Probiotics for Crohns
Investigations into using probiotics for Crohns disease (Crohn's disease) are limited as of April 2023, but are increasing. Crohns is a complex autoimmune disease and common form of inflammatory bowel disease that primarily affects the gastrointestinal (GI) tract in affected adults and children. While most people think of only small intestinal involvement, this disease can affect any part of the GI tract. The primary sites of involvement, however, are the ileum, which is the last part of the small intestine, and the beginning of the colon.
Crohns causes an abnormal immune response that results in considerable inflammation predominantly in the walls of the intestines. It can begin at any age, although it most commonly presents itself in late-teenage-to early-adult years. Common symptoms are persistent diarrhea, abdominal pain and cramping, fatigue, appetite loss, weight loss, and fever.
Complications from this disease may include intestinal obstruction from inflammation and intestinal-wall thickening, fistulas (abnormal passages usually between two organs), abscesses, anal tears, ulcers, malnutrition, anemia, and inflammation in other parts of the body such as the joints, eyes, or skin. It may also increase the risk of colon cancer.
Crohns affects approximately 100-300 persons per 100,000 people, and is most common in western Europe and North America. In 2015, an estimated 780,000 people in the US were affected. Interestingly, children are twice as likely to be diagnosed with the disease than ulcerative colitis, another form of inflammatory bowel disease.
What Causes Crohns?
Like many autoimmune diseases, Crohns etiology is complex, as genetic, lifestyle, and environmental factors are thought to be involved. Researchers have identified at least 200 genetic variations, primarily in immune function, that increase disease risk. Only approximately 15% of Crohns patients have a first-degree relative with it, so this leaves a substantial number of patients with no direct genetic linkage to the disease.
Genetic evidence shows an immune deficiency, particularly in Caucasian patients with ileum-involved Crohns, in genes associated with the innate immune system's ability to recognize and kill bacteria inside cells. While it may be premature to say that intestinal microbes are the primary cause of the disease, it is generally agreed upon that those microbes effect patient well-being and clinical manifestations of the disease.
The fact that this disease involves an immune response in the intestines makes it reasonable to expect that the microbiome and probiotics for Crohns may influence disease course.
The Microbiome in Crohns
The microbiome in Crohns disease is disrupted, and not solely from a bacterial point of view.
Studies on bacterial microbiota show states of dysbiosis. Additionally, studies show differences in bacterial populations between fecal material, mucosal intestinal tissues, and submucosal intestinal tissues. Therefore, stool and mucosal samples may not reveal the bacteria that are actively invading and colonizing deeper intestinal tissues where Crohns inflammatory disease process occurs.
Additionally, studies show that fat tissue surrounding the intestines in Crohns responds to bacteria that have migrated out of the patient's damaged intestinal tissue directly into the fat. This "creeping fat" may be the body's protective response to the bacterial invasion, but it also may contribute to restrictions and intestinal scarring that occur in many patients.
In fact, increased visceral (around the waist) fat is associated with increased risk of penetrating disease, disease recurrence, and surgery in CD.
One study that investigated creeping fat in Crohns showed that when bacteria were isolated from the fat and introduced to mice models of IBD, the bacteria were pro-inflammatory. One of the culprits was identified as Achromobacter pulmonis, a pathogen known to be present in cystic fibrosis and in many opportunistic infections.
Recent studies are investigating phage therapy for targeting pathogens, such as Klebsiella pneumoniae, that are strongly associated with disease exacerbation and severity.
The Fungal Microbiome in Crohns
It may be that the mucosa-associated fungal microbiota (mycobiota) has the most profound effect on the disease. Studies on the fungal load in Crohns patients also show dysbiosis. Although the test for anti-Saccharomyces cerevisiae antibodies (ASCA), which detects yeast cell wall mannans found in many, but not all, fungi, is used to help distinguish between Crohns and ulcerative colitis, not all Crohns patients have those antibodies. Additionally, Saccharomyces boulardii, which is a strain of Saccharomyces cerevisiae, has shown positive effects as in two trials in probiotics for Crohns as an additional therapy.
One study published in 2022 involving 168 biopsies from 44 Crohns patients (inflamed and non-inflamed tissue) and 40 healthy controls revealed significant mycobiota differences. Crohns patients had:
- reduced mycobiota evenness
- increased Basidiomycota/Ascomycota ratio
- reduced abundance of Chytridiomycota
- increased Malassezia and a depletion of Saccharomyces
- increased abundances of Candida albicans and Malassezia restricta
In fact, the mycobiota differences between inflamed and proximal non-inflamed ileum tissue within the same patients showed marked differences that are believed to be involved in disease pathogenesis.
Malassezia, in particular, was associated with the need for more aggressive treatment during follow-up compared to healthy controls. You may have heard of Malassezia in discussions on dandruff. However, this normal skin commensal yeast is also present in intestinal mucosa and is recognized by ASCA antibodies.
Probiotics for Crohns
As previously mentioned, trials of probiotics for Crohns are limited at this time. The previously-mentioned Saccharomyces boulardii has shown positive effects in trials as an adjuvant therapy. Lactobacillus species may someday also be used in trials due to the interplay with their enzymes and a human receptor. The human pattern-recognition receptor NOD2 senses bacterial peptides to regulate host immunity and maintain homeostasis. Loss-of-function mutations in NOD2 are associated with the disease. Depletion of the enzyme DL-endopeptidase contributes to disease pathogenesis through NOD2 signaling, but probiotics such as Lactobacillus salivarius, which have DL-endopeptidase, increased the NOD2 ligand level in the gut and may be a beneficial therapy, although more studies must be done.
Oral health may play a role in Crohns. One study showed that in both patients with ulcerative colitis and those with Crohns, the gut microbiome was significantly more similar to the oral microbiome than in healthy controls. This suggested that gut colonization by oral bacteria is increased in patients with IBD, so perhaps probiotics that target oral health, like the aforementioned Lactobacillus salivarius, may help patients. Previous newsletters dedicated to oral health may be applicable to probiotics for Crohns, so I would recommend you revisit them.
A recent study showed that 85% of Crohns patients have antibody responses to at least 1 antigen but that only a very small minority of patients responds to several antigens. ASCA is only one of a few known microbial antibodies involved in Crohns, with others to an E. coli and a Pseudomonas documented. Therefore, it appears than rather than a total loss of tolerance to microbes, there seem to be groups of patients with different responses to selected microbial and autoantigens. Antimicrobial therapies, including probiotics for Crohns or their products, therefore must be individualized to each patient.
Animal studies have shown beneficial effects of Bifidobacterium infantis and Bifidobacterium bifidum on the disease symptoms, cell damage, and disease course. For some conditions, animal models very closely approximate what to expect in humans. However, animal models are only simplified models of Crohns disease and do not account for genetic and external environmental influences.
TNBS (2,4,6-trinitrobenzene sulfonic acid), which is used to induce Crohns-like symptoms in animal models, was found to skew murine microbiota in favor of some opportunist/pathogens that are not the same dominant opportunists/pathogens in human Crohns microbiota. This imbalance may amplify the competitive-inhibition effects of probiotics, making them more effective than they would be in a human. Therefore, in the case of Crohns, animal study results do not necessarily mean that the same results will be achieved in humans.
Final Thoughts
Crohns is a multifactorial disease, so therapy must be personalized for each patient, and that may mean that more than one health professional's expertise is needed to address all aspects of care. As I discussed in one of my newsletters, dietary intervention in this disease can make a noticeable improvement in symptoms. The type of inflammatory changes, the severity of the disease, the microbiota composition, and any environmental and genetic aspects must be considered for successful treatment. Additionally, the status of the disease as active or in remission can also affect treatment.
Since probiotics are live organisms, their use in the active stages of disease must be carefully considered so as not to introduce the possibility of the probiotics translocating out of the intestines. The few clinical studies of probiotics for Crohns in humans with the disease suggests that probiotics may be most helpful in remission phases to help maintain intestinal barrier and influence immune imbalances rather than being used to induce remission.
I believe that more well-designed clinical trials are necessary before specific probiotic formulations can be recommended toward inducing remission in patients. These trials should differentiate patients into groups with common markers rather than expecting one probiotic to address all markers. Additionally, trials with paraprobiotics (dead probiotic cells and/or their components) and postbiotics (products from probiotics' metabolism) may show safer and better effects than live microbes in these patients. Thus, the potential for probiotics for Crohns is there, it just may take more specific trials to illuminate the ones appropriate for each variation of the disease.
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References:
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RJ Chiodini et al. "Microbial Population Differentials between Mucosal and Submucosal Intestinal Tissues in Advanced Crohn's Disease of the Ileum," PLOS One 10.7 (2015).
- https://www.cedars-sinai.org/newsroom/medical-mystery-creeping-fat-in-crohns-patients-linked-to-bacteria/
- https://www.crohnscolitisfoundation.org/clinical-pearls/mesenteric-fat-crohns-disease
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Z He at al. "Microbiota in mesenteric adipose tissue from Crohn's disease promote colitis in mice," Microbiome 9.228 (2021).
- S Fecerici et al. "Targeted suppression of human IBD-associated gut microbiota commensals
by phage consortia for treatment of intestinal inflammation," Cell 185.16 (2022).
- M Olaisen et al. "The ileal fungal microbiota is altered in Crohn's disease and is associated with the disease course,"Front Med (Lausanne) (2022).
- J Gao et al. "Gut microbial DL-endopeptidase alleviates Crohn's disease via the NOD2 pathway," Cell Host Microbe 30.10 (2022).
- "A potential pathogenic association between periodontal disease and Crohn's disease,"
- "Antibody Responses in Crohn’s Disease," Gasterenterology 126.2 (2004).
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