile at almost the same rate as fecal microbiota transplants - about 91% after 1 or 2 treatments for the pills, and 93 to 96% for FMT. This is an amazing success rate for an infection that debilitates people, is resistant to antibiotics in many cases, and even kills people.

Interestingly, these "poop pills" or "Capsule FMT" containing an entire microbiome (bacteria, viruses, fungi, etc) had fantastic results, as compared to a probiotic for the treatment of C. difficile tested by microbiome therapeutics company Seres Therapeutics Inc. In July 2016 Seres announced very disappointing results (no better than a placebo) with its product known as SER-109, a mix of various strains of bacteria.

So why did the Seres probiotic not work in clinical trails? The answer seems to be that the human gut (and so also human fecal matter) contains an entire community of microbes - hundreds of species of bacteria, as well as fungi, viruses, and archaea, but the Seres probiotic was just a mixture of some types of bacteria. This shows how little we know right now. (NOTE: For those interested, the "poop pills" or Capsule FMT is now offered as standard care for recurrent CDI at Massachusetts General Hospital.) From BioMedCentral:

Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection

Fecal microbiota transplantation (FMT) has been shown to be safe and effective in treating refractory or relapsing C. difficile infection (CDI), but its use has been limited by practical barriers. We recently reported a small preliminary feasibility study using orally administered frozen fecal capsules. Following these early results, we now report our clinical experience in a large cohort with structured follow-up. We prospectively followed a cohort of patients with recurrent or refractory CDI who were treated with frozen, encapsulated FMT at our institution. The primary endpoint was defined as clinical resolution whilst off antibiotics for CDI at 8 weeks after last capsule ingestion. Safety was defined as any FMT-related adverse event grade 2 or above.

Overall, 180 patients aged 7–95 years with a minimal follow-up of 8 weeks were included in the analysis. CDI resolved in 82 % of patients after a single treatment, rising to a 91 % cure rate with two treatments. Three adverse events Grade 2 or above, deemed related or possibly related to FMT, were observed. We confirm the effectiveness and safety of oral administration of frozen encapsulated fecal material, prepared from unrelated donors, in treating recurrent CDI. Randomized studies and FMT registries are still needed to ascertain long-term safety.

The epidemiology of Clostridium difficile infection (CDI) is evolving. Rates of infection are increasing and response to standard antimicrobial treatment with metronidazole or vancomycin may be suboptimal [1, 2].....Fecal microbiota transplant (FMT) has been shown to be safe and effective in treating refractory or relapsing CDI [4, 5, 6, 7, 8], but its use has been limited by practical barriers. Among other concerns, the administration of FMT by colonoscope or naso-gastric/duodenal tube exposes the patient to some risk and discomfort. We recently reported a preliminary feasibility study using orally administered frozen fecal capsules, prepared from unrelated donors, to treat 20 patients with recurrent CDI [9]. Following these encouraging results, we have continued treating patients with FMT capsules. We report our clinical experience in a large cohort with structured follow-up.

Donated fecal matter was blenderized, sieved, centrifuged, and suspended in concentrated form in sterile saline with 10 % glycerol. The suspension was double-encapsulated in hypromellose capsules (Capsugel, Cambridge, MA) and stored at –80 °C for up to 6 months pending use. Processing was done entirely under ambient air. FMT recipients discontinued any anti-CDI treatment for 24–48 hours prior to FMT, and were given 15 capsules on each of two consecutive days with water or apple sauce. The 30 capsules contained sieved, concentrated material derived from a mean of 48 g of fecal matter.

Of the 180 patients reaching 8 weeks, 147 were cured of CDI after the first administration of fecal capsules (82 %). Twenty six individuals relapsed within 8 weeks and were re-treated, with 17 responding, resulting in an overall cure rate of 91 % with one or two treatments. Six individuals declined re-treatment (our standard procedure in these cases is to offer long-term suppressive oral vancomycin treatment). Three patients were cured after a third administration, but were considered “non-responders” as per protocol definition. One patient received three treatments, relapsed, and was advised to continue suppressive vancomycin.

Important new research was published in January 2016 about a fecal microbiota transplant (FMT) or "poop transplant". The research compared only one patient's gut microbes (thus a case study) to her fecal transplant donor's gut microbes, but it is important for looking at how gut microbes change long-term after a fecal microbiota transplant (poop transplant) and the actual length of time that it takes for the recipient's gut microbial community  to become like the donor's gut microbiome. The patient was quickly "cured" of a serious recurrent Clostridium difficile infection after one fecal micriobiota transplant (FMT) from her sister, but there were ongoing long-term changes in the patient's gut microbes for 4.5 years, at which point the microbes (bacteria and viruses) were like the donor's (at the phylum, class, and order levels), and with similar bacterial diversity. At this point the researchers said that "full engraftment" of microbes had occurred.

Until 7 months post-FMT, the  patient's microbial communities varied over time and showed little overall similarity to the donor, indicating "ongoing gut microbiota adaption" during the first seven months. But right after the transplant, the changes were enough for the patient to be immediately "cured" of her recurrent Clostridium difficile infection. The long-term results also suggested that phages (viruses) may play an important role in gut health. From Cold Spring Harbor Molecular Case Studies:

Long-term changes of bacterial and viral compositions in the intestine of a recovered Clostridium difficile patient after fecal microbiota transplantation

Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infections (RCDIs). However, long-term effects on the patients’ gut microbiota and the role of viruses remain to be elucidated. Here, we characterized bacterial and viral microbiota in the feces of a cured RCDI patient at various time points until 4.5 yr post-FMT compared with the stool donor. Feces were subjected to DNA sequencing to characterize bacteria and double-stranded DNA (dsDNA) viruses including phages.

The patient's microbial communities varied over time and showed little overall similarity to the donor until 7 mo post-FMT, indicating ongoing gut microbiota adaption in this time period. After 4.5 yr, the patient's bacteria attained donor-like compositions at phylum, class, and order levels with similar bacterial diversity. Differences in the bacterial communities between donor and patient after 4.5 yr were seen at lower taxonomic levels.

C. difficile remained undetectable throughout the entire time span. This demonstrated sustainable donor feces engraftment and verified long-term therapeutic success of FMT on the molecular level. Full engraftment apparently required longer than previously acknowledged, suggesting the implementation of year-long patient follow-up periods into clinical practice. The identified dsDNA viruses were mainly Caudovirales phages. Unexpectedly, sequences related to giant algae–infecting Chlorella viruses were also detected. Our findings indicate that intestinal viruses may be implicated in the establishment of gut microbiota

FMT has shown impressive success rates of ∼90% against RCDIs and no severe adverse effects (Gough et al. 2011; Cammarota et al. 2014; O'Horo et al. 2014).... FMT led to increased donor-like intestinal bacterial diversities within 2 wk (van Nood et al. 2013).....Because viruses, especially phages, are the most abundant intestinal entities with the ability to influence microbial communities (Barr et al. 2013; Virgin 2014), they may well be relevant to C. difficile infection and the microbial changes following FMT.

Briefly, the female patient was 51 years old when admitted to the University Hospital of Zurich with her sixth episode of RCDI, suffering from severe diarrhea and weight loss.....Following FMT, the patient reported changes in bowel movements and intermittent obstipation, both of which ceased within 10 wk. Ever since, the patient has remained free of symptoms for almost 5 yr now.. 

The analysis of viral dsDNA sequences reported earlier revealed the presence of 22 viruses throughout samples D0, P1, P2, and P3 . In each sample, eight to 11 different viruses were identified, mainly belonging to the Caudovirales order (tailed dsDNA phages) that contains the viral families Myo-, Podo-, and Siphoviridae. Most viruses, 14 of 22, were identified uniquely in either sample. Three phages, the Erwinia phage vB_EamP-L1 (Podoviridae) and the two Bacteroides phages B124-14 and B40-8 (Siphoviridae), were consistently detected in all four samples and each contained phages of all three Caudovirales groups.

The bacterial composition of the donor was relatively stable and comparable at the time of FMT and 4.5 yr later (Fig. 1B), which is in accordance with the known temporal stability of adult intestinal microbiota (Zoetendal et al. 1998)....The patient's fecal microbiota underwent extensive compositional fluctuations and were dominated by Firmicutes up to 7 mo post-FMT, suggesting ongoing adaptation processes of donor microbiota in the patient's intestine that may also reflect changes in nutrition over the observation period. This is in accordance with our and other groups’ recent findings that showed high degrees of bacterial variation in RCDI patients up to 7 mo post-FMT (Broecker et al. 2013; Weingarden et al. 2015).

However, 4.5 yr post-FMT, the patient's bacteria have attained a donor-like composition at the phylum level, indicating full and stable engraftment of the donor's microbiota.....Of note, four of the five most prominent genera identified in both donor samples as well as the patient sample after 4.5 yr, Alistipes, Bacteroides, Dialister, and Faecalibacterium (Fig. 1D), are known constituents of healthy fecal microbiota (Claesson et al. 2011; Joossens et al. 2011). This further indicated that FMT led to healthy and sustainable microbiota in the patient.

One notable species detected in these three samples is Faecalibacterium prausnitzii (Fig. 1D). This species was also detected in the patient samples 6–7 mo post-FMT with abundances of <0.1% (data not shown). Faecalibacterium prausnitzii is recognized as one of the most important species of healthy individuals and normally constitutes >5% of the gut microbiota (Miquel et al. 2013). 

The fact that the patient's clinical symptoms, which included severe diarrhea in the absence of antibiotic treatment against C. difficile (Broecker et al. 2013), resolved promptly after FMT suggests that gut microbiota were able to exert normal metabolic functions even before full engraftment. This may be explained by the fact that the patient's bacterial diversity even during the highly variable time period up to 7 mo post-FMT was already in the range of the healthy donor. In agreement with the absence of symptoms until today, C. difficile bacteria were undetectable in the samples of the patient, similar to the donor who tested negative for C. difficile before FMT.....The finding that the patient's fecal microbiota attained a highly donor-like composition after 4.5 yr suggests that long-term follow-up should be implemented into clinical practice. 

The analysis of viral dsDNA sequences from a previous study revealed the presence of Caudovirales phages in all investigated samples of the donor and the patient. Caudovirales have been shown before to be the dominant viruses in the human intestine, followed by ssDNA phages of the Microviridae family that we were unable to detect with the metagenomic sequencing approach (Lepage et al. 2008; Norman et al. 2015). Three phages were identified in all of the analyzed samples of the donor and the patient. 

This is very interesting, and raises all sorts of possibilities for microbial transplants. While it's looking at only one person, this seems to be evidence that microbes are involved with our weight and manipulating them may result in weight gain or loss. From Science Daily:

Rapid and unexpected weight gain after fecal transplant

A woman successfully treated for a recurrent Clostridium difficile infection with stool from an overweight donor rapidly gained weight herself afterwards, becoming obese, according to a case report published in the new journal Open Forum Infectious Diseases.

Fecal microbiota transplant (FMT) is a promising treatment for relapsing C. difficile infections, a common cause of antibiotic-related diarrhea that in severe cases may be life-threatening. The case suggests that clinicians should avoid selecting stool donors who are overweight. The report also raises questions about the role of gut bacteria in metabolism and health.

At the time of the woman's fecal transplant in 2011, her weight was stable at 136 pounds, and her Body Mass Index (BMI) was 26. Then 32 years old, she had always been of normal weight. The transplant used donor stool from the woman's overweight but otherwise healthy teenage daughter, administered via colonoscopy, to restore a healthy balance of bacteria in the woman's gut, curing her C. difficile infection.

Sixteen months later, the woman weighed 170 pounds, and her BMI was 33, meeting medical criteria for obesity. The weight gain persisted despite a medically supervised liquid protein diet and exercise program. Continuing efforts to diet and exercise did not lower her weight: Three years after the transplant, she weighed 177 pounds with a BMI of 34.5, and she remains obese today.

"We're questioning whether there was something in the fecal transplant, whether some of those 'good' bacteria we transferred may have had an impact on her metabolism in a negative way," said Colleen R. Kelly, MD, of the Warren Alpert Medical School of Brown University, who wrote the case report with Neha Alang, MD, of Newport Hospital in Rhode Island. Such a link between bacteria in the gastrointestinal tract and weight is supported by previously published animal studies, where transfer of gut bacteria from obese to normal-weight mice can lead to a marked increase in fat. In light of the case and the animal data, the authors recommend selecting stool donors who are not overweight for fecal transplants.

Importantly, the FMT was not the only possible cause of the woman's weight gain. In addition to treatment for C. difficile, she had also been treated with several antibiotics for Helicobacter pylori infection. Other possible contributing factors in the woman's weight gain include the resolution of her C. difficile infection, genetic factors, aging, and stress related to illness. However, as noted above, she had never been overweight before.