Welcome to my blog on Clostridium butyricum.
What Is Clostridium butyricum?
C. butyricum, a butyrate-producing, spore-forming anaerobic bacterium, is found in a wide variety of environments, including soil, cultured milk products, and vegetables. It is also present in the human gut: it is detected in 10–20% of the adult human population and is often one of the earliest colonizers in infants. In the human gut, where it is considered a ‘symbiontʹ (living together with the host), Clostridium butyricum has a fermentative lifestyle and can consume undigested dietary fibers and generate short-chain fatty acids (SCFAs), specifically butyrate and acetate. Butyrate is one of the dominant fermentation end-products and is produced by Clostridium butyricum via the butyrate kinase (buk) pathway.
SCFAs produced by microbial organisms in the colon are known to have myriad and important effects on host health, including modulating intestinal immune homeostasis, improving gastrointestinal barrier function, and alleviating inflammation. As such, butyrate-producing organisms like Clostridium butyricum have become attractive candidates to test for beneficial effects in a host. Genomic analyses are increasingly identifying novel bacterial strains with health-promoting potential that are distinct from classic probiotics (Lactobacilli and Bifidobacteria).
Can You Supplement Clostridium butyricum?
Clostridium butyricum is a species that encompasses various known strains, some of which have genes equipping them to produce toxins. However, genomic analyses confirm that other strains do not have these genes nor other markers of pathogenesis potential, and that these nonpathogenic strains have excellent potential to benefit host health through several mechanisms. Certain strains of Clostridium butyricum have been used as a probiotic for decades. Strain MIYAIRI 588, first isolated from the faeces of a healthy human by Dr. Chikaji Miyairi in 1933, and later from soil in 1963, is a commercially-available, over-the-counter probiotic widely used in Japan, Korea, and China for the treatment of (antimicrobial-associated) diarrhoea.
Strain CBM 588 is also authorised under the regulation of the European Parliament and of the Council as a novel food ingredient. Its widespread use is enabled by its safe, nonpathogenic and nontoxic profile: studies have shown that it is sensitive to antibiotics, devoid of pathogenic markers, and lacks clostridial toxin genes.
What Does Clostridium butyricum Do?
Across many of these disorders there is evidence to suggest that Clostridium butyricum is a promising therapeutic candidate. Although the precise mechanisms explaining these health benefits are not fully elucidated, current evidence suggests that in vivo, localized production of SCFAs is important for conferring health benefits. There are numerous pathways by which acetate and butyrate impact immune homeostasis and the physiology of the gut barrier. It is also suggested that C. butyricum may modulate the composition of the gut microbiome, possibly increasing certain beneficial bacterial taxa such as Lactobacillus and Bifidobacterium.
Clostridium butyricum strengthens the gut barrier
The intestinal barrier performs a critical balancing act: maintaining the tolerance of gut microbiota and absorption of nutrients on the one hand, and defense against pathogen invasion on the other. It acts as a selective barrier, preventing the permeation of toxins and antigens, while facilitating the absorption of nutrients, electrolytes, and water.
The mucus layer represents the primary physical barrier against pathogen invasion. This gel-like layer varies in thickness along the length of the GI tract and is primarily composed of glycoproteins (i.e mucins) secreted by goblet cells in the epithelium. Mucin 2 (MUC2) is the most abundant and well studied secreted gastrointestinal mucin. Knocking out MUC2 in mice can cause the development of spontaneous colitis and increases the risk of colorectal cancer, highlighting the importance of this barrier for immune homeostasis and overall health. Introducing Clostridium butyricum has been shown to protect properties of the mucosal layer in two different mouse models.
Clostridium butyricum modulates immune function and inflammation
The intestinal epithelium monitors the gut microbiota via pathogen recognition receptors (PRRs) capable of recognizing pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS). PRRs distinguish the pathogens from non-pathogens and mediate immune response against the former. The inflammatory mediators released by the epithelium upon detection of pathogens trigger the maturation of antigen presenting cells (APCs) such as dendritic cells. Mature APCs then produce signals to activate the differentiation and expansion of appropriate T cell types.
Additionally, microbial components and metabolites of both pathogens and commensals can stimulate the release of host-derived antimicrobial peptides (AMP) or secreted immunoglobulin A (IgA) that provide an additional chemical barrier between the luminal microorganisms and the host. Therefore, changes in bacterial composition in the gut can shift the immune system, with effects often extending beyond the gut.
Clostridium butyricum restores immune homeostasis by promoting Treg responses
The Treg response suppresses activation of inflammatory responses driven by effector T cells such as Th1, Th2 and Th17. The balance between Tregs and pro-inflammatory effector T cells in the intestine is increasingly recognized as regulated by the gut microbiome.
Clostridium butyricum promotes intestinal immune tolerance by increasing the abundance of Tregs, as evidenced by the accumulation of induced Tregs especially in the mesenteric lymph node, along with the decreased proportion of Th1 and Th17 cells in the disease target organs such as the pancreas, spleen, liver, brain, and intestines.
Clostridium butyricum and gastrointestinal health
Several studies in animal models have demonstrated C. butyricum’s ability to reduce the incidence of antibiotic-associated diarrhea (AAD) and antibiotic-induced gut dysbiosis.
Studies have also identified Clostridium butyricum as a preventative intervention for gut pathogen infection. Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes diarrhea and hemorrhagic colitis in humans. Takahashi et al. demonstrated that EHEC O157:H7 growth, toxin production, and adhesion to epithelial cells is inhibited in vitro by CBM 588.
Clostridium butyricum supplementation has also demonstrated a positive effect across several murine models of colitis, ulcerative colitis (UC), and irritable bowel syndrome (IBS).
Clostridium butyricum in the management of metabolic diseases
Metabolic diseases including diabetes (type 1 and type 2) and liver diseases are considered systemic conditions, as they arise from and continue to affect dysregulated inter-organ crosstalk. Even though C. butyricum and other gut microbes are physically located in the gut lumen, their indirect effects extend from gut barrier integrity to immune modulation and endocrine regulation, consequently influencing metabolic signals throughout the body.
C. butyricum has potential anti-diabetic effects as murine type 2 diabetes studies have reported that C. butyricum supplementation ameliorates abnormalities in host metabolism and microbial butyrate production, which is shown to be deficient in humans with this condition. Jia et al. examined both leptin receptor-deficient (lepdb/db) and high-fat diet (HFD) + streptozotocin induced diabetic mice and Shang et al. examined HFD-induced diabetic mice. Both studies noted C. butyricum supplementation reduced weight gain and fat accumulation, and improved glucose tolerance and insulin sensitivity.
Liver disease and Clostridium butyricum
The potential benefits of C. butyricum have also been investigated in liver metabolic dysfunction. Nonalcoholic fatty liver disease (NAFLD) is common in obese and insulin resistant individuals, especially those with type 2 diabetes. Studies of C. butyricumsupplementation in murine models of NAFLD reported improved hepatic lipid metabolism and immunoregulation. Seo and colleagues investigated the effect of CBM 588 supplementation in a rat model of HFD-induced NAFLD and found C. butyricum treatment helped maintain metabolic parameters including body weight, fat mass, and insulin resistance at normal levels while also protecting from liver injury and dysregulation of lipid metabolism.
Clostridium butyricum in neuroprotection
The microbiota-gut-brain axis is a developing area of research that posits microbial influence on the bi-directional communication between the central and enteric nervous systems. Gastrointestinal bacteria have the ability to alter the endocrine and neurotransmitter signaling, as well as incite immune reactions in response to inflammatory neurological conditions. Therefore, probiotics have been suggested as a potential intervention for various neurological disorders. C. butyricum engages in cross-functional communication between systems by influencing several immune and metabolic pathways, deterring the progression of detrimental neuroinflammatory reactions.
Clostridium butyricum in human clinical trials
In humans, we could find seven additional papers examining C. butyricum’s potential as a probiotic in clinical trials of gastrointestinal, psychiatric, and metabolic disorders.
Two of these clinical studies pertain to antibiotic-associated diarrhea (AAD), both in children and in adult patients with gastro-duodenal ulcers undergoing Helicobacter pylori eradication therapy. The primary endpoint, diarrhea incidence, decreased across both open-label trials: Seki et al. reported a decrease from 59% in the antibiotics-only arm, to 5% in children receiving C. butyricum for three days, and to 9% in those that received treatment for all six days. Imase et al. similarly saw a decrease from 43% in the antibiotics-only group to 14% in low dose and 0% in high dose C. butyricum supplementation groups; the H. pylori eradication rate was unaffected by the supplementation.
Similarly, Sun et al. reported improved diarrhea symptoms (IBS symptom severity scale) and quality of life ((IBS-QOL scores) in a double-blind, placebo-controlled study of subjects with diarrhea-predominant IBS receiving C. butyricum daily for 4 weeks, compared to the placebo group.
Finally, C. butyricum has also been investigated in humans for the management of pouchitis. Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is the standard surgical procedure for patients with UC, whereby surgeons create a pouch to replace the damaged colon and rectum. However, the pouch can become inflamed and damaged in a complication known as pouchitis. Yasueda et al. found that commercially available CBM 588 tablets reduced the incidence of pouchitis in UC patients from 50% in the placebo group to 11% in the C. butyricum-treated group. Due to a small sample size (9 treatment, 8 placebo patients), this decrease was non-significant.
C. butyricum has also been investigated in humans as a treatment for psychological disorders: treatment-resistant major depressive disorder (TRD) and minimal hepatic encephalopathy (MHE). Miyaoka et al. found that subjects with TRD receiving C. butyricum in addition to SSRI (selective serotonin reuptake inhibitors) antidepressants reported significantly lower median scores across several indices compared to the control group. Along these lines, Xia et al. reported that a probiotic multi-strain formulation featuring C. butyricum CGMCC0313.1 and B. infantis CGMCC0313-2 improved cognition (measured via the number connection test A and digit symbol test) in subjects with minimal hepatic encephalopathy (MHE), a complication of liver cirrhosis that leads to mild cognitive and motor impairment.
Read my blog Can Gut Health Affect Mental Health for more on this connection.
How To test For Clostridium butyricum
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How To Take Clostridium butyricum
Across these studies, a similar dose of the chosen strains of C. butyricum (~ 107 CFU/g) administered orally was well tolerated and deemed safe, and had a positive impact across the primary endpoints of each study. However, of the seven studies, only three were placebo-controlled and only two were double-blind; hence, interpretations of benefit must be made with caution. Additional double-blind and placebo-controlled clinical studies are needed across indications to resolve and expand upon these findings.