Abstract
Background/Aim: It has been reported that oral administration of lipopolysaccharide (LPS) recovers an individual's immune condition and induces the exclusion of foreign matter, inflammation and tissue repair. We orally administered LPS from the wheat symbiotic bacteria Pantoea agglomerans, which has been ingested and proven to be safe, to cancer patients. Our observation of clinical improvements resulting from this treatment are reported. Patients and Methods: Sixteen cancer patients who exhibited declined small intestinal immune competence were treated between June and September, 2015. Diagnosis was based on our evaluation on small intestinal immune competence and macrophage activity. Results: The state of malignant tumors at 3 months after starting this treatment was complete recovery for 3 cases, remission for 7 cases, maintenance for 4 cases, exacerbation for 1 case and death for 1 case (total response rate=62.5%). Small intestinal immune competence and macrophage activity recovered in all cases, suggesting that oral administration of LPS contributes to disease improvement. No clear side-effects that appeared to be related to LPS intake were noted. Conclusion: Intake of an appropriate level of Pantoea agglomerans LPS recovers small intestinal immune competence and macrophage activity, contributing to improvement of malignant tumors' therapy.
In recent years, it has been reported that oral administration of lipopolysaccharide (LPS) activates immune cells through toll-like receptor (TLR) 4, inducing foreign body exclusion, inflammatory action and tissue repair action (1). We reported that a hot water extract of wheat flour (oral administration) contains macrophage-activating substances derived from concomitant Gram-negative plant-associated bacteria, such as Pantoea agglomerans. LPS of this bacterium is a major macrophage-activating substance (2, 3). It has been reported that Pantoea agglomerans were found to be symbiotic in many plants, such as wheat and brown rice (4, 5). Oral administration of LPS from Pantoea aggomerans amplified phagocytic activity of peritoneal macrophages through TLR 4 (6). It has been reported in animal models and clinical studies of humans that oral intake of LPS from Pantoea agglomerans can prevent the onset of type I diabetes, control blood glucose levels in type II diabetes and decrease low-density lipoprotein (LDL) cholesterol (7, 8). Furthermore, when treating a mouse melanoma transplantation model with an anti-carcinogenic agent (doxorubicin), oral administration of Pantoea agglomerans LPS improves the survival of the B16 melanoma-inoculated murine model (9). Therefore, oral administration of LPS is thought to lead to superior improvement in treatment outcomes (9).
At our hospital, we have implemented immunity-improving therapies in the form of intestinal flora using kampo medicine or lactic acid bacteria supplements. However, as these mainly recover functioning of the large intestine and do not recover small intestinal competence, they do not completely increase immunity. To sufficiently increase immunity, small intestinal immune competence also needs to be recovered. Therefore, we focused on the substance called LPS, which recovers small intestinal immune competence.
Here, we used LPS from wheat symbiotic bacteria, Pantoea agglomerans, which has been ingested and confirmed as safe. In the present article, we report on the effects observed in our evaluation of the oral administration of LPS to 16 patients with malignant tumors who requested alternative therapy.
Materials and Methods
Patients. Our cohort comprised 16 malignant tumor patients who presented at our hospital as outpatients between June and September 2015 and who exhibited declined small intestinal immune competence.
Treatment. After receiving written consent from the subjects to participate in this study, administration of LPS from Pantoea agglomerans (wheat symbiotic bacteria LPS; Macrophi Inc., Kagawa, Japan) commenced with tablets containing 0.25 mg/tablet. Intake volume was adjusted based on testing in accordance with the status of each patient. For these tests, we used frequency measuring equipment (Rayocomp PS 1000 Polar; Layonex, Lennestadt Germany) and evaluated small intestinal immune competence and macrophage activity at the initial examination and 3 months after starting administration. Evaluation of malignant tumor treatment was also performed at the same time points as above.
Apparatus for diagnosis. The Rayocomp PS 1000 Polar is a type of frequency measuring equipment made by Leyonex. It was fundamentally developed in 1976 by Paul Schmidt, a German physicist, who discovered that each cell and tissue exhibited individual frequency (vibration), which could change depending on its status. A treatment device that resonated these individual frequencies using electromagnetic vibration was developed and related treatment methods were established. Currently, various programs have been developed based on individual vibration data from tens of thousands of measurement results that are, currently, being applied clinically and in research (10). Measurement results are divided into six classifications (resonance present (large): very good, resonance present (small): good, resonance absent: mild, moderate, severe or extreme). These were digitized and used as bioresonance indices (very good, 1; good, 2; mild, 3; moderate, 4; severe; 5; extreme, 6) for evaluation.
Statistical analysis. The Student's t-test with StatView (https://en.wikipedia.org/wiki/StatView) was used to statistically analyze test results. The level of significance was set at p<0.05.
Results
Malignant tumor therapy. The male-to-female ratio of the 16 subjects was 5:11. When classified according to primary lesion, the malignant tumors included 4 cases of lung cancer, 4 cases of breast cancer, 1 case of thyroid gland cancer, 2 cases of gastric cancer, 1 case of colorectal cancer, 1 case of uterine cancer, 1 case of melanoma and 2 cases of kidney cancer. When classified by stage, 3 cases were stage 1, 4 cases were stage 2, 1 case was stage 3 and 8 cases (50%) were stage 4. Metastatic lesions included 1 case in the liver, 1 case in the brain, 2 cases in the lungs, 2 cases in the lymph nodes, 3 cases in the bones and 1 case in the peritoneum. There were 11 cases (68.8%) that had received conventional tumor treatment from a previous doctor of which 8 cases received surgery, 2 cases radiotherapy and 8 cases chemotherapy. There were 2 cases (12.5%) that were receiving treatment from our department while continuing to receive treatment from their previous doctor. Treatment involved mega vitamin C infusion therapy (25 g~75 g/person/day) for 16 cases, ozone therapy for 12 cases and alpha-lipoic acid infusion for 11 cases. As immunity-improving therapy works in combination with these infusion therapies, all 16 cases were administered daio kanzo to or Pro5®, a probiotic bacteria supplement, to improve their intestinal environment. After one month of this treatment, oral administration of LPS was started with the aim of recovering small intestinal competence. To improve the intestinal environment before LPS administration, daio kanzo to was administered to 11 cases and Pro5® was administered to 5 cases. The daily oral dose of LPS was 0.75 mg/day/person for 1 case, 1 mg/day/person for 14 cases and 1.5 mg/day/person for 1 case. The average initial dosage of LPS was 1.02 mg/day (Figure 1).
The mean number of days of oral administration of LPS until bioresonance testing indicated recovered small intestinal immune competence was 18.3 days. Mean small intestinal immune competence, which was 4.88 at the initial examination, had improved to 1.69 at 3 months after starting LPS administration (p<0.05). Macrophage activity, which was 4.94 at the initial examination, was 2.25 at 3 months after starting LPS administration (p<0.05). These two indices showed a statistically significant difference together (Figure 2). The state of malignant tumors at 3 months after starting LPS treatment was complete recovery for 3 cases (1 case each of kidney cancer, uterine cancer and breast cancer) (Figure 3), remission for 7 cases (3 cases of breast cancer, 1 case of gastric cancer, 1 case of colorectal cancer and 2 cases of lung cancer), maintenance for 4 cases (1 case each of thyroid gland cancer, melanoma, lung cancer and gastric cancer), exacerbation for 1 case (lung cancer) and death for 1 case (kidney cancer). Thus, outcomes of remission or better were achieved for 10 cases (62.5%). No clear side-effects that appeared to be related to LPS intake were noted.
Discussion
The 16 patients with malignant tumors included 8 stage 4 cases in a terminal state and 7 cases that were stage 1 or 2. Of the 3 cases for which complete recovery was achieved, 2 cases were stage 1 and 1 case was stage 4. Many patients come to our hospital to receive preventive treatment after being treated for cancer or to receive alternative therapies for terminal cancer after being told that their condition is untreatable. This range of case types is reflected in the results.
At our hospital, mega vitamin C infusion (25 g~75 g/person/day), ozone therapy and alpha-lipoic acid infusion are used as alternative therapies for cancer patients who are difficult to treat with conventional treatment (surgery, chemotherapy and radiation) or for patients who do not wish to receive these conventional treatments. There have been proposals made for immunity-improving therapy to be conducted together with the above therapies that, when used jointly with infusions, improve the patients' immunity.
To improve the intestinal environment for immunity-improving therapy, we first administer daio kanzo to (kampo) or Pro5® to recover large intestinal competence. Patients (11/16 cases) were prescribed kampo by determination based on Oriental medical diagnosis. Patients determined unsuitable (5/16 cases) for kampo were prescribed a probiotic bacteria supplement. At our hospital, we implement treatment to recover small intestinal competence after recovering large intestinal competence.
Background of 16 malignant tumors patients.
The method of recovering small intestinal immune competence employed was administration of LPS from the wheat symbiotic bacteria Pantoea agglomerans. Compared to the initial diagnosis using the bioresonance apparatus, it was found that small intestinal competence had improved in all cases after administration of LPS (average 1.02 mg/day/person over 18.3 days). It has been suggested that the mechanism for LPS-recovering small intestinal immune competence involves activation of small intestinal immune tissue through TLR 4 in the small intestinal mucous membrane and, thereby, increasing antimicrobial peptides so that small intestinal mucous membrane returns to a normal state and immune competence is recovered (11). In particular, macrophages are activated to improve innate immune competence (12). We have previously demonstrated that, in mice, oral administration of 10-1,000 μg/kg of LPS from Pantoea on consecutive days for a week led to dose-dependent increases in the phagocytic activity of abdominal cavity macrophages, which was found to originate in TLR 4 (6). While it is clear that LPS stimulates TLR 4, it is unknown whether this involves information transmission from intestinal mucosa or through resorption. Other than recovering immune competence, macrophages are also involved in metabolism, wound healing and metabolic regulation. When treating cancer, it is extremely important to improve macrophage function. Tumor-associated macrophages (TAMs) are known to improve two phenotypes (M1 and M2) (13-14). M2 produces interleukin-10, exhibits anti-inflammatory action and improves tissue repair. M1 is activated by bacteria-derived substances and interferon gamma via releasing inflammatory cytokines to kill tumors. We have previously demonstrated that intradermal administration of LPS from Pantoea can persistently induce tumor necrosis factors at the tumor site (15-16). It is known that anti-tumor effects can be obtained by switching TAMs from M2 to M1 (17) and, since LPS might be able to activate M1 macrophages, it may contribute in killing tumors as well. Accordingly, the use of LPS as an immunity-improving therapy may amplify anti-tumor effects due to immune cells directly impairing the malignant tumor.
Improvement of small intestinal immune competence and the degree of activated macrophage by intake of oral LPS. X axis shows the change after a mean of 3 months of oral LPS. Y axis is based on bioresonance indices (very good, 1; good, 2; mild, 3; moderate, 4; severe; 5; extreme, 6) for evaluation. A: Average of 16 patients of small intestinal immune activity index. B: Average of 16 patients of macrophage activating index. Columns and bars indicate mean and standard deviation (n=16), respectively. Average duration and amount of administration of oral LPS is 1.02 mg/person/day over 18.3 days.
Comparison of lung X-ray picture before and after oral administration of LPS. The right picture shows the complete regression of multiple metastatic lung tumors (Male, 66-year-old, administered 1.25mg/ day of LPS for 10 months).
Intestinal tracts with normal lactic acid bacterial flora, once the intestinal environment has been improved with lactic acid bacteria, exhibition of increased nitric oxide production and interferon gamma is noticed. This activates macrophages, which are responsible for innate immunity, leading to increased immune competence against pathogens (16). Thus, synergistic immune function effects can be anticipated for lactic acid bacteria and LPS. In the cases of this study, we believe that improving the intestinal environment with kampo medicine or probiotic bacteria supplements before adding LPS, greatly recovered immune competence and led to the comprehensive effects observed.
Conclusion
The appropriate oral administration of LPS from the wheat symbiotic bacteria Pantoea agglomerans recovers small intestinal immune competence and macrophage activity. Together with an improved intestinal environment, this led to greatly recovered immune competence that may have induced anti-tumor effects against malignant tumors. The present results suggested that oral administration of LPS could also induce synergistic effects with alternative infusion therapies and contribute to treatment of malignant tumors.
Footnotes
Disclosures
The Authors have no financial conflicts of interest.
- Received April 5, 2016.
- Revision received May 12, 2016.
- Accepted May 16, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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