We are not one organism, we are many organisms. There is continued scientific interest in studying how our bodies interact with the organisms that we carry, on and in us. Probiotics, which are live bacteria given to treat or prevent illness, have been a subject of blog posts back to SBM’s early years. They’re an interesting subject, with scientific plausibility (and some real science) but layered with lots of myth and pseudoscience. The interaction between our gastrointestinal microbes and our own body can affect our wellbeing as well as illnesses like inflammatory bowel disease, Crohn’s disease, and ulcerative colitis. We can look to the evolving evidence for fecal transplantation as an illustration of how our microbiome matters. My favorite analogy is from former SBM blogger Mark Crislip who likened the gastrointestinal tract to a “metaphorical rainforest” giving a vivid mental image of the number of species (thousands) in our guts, and the complexity of that ecology. If the gastrointestinal tract is a rainforest, then can oral doses of “good” bacteria provide meaningful health benefits?
New practice guidelines
The American Gastroenterology Association (AGA) is the professional organization that represents gastroenterologists. Gastroenterologists are medical doctors that have taken postgraduate specialized training in gastrointestinal diseases. The AGA publishes guidelines on different conditions, which are said to represent clinical best practices and are intended to support medical practice. They state their guidelines follow best practices with respect to methodologic rigor, comprehensiveness, transparency, and conflict of interest. The AGA recently published a clinical practice guideline on probiotics in the journal Gastroenterology.
Probiotics are not drugs, and consequently the regulatory status can vary from country to country. In general, they are lightly regulated and do not require a prescription. Direct-to-consumer advertising is common, and the evidence behind efficacy claims is often unclear. Over time, the usage of probiotics has grown significantly, but that growth has not been accompanied by a solid evidence base to demonstrate that these products are beneficial. These new clinical practice guidelines are intended to help physicians and patients make decisions that are informed by the best evidence.
When it comes to assessing clinical practice guidelines, the fine print matters. In this case, funding for the work was provided by the AGA – not by any manufacturer, pharma, probiotic, or otherwise. The guidelines underwent independent peer review and was also open to public comment. Using methodologists, relevant questions were developed and the medical literature was searched systematically for high-quality evidence. In some cases, systematic reviews existed. In others, a Technical Review Panel completed the systematic review. Following the evidence search and retrieval, a Guideline Panel independently formulated the guideline recommendations. Considerations included evidence, risks/benefits, patient values, costs, and other factors. Here are the main recommendations and some comments:
In patients with Clostridioides difficile infection, we recommend the use of probiotics only in the context of a clinical trial.
C. difficile infections are very difficult to treat, often recur, and cause 29,000 deaths per year in the US. This is an infection that can be effectively treated with fecal transplantation. The evidence for probiotics is poor. Five trials with different products were identified, and because they were so different (in terms of patient populations and other considerations) the results couldn’t be combined. Due to high risk of bias (unpublished trials) and mixed results (one product appeared to increase C. difficile infection recurrence) there was little certainty that these products are effective.
In adults and children on antibiotic treatment, we suggest the use of S boulardii; or the 2-strain combination of L acidophilus CL1285 and Lactobacillus casei LBC80R; or the 3-strain combination of L acidophilus, Lactobacillus delbrueckii subsp bulgaricus, and Bifidobacterium bifidum; or the 4-strain combination of L acidophilus, L delbrueckii subsp bulgaricus, B bifidum, and Streptococcus salivarius subsp thermophilus over no or other probiotics for prevention of C difficile infection.
There is low quality evidence for some probiotics to prevent C. difficile infections. While there are many studies, the data is difficult to interpret owing to variations in patient type, antibiotic therapies, and the treatment setting (in-hospital vs. outpatient). Perhaps not surprisingly, the beneficial effects were seen mainly in patients already at high risk of a C. difficile infection. The guidelines note:
It should be pointed out that beneficial effect of probiotics was seen mainly in patients with very high risk of developing C difficile infection (>15% baseline risk) and that the analysis of most studies had a wide CI that includes the potential for some benefit, as well as for some harm. Thus, patients who place a high value on avoiding associated financial cost or potential harms (especially those immunocompromised patients) and who have low risk of developing C difficile infection (mainly outpatients in the community) may choose not to use any probiotics.
In adults and children with Crohn’s disease, the AGA recommends use of probiotics only in the context of a clinical trial.
Crohn’s disease is a chronic inflammatory bowel disease with no cure, and often requiring surgery. Given the interest in the microbiome and its relationship with Crohn’s disease, there has been significant interest in the potential for probiotics to help manage this debilitating disease. Given the evidence found it isn’t clear if probiotics have any potential value in Crohn’s disease.
In adults and children with ulcerative colitis, the AGA recommends the use of probiotics only in the context of a clinical trial.
Ulcerative colitis is another form of chronic inflammatory bowel disease. Like Crohn’s disease, the quality of evidence for probiotics was felt to be low.
In adults and children with pouchitis, the AGA suggests the use of the 8-strain combination of L paracasei subsp paracasei DSM 24733, L plantarum DSM 24730, L acidophilus DSM 24735, L delbrueckii subsp bulgaricus DSM 24734, B longum subsp longum DSM 24736, B breve DSM 24732, B longum subsp infantis DSM 24737, and S salivarius subsp thermophilus DSM 24731 over no or other probiotics.
When the large intestine and rectum is removed surgically to treat ulcerative colitis, the intestines can be operated on to formed a type of pocket which can hold waste before it is eliminated which eliminates the need for an external bag. Pouchitis is a common complication of this surgery and is an inflammation of the lining of the pouch. While the overall evidence was felt to be low there was weak evidence to support specific probiotics. The AGA supports the use under these circumstances, considering risk and benefit.
In symptomatic children and adults with irritable bowel syndrome, we recommend the use of probiotics only in the context of a clinical trial.
Irritable bowel syndrome is a disorder of the large intestines that can include cramping, pain, bloating, gas, and diarrhea or constipation. The causes of IBS are not known and may be multifactorial. Foods, medicines, and stress can trigger IBS. Given the difficulty in treating IBS there is a lot of interest in probiotics as a potential simple treatment. The evidence is lacking. Some studies use the same strain (S. boulardii) but found no overall difference in abdominal pain. An 8-strain combination found a reduction in abdominal pain but due to a number of methodologic problems, the overall significance is unclear. Single studies exist for other products but the overall quality of these trials was felt to be low. Additionally, publication bias due to registered-but-unpublished trials means that there is a lack of good data to inform decision-making.
In children with acute infectious gastroenteritis, we suggest against the use of probiotics.
Gastroenteritis is the infamous “stomach flu” that is common in children. It can be caused by bacteria and viruses, and causes diarrhea, cramping, nausea/vomiting, and sometimes a fever. Gastroenteritis is usually self-limiting and rehydration is typically all that is necessary. This is also an area where there have been dozens of trials but the number of high-quality trials is actually quite small. Most of the trials that show benefit were conducted outside of North America and were felt to be at high risk of bias. Two high-quality trials conducted in the US and Canada, conversely, showed no benefit. The guidelines note:
Given likely differences in host genetics, diet, sanitation, and endemic enteropathogens between North America and the other global regions, as well as different causes of acute infectious gastroenteritis in children, we do not feel that the studies conducted in other regions can be generalized to the population served by the AGA and thus suggest against the use of probiotics for acute infectious gastroenteritis in children.
In preterm (less than 37 weeks gestational age), low-birth-weight infants, we suggest using a combination of Lactobacillus spp and Bifidobacterium spp (L rhamnosus ATCC 53103 and B longum subsp infantis; or L casei and B breve; or L rhamnosus, L acidophilus, L casei, B longum subsp infantis, B bifidum, and B longum subsp longum; or L acidophilus and B longum subsp infantis; or L acidophilus and B bifidum; or L rhamnosus ATCC 53103 and B longum Reuter ATCC BAA-999; or L acidophilus, B bifidum, B animalis subsp lactis, and B longum subsp longum), or B animalis subsp lactis (including DSM 15954), or L reuteri (DSM 17938 or ATCC 55730), or L rhamnosus (ATCC 53103 or ATC A07FA or LCR 35) over no and other probiotics.
Necrotizing enterocolitis (NEC) is a very serious infection of the gastrointestinal tract that can affect preterm babies, often with devastating consequences. Preterm infants with NEC have different microbial flora compared with healthy infants, leading to the hypothesis that probiotics may be beneficial. And they are. There is moderate/high quality evidence that specific probiotics given to preterm infants can reduce the risk of death compared to placebo. They can also reduce the number of days of hospitalization, as well as the number of days for a preterm infant to reach full feeding.
Don’t believe (all) the hype
There is a lack of evidence to support the use of probiotics for digestive conditions like C. difficile infection, Crohn’s disease, ulcerative colitis, and irritable bowel syndrome. The AGA recommends against probiotic use for these conditions. And importantly, there is moderate evidence that probiotics do not improve the treatment of acute infectious gastroenteritis in children. However, the AGA found that there is evidence to suggest that probiotics may be useful in other, very specific clinical circumstances. Given the variety of species, strains, and manufacturing methods, it’s not possible to extrapolate across different products to assume that one will provide the same benefits as another. While manufacturers and marketers continue to make vague and often unproven claims of effectiveness, the evidence for probiotics is far less impressive than the hype. An editorial that accompanies the guidelines comments that the emergence of better evidence is held back by a regulatory framework for probiotics that isn’t designed to give clinicians and patients products that have been carefully evaluated. Given the potential value of microbial therapeutics, it is discouraging that we face an ongoing situation of a lack of good information to inform personal decision-making.