Clostridium butyricum (CBM588 / Probiotics) and Sodium Butyrate

Clostridium butyricum CBM 588 probiotic strain (link)

A probiotic containing a specific strain of the anaerobic, butyric acid-forming Gram-positive bacterium Clostridium butyricum (C. butyricum), with potential immunomodulatory, anti-inflammatory and antineoplastic activities. Clostridium butyricum MIYAIRI (CBM) 588 is the 588th MIYAIRI strain, isolated from a soil sample in Japan in 1963. Upon oral administration of C. butyricum CBM 588 probiotic strain, C. butyricum modulates the composition of the normal gastrointestinal (GI) microflora, by increasing the beneficial bacteria and decreasing the harmful bacteria, and helps maintain adequate colonization of the GI tract, thereby improving digestion and preventing GI disturbances. These bacteria and the butyric acid produced by them create an environment unfavorable to pathogens by adhering to human epithelial cells and forming a protective mucosal barrier. This prevents attachment of pathogens and reduces the risk of infection. By restoring gut microbiota, these bacteria may restore or enhance intestinal immune responses. C. butyricum induces interleukin-10-producing macrophages in inflamed mucosa via the Toll-like receptor 2 (TLR2)/myeloid differentiation primary response gene 88 (MyD88) pathway, thereby decreasing inflammatory responses. In addition, CBM588 may exert antineoplastic activity by inducing the release of the endogenous cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from intracellular stores in polymorphonuclear neutrophils (PMNs), most likely involving matrix metalloproteinase 8 (MMP-8) and the Toll-like receptors (TLR)2/4 signaling pathways. This results in TRAIL-mediated induction of apoptosis in susceptible tumor cells.

First results of a randomized phase IB study comparing nivolumab/ipilimumab with or without CBM-588 in patients with metastatic renal cell carcinoma.

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.4513

Background: Recent evidence suggests that the gut microbiome is a potent mediator of immune checkpoint inhibitor (ICI) activity in metastatic renal cell carcinoma (mRCC), with both specific bacterial species and cumulative microbial diversity driving response (Routy et al Science 2018; Salgia et al Eur Urol 2020). We examined whether the butyrate-producing bacterium Clostridium butyricum, the key constituent of CBM-588, could modulate the gut microbiome in patients (pts) with mRCC receiving nivolumab/ipilimumab (N/I) and secondarily improve clinical outcome. Methods: An open-label, randomized study was conducted, with key eligibility criteria including confirmed clear cell and/or sarcomatoid mRCC, intermediate/poor risk by IMDC criteria and no systemic therapy for metastatic disease. Patients were randomized 2:1 to receive either N/I+CBM-588 or N/I alone. N/I was dosed at 3 mg/kg and 1 mg/kg IV every 3 weeks for 12 weeks, followed by N at 480 mg IV every 4 weeks. CBM-588 was dosed orally at 80 mg bid. Stool was collected for bacteriomic profiling at baseline and 12 weeks. Metagenomic sequencing was employed using previously published methods (Dizman et al Cancer Med 2020). The primary endpoint of the study was change in Bifidobacterium spp. from baseline to week 12. Secondary endpoints included change in microbial diversity and clinical outcomes including response rate (RR) and progression-free survival (PFS). Results: 30 pts were randomized between April 2019 and Nov 2020; 1 pt was excluded after genomic sequencing clarified a diagnosis of sarcoma. Among 29 evaluable patients (21:8 M:F), median age was 66, 10 pts (34%) had sarcomatoid features and 24 pts (83%) were intermediate risk. Metagenomic sequencing of paired stool specimens showed an 8-fold increase in B. bifidum and a 6-fold increase in B. adolescentis in pts receiving N/I+CBM-588 from baseline to week 12. C. butyricum was detected only in pts receiving CBM-588. Pathogenic species (e.g., Escherichia. coli and Klebsiella spp.) were more prevalent in pts not receiving CBM-588. RR was significantly higher among pts receiving N/I+CBM-588 vs N/I alone (59% vs 11%; P = 0.024). Median PFS was also prolonged with the addition of CBM-588 to N/I (NR vs 11 weeks; P < 0.001). No significant difference in grade 3/4 toxicities were observed between study arms. Conclusions: This is the first randomized, prospective study to suggest enhancement of ICI response with a live bacterial product. The observed clinical impact is corroborated by biologic findings supporting gut modulation by CBM-588. Clinical trial information: NCT03829111.

The Butyrate-Producing Bacterium Clostridium butyricum Suppresses Clostridioides difficile Infection via Neutrophil- and Antimicrobial Cytokine-Dependent but GPR43/109a-Independent Mechanisms

Short-chain fatty acids, such as butyrate, are major gut microbial metabolites that are beneficial for gastrointestinal health. Clostridium butyricum MIYAIRI588 (CBM588) is a bacterium that produces a robust amount of butyrate and therefore has been used as a live biotherapeutic probiotic in clinical settings. Clostridioides difficile causes life-threatening diarrhea and colitis. The gut resident microbiota plays a critical role in the prevention of C. difficile infection (CDI), as the disruption of the healthy microbiota by antibiotics greatly increases the risk for CDI. We report that CBM588 treatment in mice significantly improved clinical symptoms associated with CDI and increased the number of neutrophils and Th1 and Th17 cells in the colonic lamina propria in the early phase of CDI. The protective effect of CBM588 was abolished when neutrophils, IFN-γ, or IL-17A were depleted, suggesting that induction of the immune reactants is required to elicit the protective effect of the probiotic. The administration of tributyrin, which elevates the concentration of butyrate in the colon, also increased the number of neutrophils in the colonic lamina propria, indicating that butyrate is a potent booster of neutrophil activity during infection. However, GPR43 and GPR109a, two G protein-coupled receptors activated by butyrate, were dispensable for the protective effect of CBM588. These results indicate that CBM588 and butyrate suppress CDI, in part by boosting antimicrobial innate and cytokine-mediated immunity.

KCRS21: Abstract Oral Presentations: Nivolumab/ipilimumab with or without CBM588 in metastatic renal cell carcinoma: a randomized phase Ib study and in-depth analysis of gut microbiome evolution (link)

- Nazli Dizman, Yale New Haven Hospital

C. butyricum was detected only among those receiving CBM-588. Further, pathogenic species including Escherichia. coli and Klebsiella spp. were more prevalent in patients who did not receive CBM-588.

Where to get? (Google Search)

CBM588 is manufactured under good manufacturing practices and marketed in Japan by Miyarisan Pharmaceutical as a prescription product known as Clostridium butyricum MIYAIRI 588 strain for the treatment of gastrointestinal indications. It has an excellent safety profile in all age groups and immunocompromised patients, as confirmed by postmarketing surveillance. 

 

Product Description

"Strong Miyarisan Tablets 1000" is an intestinal regulator containing butyric acid bacteria (Miyairi bacteria) that maintain a normal intestinal balance. 9 tablets contain 270 mg of butyric acid bacteria (Miyairi bacteria). Quasi-drugs. Contains 1000 tablets.

Take the following dose 3 times a day after meals.

≥ 15 years of age ・・・ 3 tablets per dose

Association of Probiotic Clostridium butyricum Therapy with Survival and Response to Immune Checkpoint Blockade in Patients with Lung Cancer, 2020

Gut dysbiosis caused by antibiotics impairs response to immune checkpoint blockade (ICB). Gut microbiota is becoming an attractive therapeutic target for cancer. The Clostridium butyricum MIYAIRI 588 strain is a probiotic therapy used to improve symptoms related to antibiotic-induced dysbiosis in Japan. We hypothesized that probiotic Clostridium butyricum therapy (CBT) may affect the therapeutic efficacy of ICBs. We retrospectively evaluated 118 patients with advanced non–small cell lung cancer treated with ICBs at Kumamoto University Hospital (Kumamoto-shi, Kumamoto, Japan). Survival analysis comparing patients given CBT before and/or after ICB was conducted using univariate analyses and Cox proportional hazards regression models using propensity score. Propensity score analyses confirmed that probiotic CBT significantly prolonged progression-free survival (PFS) and overall survival (OS). Probiotic CBT significantly associated with longer PFS and OS even in patients who received antibiotic therapy. This study suggests that probiotic CBT may have a positive impact on therapeutic efficacy of ICB in patients with cancer.

Clostridium butyricum MIYAIRI 588 shows antitumor effects by enhancing the release of TRAIL from neutrophils through MMP-8, 2013

Bacillus Calmette-Guérin (BCG) intravesical therapy against superficial bladder cancer is one of the most successful immunotherapies in cancer, though the precise mechanism has not been clarified. Recent studies have demonstrated urinary tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels to be higher in BCG-responsive patients than non-responders and shown that polymorphonuclear neutrophils (PMNs) migrating to the bladder after BCG instillation release large amounts of TRAIL. To establish a safer and more effective intravesical therapy than BCG, we examined whether other bacteria induced similar effects. We stimulated PMNs or peripheral blood mononuclear cells (PBMCs) with BCG or other bacteria, and then aliquots of the culture supernatants or cell lysates were assayed for TRAIL. We examined the signaling pathway regulating the release of TRAIL from PMNs and evaluated the antitumor effects of BCG or other bacteria in vitro and in vivo. We have found that Clostridium butyricum MIYAIRI 588 (CBM588) induces the release of endogenous TRAIL from PMNs as well as BCG. In addition, we have shown that matrix metalloproteinase 8 (MMP-8) is one of the key factors responsible for the release. Interestingly, TLR2/4 signaling pathway has been suggested to be important for the release of TRAIL by MMP-8. CBM588 has been proven to be as effective as BCG against cancer cells by inducing apoptosis in vivo as well as in vitro. Taken together, these results strongly suggest that CBM588 is promising for a safer and more effective therapy against bladder cancer.

Effects of probiotics on chemotherapy in patients with lung cancer, 2019

Chemotherapy damages the intestinal mucosa, causing adverse gastrointestinal reactions. Clostridium butyricum (C. butyricum) reduces the incidence of diarrhea in digestive diseases, including inflammatory bowel disease. Therefore, the aim of the present study was to investigate the role of C. butyricum in patients undergoing chemotherapy. A total of 41 participants with lung cancer were enrolled, and divided into the C. butyricum (CB) or placebo group using 1:1 randomization to obtain 20 CB and 21 placebo participants. On the first and last day of the 3‑week intervention, blood and stool samples were collected and analyzed. To analyze stool flora, 16S ribosomal RNA sequencing was performed. The incidence of chemotherapy‑induced diarrhea was lower in the CB group compared with the placebo group. The lymphocyte count and platelet/lymphocyte ratio (PLR) was markedly altered between the two groups. Neutrophil/lymphocyte ratio (NLR) and PLR decreased within the CB group. At week 3, the lymphocyte/monocyte ratio (LMR) was higher in the CB group compared with the placebo group. Alterations in lymphocyte subsets and immunoglobulin levels were not significantly different. Albumin (ALB) level and weight did not differ significantly between the two groups. At 3 weeks the total flora diversity did not decrease in either group. Phyla in the CB group varied slightly, while the proportion of Firmicutes in the placebo group decreased significantly. No statistically significant difference was observed between the two groups, though the genera producing short‑chain fatty acids tended to increase, and the pathogenic genera tended to decrease in the CB group, which was almost the opposite of the observation in the placebo group. Operational taxonomy unit analysis revealed a notable increase in beneficial flora, including the Clostridium and Lactobacillus genera of the CB group, compared with the placebo group. The present study highlighted that C. butyricum reduced chemotherapy‑induced diarrhea in patients with lung cancer, reduced the systemic inflammatory response system and encouraged homeostatic maintenance.

Clostridium butyricum MIYAIRI 588 Increases the Lifespan and Multiple-Stress Resistance of Caenorhabditis elegans, 2018

Clostridium butyricum MIYAIRI 588 (CBM 588), one of the probiotic bacterial strains used for humans and domestic animals, has been reported to exert a variety of beneficial health effects. The effect of this probiotic on lifespan, however, is unknown. In the present study, we investigated the effect of CBM 588 on lifespan and multiple-stress resistance using Caenorhabditis elegans as a model animal. When adult C. elegans were fed a standard diet of Escherichia coli OP50 or CBM 588, the lifespan of the animals fed CBM 588 was significantly longer than that of animals fed OP50. In addition, the animals fed CBM588 exhibited higher locomotion at every age tested. Moreover, the worms fed CBM 588 were more resistant to certain stressors, including infections with pathogenic bacteria, UV irradiation, and the metal stressor Cu2+. CBM 588 failed to extend the lifespan of the daf-2/insulin-like receptor, daf-16/FOXO and skn-1/Nrf2 mutants. In conclusion, CBM 588 extends the lifespan of C. elegans probably through regulation of the insulin/IGF-1 signaling (IIS) pathway and the Nrf2 transcription factor, and CBM 588 improves resistance to several stressors in C. elegans.

Clostridium butyricum MIYAIRI 588 as Adjunctive Therapy for Treatment-Resistant Major Depressive Disorder: A Prospective Open-Label Trial, 2018

Abstract

Aim 

Up to 60% of depressed patients do not obtain sufficient relief from a course of antidepressant therapy, and these treatment-resistant major depressive disorder (TRD) patients are at increased risk for relapse, chronicity, persistent psychosocial impairments, and suicide. Probiotics actively participate in treatment of neuropsychiatric disorders. However, the role of gut microbiota in brain disorders and depression remains unclear. We performed a prospective study to evaluate the effects of Clostridium butyricum MIYAIRI 588 (CBM588).

Methods 

This was an 8-week open-label study to evaluate the efficacy and safety of CBM588 in combination with antidepressants in adult patients diagnosed with TRD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Forty antidepressant-treated inpatients were included. Patients were randomized to adjuvant treatment with CBM588 (n = 20) or control (n = 20). The primary endpoint was the change in the 17-item Hamilton Depression Rating Scale score from baseline to week 8. Secondary end points were changes in the Beck Depression Inventory and the Beck Anxiety Inventory scale scores from baseline to week 8. The Systematic Assessment of Treatment Emergent Events—General Inquiry was used to assess adverse effects.

Results 

CBM588 (60 mg/d) in combination with antidepressants (flvoxamine, paroxetine, escitalopram, duroxetine, and sertraline) provided significant improvement in depression. All patients completed the trial, and 70% responded to treatment; the remission rate was 35.0%. No serious adverse events occurred.

Conclusions 

These preliminary data suggest that CBM588 in combination with antidepressants is effective and well tolerated in the treatment of TRD. Further studies using a larger, double-blind, parallel-group design are warranted to confirm these findings.

[NEGATIVE] Cancer: Are probiotics making immunotherapy less effective?

Immunotherapy is a cancer treatment with several benefits. For this reason, improving its effectiveness is vital. In studying the gut microbiome, scientists have found some rather unusual results.

Probiotic supplements may hinder cancer treatment.

Cancer immunotherapy is a relatively young field.

However, it has the potential for long-term remission and less likely side effects.

According to the Cancer Research Institute, scientists have shown that it is effective at treating cancers that are resistant to both chemotherapy and radiation therapy.

Immunotherapy works by helping the immune system fight off the disease. Cancer cells normally go undetected by the immune system, but the treatment uses drugs and other substances to produce a stronger response.

Checkpoint inhibitors are one type of immunotherapy. They affect cancer cells’ ability to dodge immune system attacks. However, they only work for 20–30 percent of people with cancer.

Scientists have recently found that the gut microbiome, which comprises trillions of intestinal microorganisms, has the ability to control the immune system.

A group of researchers from the Parker Institute for Cancer Immunotherapy in San Francisco, CA, and the University of Texas MD Anderson Cancer Center in Houston has examined whether this could be impacting immunotherapy success rates.

A surprising result

The preliminary study is the first to look at the link between immunotherapy, the gut microbiome, and diet in people with cancer. In all, 113 individuals with metastatic melanoma who had started treatment at MD Anderson took part.

The scientists presented their findings at the American Association for Cancer Research’s recent annual meetings, which took place in Atlanta, GA.

The participants filled out a lifestyle survey on their diet, medication, and use of supplements. The researchers also analyzed their fecal samples to build up a picture of each individual gut microbiome. They also tracked the participants’ treatment progress.

One surprising finding came to light. Taking over-the-counter probiotic supplements correlated with a 70 percent lower chance of responding to checkpoint inhibitor immunotherapy. Almost half (42 percent) of the participants reported taking such supplements.

The researchers also noticed a relationship between probiotics and lower gut microbiome diversity. Scientists had already seen this in people with cancers that respond poorly to immunotherapy.

“The general perception is [that probiotics] make your gut microbiome healthier,” says first study author Christine Spencer, a research scientist at the Parker Institute. “While more research is needed, our data suggest that may not be the case for cancer patients.”

 

Sodium butyrate

Sodium butyrate enhances the growth inhibitory effect of sunitinib in human renal cell carcinoma cells

Sunitinib (SU) is a small molecule that inhibits the receptor tyrosine kinase (RTK) signaling pathway, and has been clinically used to treat advanced renal cell carcinoma (RCC). However, SU is not always effective as RCC is a highly chemoresistant type of cancer. One of the factors that confer chemoresistance to RCC is a hypoxic condition. Lack of oxygen activates hypoxia-inducible factor (HIF) protein, which is followed by the upregulation of growth factors, including vascular endothelial growth factor and activation of the RTK signaling pathway. In this context, histone deacetylase inhibitors (HDACIs) are considered prominent combined agents for SU as they downregulate the expression of HIFs. Therefore, the present study aimed to investigate the effectiveness of combined treatment with SU and sodium butyrate (NaBu), an HDACI. Long-term exposure to these agents exerted a stronger growth inhibitory effect in RCC cell lines compared with single treatment groups. Furthermore, combined treatment suppressed HIF-2α protein, which was induced under hypoxic conditions. In addition, this combination sustained the activity of the RTK signaling pathway to the level of intact cells, although a single treatment with SU or NaBu was demonstrated to increase this activity. Overall, it is suggested that the combination of SU and NaBu is effective for overcoming drug resistance in RCC.

Sodium butyrate induces apoptosis in human renal cell carcinoma cells and synergistically enhances their sensitivity to anti-Fas-mediated cytotoxicity

Sodium butyrate (NaBt), one of the short chain fatty acids naturally formed in the gastrointestinal tract, induces differentiation as well as apoptosis in numerous cell types. The objectives of this study were to characterize the effects of NaBt on the growth, cell cycle, and apoptosis of human renal cell carcinoma (RCC) cells, and to determine whether NaBt enhances the Fas-mediated cytotoxicity in these cells. NaBt reduced the in vitro growth rate of human RCC ACHN cells in a time- and dose-dependent manner. Treatment of ACHN cells with 1 mM NaBt resulted in G1 cell cycle arrest, accompanied by up-regulation of p21 (waf1/cip1) and down-regulation of cyclin D1. In contrast, 5 mM NaBt-induced apoptotic cell death in ACHN cells, accompanied by up-regulation of BaK and down-regulation of Bcl-2. Furthermore, NaBt synergistically enhanced the growth-inhibitory effect of anti-Fas monoclonal antibody, CH11 on CH11-sensitive ACHN cells, and apoptotic cell death was induced by the combination of sublethal doses of NaBt and CH11, but not by either agent alone. Similar synergy was also observed in CH11-resistant human RCC KN39 cells. These findings suggest that NaBt could be a novel attractive approach for patients with RCC, and that the efficacy of NaBt may be enhanced by the combined use of Fas-mediated therapy.

Sodium butyrate induces cell death by autophagy and reactivates a tumor suppressor gene DIRAS1 in renal cell carcinoma cell line UOK146. 2018

Sodium butyrate (SB), a histone deacetylase inhibitor, is emerging as a potent anti-cancer drug for different types of cancers. In the present study, anti-cancer activity of SB in Xp11.2 (TFE3) translocated renal cell carcinoma cell line UOK146 was studied. Anti-proliferative effect of SB in renal cell carcinoma (RCC) cell line UOK146 was evaluated by MTT assay and morphological characteristics were observed by phase contrast microscopy which displayed the cell death after SB treatment. SB induces DNA fragmentation and change in nuclear morphology observed by increased sub-G1 region cell population and nuclear blebbings. Cell cycle arrest at G2/M phase was found after SB treatment. UOK146 cell line shows autophagy mode of cell death as displayed by acridine orange staining and flow cytometry analysis. LC3-II, a protein marker of autophagy, was also found to be upregulated after SB treatment. A tumor suppressor gene DIRAS1 was upregulated after SB treatment, displaying its anti-cancer potential at molecular level. These findings suggest that SB could serve as a novel regulator of tumor suppressors and lead to the discovery of novel therapeutics with better and enhanced anti-cancer activity.

Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms, 2013

Constitutive activation of Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling has an important role in the oncogenesis of myeloproliferative neoplasms (MPNs) and leukemia. Histone deacetylases (HDACs) inhibitors have been reported to possess anticancer activity through different mechanisms. However, whether HDACs inhibitors suppress JAK2/STAT signaling in MPNs is still unknown. In this study, we show that the HDAC inhibitor sodium butyrate (SB) inhibited JAK2/STAT signaling and increased the expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3, both of which are the potent feedback inhibitors of JAK2/STAT signaling. SB upregulated the expression of SOCS1 and SOCS3 by triggering the promoter-associated histone acetylation of SOCS1 and SOCS3 in K562 and HEL cell lines. Importantly, we found that upon knockdown of each class I HDACs, only knockdown of HDAC8 resulted in the increased expression of SOCS1 and SOCS3. Moreover, overexpression of SOCS1 and SOCS3 significantly inhibited cell growth and suppressed JAK2/STAT signaling in K562 and HEL cells. Furthermore, SB increased the transcript levels of SOCS1 and SOCS3 and inhibited the clonogenic activity of hematopoietic progenitors from patients with MPNs. Taken together, these data establish a new anticancer mechanism that SB inhibits JAK2/STAT signaling through HDAC8-mediated upregulation of SOCS1 and SOCS3. Thus, HDACs inhibitors may have therapeutic potential for the treatment of MPNs.

Short Chain Fatty Acids in the Colon and Peripheral Tissues: A Focus on Butyrate, Colon Cancer, Obesity and Insulin Resistance, 2018

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748798/

Microencapsulated sodium butyrate administered to patients with diverticulosis decreases incidence of diverticulitis—a prospective randomized study

Background

Microencapsulated sodium butyrate (MSB) has been previously associated with anti-inflammatory and regenerative properties regarding large bowel mucosa. We aimed to examine a role of MSB in patients with diverticulosis, hypothesizing its potential for reduction of diverticulitis episodes and diverticulitis prevention.

Methods

Seventy-three patients with diverticulosis (diagnosed in colonoscopy or/and barium enema or/and CT colography) were recruited for the study and randomized. The investigated group was administered MSB 300 mg daily; the control group was administered placebo. After 12 months, a total of 52 patients completed the study and were subject to analysis (30 subjects and 22 controls). During the study, the number of episodes of diverticulitis (symptomatic diagnosis with acute pain, fever, and leukocytosis), hospitalizations, and surgery performed for diverticulitis were recorded. Additionally, a question regarding subjective improvement of symptoms reflected changes in quality of life during the analysis.

Results

After 12 months, the study group noted a significantly decreased number of diverticulitis episodes in comparison to the control group. The subjective quality of life in the study group was higher than in the control group. There were no side effects of the MSB during the therapy.

Conclusions

MSB reduces the frequency of diverticulitis episodes, is safe, and improves the quality of life. It can play a role in the prevention of diverticulitis.