I always cringe when I see an acupuncture headline with ‘needle’ or ‘point’ in the title. Can’t the writer avoid the clichéd pun? I had an editor who commented that the titles of my essays are often obtuse. Probably true. In going back over my essays on SBM I often can’t tell from the title what I have written about until I read the article. It is a fine line between (what I think) is a clever title and obscurity. So gut check it is.
Time flies when you are having fun. I wrote about probiotics back in 2009.
My conclusion at the time:
Probiotics are useful for the prevention of antibiotic-associated diarrhea. Probiotics may be helpful in preventing other overgrowth syndromes or diseases associated, and perhaps with perturbations of the gut microbial flora such as IBS and colic.
Probiotics are foreign bacteria that are not a normal part of your GI tract; they do not enhance your immune system and, in normal people do not promote the nebulous bowel health.
If you are a normal human, with a normal diet, save your money. Probiotics have nothing to offer but an increased cost.
Medicine is not static and there have been interesting advances in the understanding of the human microbiome in health and disease since 2009, so for SBM and my own medical understanding, I thought it would be a good opportunity to review the topic. Although with over 12,000 references on the PubMeds, I will only touch on a smattering of the papers. My ID attending in medical school always referred to reading the medical literature as drinking from a fire hose. Indeed.
The more I understand about normal GI flora, the more I suspect probiotics are the wrong answer to a wide variety of medical questions. We have a complex bacterial flora in and on us. We carry with us 10–100 times more bacteria than there are cells that make us up. We may think we are the pinnacle of evolution, but we are just sentient transport and feeding machines for bacteria.
The human GI tract is predominantly a bacterial ecosystem. Cell densities in the colon (1011–1012/ml contents) are the highest recorded for any known ecosystem. The vast majority belong to two divisions (superkingdoms) of Bacteria – the Bacteroidetes (48%) and the Firmicutes (51%).
There are over a 1,000 species in the GI tract with over 5 million genes. Most of these bacteria cannot be cultured but only identified by molecular techniques.
While they are often called “good” bacteria, the constituents of probiotics are not part of the normal GI tract in significant numbers if at all. The Lactobacilli, Bifidobacteria and Saccharomyces (a yeast) found in most of the products are better-classified as “less pathogenic organisms” rather than good.
As a treatment for C. difficile, protiotics have marginal benefits and the clinical trials have had difficulty definitively demonstrating efficacy although for prevention, the most recent meta-analysis suggests benefit:
Pooled analyses revealed significant reductions in the risks of AAD [antibiotic-associated diarrhea] (RR 0.61, 95% CI 0.47 to 0.79) and CDI [Clostridium difficile infection] (RR 0.37, 95% CI 0.22 to 0.61) among patients randomly assigned to co-administration of probiotics. The number needed to treat for benefit was 11 (95% CI 8 to 20) for AAD and 14 (95% CI 9 to 50) for CDI.
Even though well-conducted studies suggest otherwise:
We found no evidence that probiotic administration was effective in preventing AAD. Although there was a trend towards reduced [Clostridium difficile diarrhea] in the probiotic arm, on balance, the administration of this probiotic seems unlikely to benefit older patients exposed to antibiotics.
Like much of the medical literature when using an intervention of perhaps-uncertain biologic plausibility, you can read the literature as you see fit. I tend to see the preponderance of data suggesting ‘yes’ for prevention and ‘no ‘for treatment.
It is instructive to compare the efficacy of probiotics, uncertain, with the real deal, bacteria that actually belong in the GI tract.
Stool transplants cure 90% of people with C. difficile. That’s impressive. Even more impressive are frozen poo pills derived from humans, which lack the ick factor of a stool slurry.
Resolution of diarrhea was achieved in 14 patients (70%; 95% CI, 47%–85%) after a single capsule-based [fecal microbiota transplantation]. All 6 nonresponders were re-treated; 4 had resolution of diarrhea, resulting in an overall 90% (95% CI, 68%–98%) rate of clinical resolution of diarrhea (18/20).
And there is also synthetic stool, which is also effective and has the following recipe:
Thirty-three isolates, representing commensal species that were generally sensitive to a range of antimicrobials and were relatively straightforward to culture, were selected for the final stool substitute formulation.
So when I read the literature, I suspect we are seeing the beginning of the end of the stone knives and bear skins era of probiotics. Currently we are using organisms that are of low pathogenicity, but foreign and have the potential to generate an inflammatory response as well as the rare illness. As we gain more understanding of both the composition of the normal microbiome and its interactions with the immune and other systems, I suspect we will have more sophisticated and complex probiotics, made from the real “good bacteria”, those that belong in the GI tract.
Microbiome as treatment for other diseases
It is probably why the studies of probiotics for diseases besides diarrhea are less than compelling. Inflammatory bowel disease, bowel cancer and allergies all may have a link to the gut microbiome. The complexity of the ecosystem and the interactions of human genetics and diet will make this a complicated issue to tease out causality. This is an area with more speculation and intriguing hints than hard data. The identification and tracking of the gut microbiome is in its early days and definitive clinical trials are lacking. For instance:
To date, there is insufficient data to recommend probiotics for use in CD [Crohn’s disease]. There is evidence to support the use of probiotics for induction and maintenance of remission in UC [ulcerative colitis] and pouchitis. Future quality studies are needed to confirm whether probiotics, prebiotics, and synbiotics have a definite role in induction or maintenance of remission in CD, UC, and pouchitis.
Many studies demonstrated that the administration of probiotics is able to prevent the onset of allergic sensitizations and improve the symptoms of atopic dermatitis and allergic rhinitis; however, studies were published, too, that achieved negative outcomes. The overall evaluation of results is, however, difficult, as the strains used and the study design are markedly heterogeneous.
If there is going to be benefit in probiotics, perhaps it will come from transplanting ecosystems of bacteria rather than the odd Lactobacillus.
It is fascinating that the microbiome is associated with weight gain. Have the wrong microbiome and you will gain weight. At least if you are a mouse. Transplant a fat-promoting microbiome into thin mice and they will gain weight. So if you are going to get a stool transplant, I suppose you should make sure you obtain the specimen from a thin person. But as the NEJM review points out:
Currently, however, there is no direct evidence for a causal relationship in humans. And the translation of findings from mouse to human is challenging.
Still, it has long been known that low concentrations of antibiotics in animal feed leads to fatter animals, perhaps by changing the microbiome. It is interesting that there is an association between otitis media and obesity in children and those children often get lots of antibiotics. The potential reasons for the association are probably many, of course, and the data to support early antibiotic use with subsequent weight gain are both pro and con.
In my world, some antibiotic regimens are more likely to result in weight gain. Vancomycin as well as doxycycline and hydroxychloroquine used for endocarditis have both been associated with weight gain, the latter with a documented change in the gut microbiome.
The information is preliminary but is pointing in one direction. It is a fun and fascinating topic, but it is far too early to use clinically. I do expect that in the future we will have a better understanding of what the ‘correct’ microbiome(s) should be, and it will likely not include the currently-touted products despite the numerous sites that offer probiotics, prebiotics, herbs and supplements to promote and support bowel health. I am also willing to bet that preliminary data will be hyped far out of proportion to clinical applicability in the SCAM community.
And there is always someone who will take preliminary information and make it a diet: The Microbiome Diet. It is “scientifically proven” so it must be good. Me? I am writing the Paleo-Microbiome diet, getting back to the microbiome of our ancestors, before we started farming. I’ll make a mint.
For 89 bucks you can even find out what your own microbiome is. I am half tempted to spend the money just out of curiosity. I would be doubly curious given my ability to pack on weight given my total colectomy. They look legit.
A week or so ago I was asked a quick question outside the stairwell.
“How do you treat Archaea?”
“Huh? You mean the third domain of life, after Bacteria and Eukaryota?”
“You don’t. They don’t cause disease in humans. They are extremeophiles. Why would you want to do that?”
“A naturopath has diagnosed bowel overgrowth and is treating a patient.”
Well, I had never heard of that and if you judge an idea by the company it keeps…
“That’s stupid. I don’t buy it.”
And I walked on up the stairs.
But as I walked up the steps I thought, is it? What do I really know about Archaea and human disease? Nothing. And purveyors of pseudo-medicines do love to wildly extrapolate from preliminary basic science or small clinical trials to develop grand diagnostic and treatment schemes for all diseases. So maybe there is a nugget of truth of which I am unaware.
So I went to Pubmed. Yep. I was ignorant on the topic.
For it turns out that Archaea are part of the human GI tract and are responsible for the production of methane:
Methanogenic archaea are known as human gut inhabitants since more than 30 years ago through the detection of methane in the breath and isolation of two methanogenic species belonging to the order Methanobacteriales, Methanobrevibacter smithii and Methanosphaera stadtmanae.
I suppose the colon qualifies as an extreme environment. I would not want to live in one. Archaea are found in about 50% of adults.
Methanogenic archaea are strict anaerobes that occur in a large range of environments, such as freshwater and marine sediments, soils and the gut of numerous animal species, including humans. Their physiology and ecology is widely studied for their intrinsic capacity to produce methane which is both an energy source (biogas) in bioreactor and a greenhouse gas emitted from natural and anthropic environments, including livestock. As a recurrent component of the human digestive tract, impact of archaea and more particularly methanogens on human health have been questioned for many years.
There are some intriguing associations between the presence of Archaea and colorectal cancer, obesity, IBD, IBS, diverticulosis, constipation (perhaps the most robust data), and periodontitis, remembering the mantra that association is not causation. The review has a nice pro/con table of the evidence.
One author notes:
It is important to consider the above findings using an evidence-based medicine approach. A recent meta-analysis evaluated the existing literature comparing the presence of methane and constipation. Although not all studies have confirmed these results, most do to support a significant association.
Links with diseases/human health, if any, will therefore be established in the next years, considering the archaea as a diverse population, as it is for bacteria, with more discriminant methods than methane in breath for methanogens…Genomics has strongly helped in the determination of their putative roles in the [gastrointestinal tract], and indicated their unique metabolic properties before experimental proofs. This shows the potent physiological importance of the still poorly known domain Archaea in the human gut, and the role of its members, beneficial or deleterious, remaining to be determined.
And the ND connection? Evidently it is considered part of bacteria of SIBO, small intestine bacterial overgrowth, for which Portland has a specialty ND clinic. With the usual pseudo-medical ability of making a mountain range from a grain of sand, besides IBS, according to the ND site, SIBO is associated with:
Acne Roseacea, Acromegaly, Age: Elderly, Alcohol Consumption (moderate intake), Anemia, Atrophic Gastritis, Autism, Celiac Disease, Chronic Fatigue Syndrome, CLL (Chronic Lymphocytic Leukemia), Cystic Fibrosis, Diabetes, Diverticulitis, Dyspepsia, Erosive Esophagitis, Fibromyalgia, Gallstones, Gastroparesis, GERD (Gastroesophageal Reflux Disease) , Hepatic Encephalopathy (Minimal), Hepatic Steatosis, H pylori Infection, Hyprochlorhydria, Hypothyroid/ Hashimoto’s Thyroiditis, IBD (Inflammatory Bowel Disease), -Crohn’s, -Ulcerative Colitis, IBS (Irritable Bowel Syndrome), Interstitial Cystitis, Lactose Intolerance, Leaky Gut, Liver cirrhosis, Lyme, Medications: Proton Pump Inhibitors, Opiates, NSAIDS Myelomeningocele, Muscular Dystrophy (myotonic Type 1), NASH/NAFLD (non-alcoholic: steatohepatitis/fatty liver disease), Obesity, Pancreatitis, Parasites, Parkinson’s , Prostatitis (chronic), Radiation Enteropathy, Restless Leg Syndrome, Rheumatoid Arthritis, Scleroderma.
And more. Color me skeptical. Perhaps yet another one true cause of all disease. I got me a hammer, look, everything is a nail.
It is cool that as one branch of the tree of life, we carry around the other 3. Or is it 4?