Patent Application
20230080345
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The present disclosure relates generally to low-level light therapy (LLLT) and, more specifically, to systems and methods that apply LLLT to a subject suffering dysbiosis of the gut in order to restore the subject's gut microbiota to a state of health.
The human gastrointestinal (GI) tract is the continuous series of organs beginning at the mouth and ending at the anus. Throughout its length the GI tract is colonized by microorganisms of a variety of different species. The collection of bacteria, archaea, and eukarya colonizing the GI tract is termed the “gut microbiota.” The microbiota, especially the gut microbiota, affect metabolism, neurological and cognitive functions, hematopoiesis, inflammation and immunity. An intact and functional gut epithelium maintains a healthy body and gut epithelial homeostasis is maintained by continuous crosstalk between the gut microbiota, immune cells and mucosal barrier.
Despite recent advances in anti-cancer drugs, chemotherapeutic agents that impair cell proliferation remain the standard method of treatment for many types of cancer. However, the use of chemotherapeutic agents results in numerous detrimental side effects due to the combination of systemic administration of chemotherapy and its lack of cellular specificity. For example, chemotherapy is known to perturb the mutualism between microbiota and epithelial cells particularly in the gut, leading to body weight loss and altered susceptibility to certain chemotherapy drugs. An effective way to minimize the side-effects of chemotherapy would be beneficial.
The present disclosure relates generally to low-level light therapy (LLLT) and, more specifically, to methods and systems that apply low-level light (LLL) to a subject suffering from gut dysbiosis brought on by a bodily stress in order to restore the subject's gut microbiota to a state of health. Chemotherapy is one bodily stress that can cause dysbiosis of the gut, and it has been discovered that LLLT can restore the mutualism between the microbiota and epithelial cells in the gut, and thus, restore the heath of the gut microbiota.
In one aspect, the present disclosure can include a method that includes placing a subject's abdomen and/or back proximal to a light source device. The subject can be suffering from dysbiosis of the gut caused by a bodily stress. The light source device can be configured to apply LLL at a certain wavelength. The LLL can be applied to the subject's abdomen and/or back at a power density and for a time sufficient to restore the subject's gut microbiota to a state of health.
In another aspect, the present disclosure can include a method that includes applying LLL to a subject's abdomen and/or back at a certain wavelength where the subject has previously undergone chemotherapy and/or radiation therapy. The LLL can be applied at a power density and for a time sufficient to restore the subject's gut microbiota to a state of health.
In another aspect, the present disclosure provides a fecal preparation made by a process comprising: obtaining a fecal sample from a subject diagnosed with gut dysbiosis; and applying low level light (LLL) to the fecal sample at a certain wavelength and at a certain power. density and for a time sufficient to restore the gut microbiota to a state of health. In some embodiments, the certain wavelength is from 600-1640 nm, while in further embodiments the certain power density is from 0.001-1 W/cm2.
In another aspect, the present disclosure provides a method of treating gut dysbiosis, comprising: administering treated feces to a subject that has undergone bodily stress, wherein the treated feces comprise feces obtained from the subject before the subject has undergone bodily stress to which low level light (LLL) has been applied at a certain wavelength and at a certain power density and for a time sufficient to restore the feces obtained from the subject to a state of health. In some embodiments, the bodily stress is treatment with chemotherapy and/or radiation therapy.
In a further aspect, the present disclosure can include a light source device configured to apply LLL to a subject's abdomen and/or back. The light source device can include a light source configured to generate a light signal with a wavelength from 600 nm to 1640 nm and a power density of from 0.001-1 W/cm2, a processing unit preprogrammed with a time for application of the light signal to the abdomen and/or back, and a power source. The time for application can be sufficient to restore the subject's gut microbiota to a state of health.
The foregoing and other features of the present disclosure will become apparent to those skilled in the art to which the present disclosure relates upon reading the following description with reference to the accompanying drawings.
Low level light (LLL) can be used to restore a subject's gut microbiota to a state of health. In some embodiments, the LLL can be applied directly to the subject's abdomen and/or back, while in other embodiments the LLL can be applied to a feces sample obtained from the subject, which is subsequently administered back to the subject. The subject may be suffering from guy dysbiosis resulting from a variety of different types of bodily stress, such as chemotherapy or radiation therapy.
Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure pertains.
In the context of the present disclosure, the singular forms “a,” “an” and “the” can also include the plural forms, unless the context clearly indicates otherwise.
As used herein, the term “and/or” can include any and all combinations of one or more of the associated listed items.
As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.
Also herein, where a range of numerical values is provided, it is understood that each intervening value is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.
As used herein, the terms “treatment,” “treating,” and the like, refer to obtaining a desired pharmacologic or physiologic effect. The effect may be therapeutic in terms of a partial or complete cure for a disease or disorder such as gut dysbiosis, or an adverse effect attributable to the disease or disorder. “Treatment,” as used herein, covers any treatment of a disease or disorder in a mammal, particularly in a human, and can include inhibiting the disease or condition, i.e., arresting its development; and relieving the disease, i.e., causing regression of the disease.
As used herein, the terms “microbiota”, “microflora” and “microbiome” refer to a community of living microorganisms that typically inhabits a bodily organ or part.
The “gut,” as defined herein, refers to the gastrointestinal tract, and any portion thereof. Parts of the gastrointestinal tract include the stomach, colon, small intestine, rectum, anus, and mouth.
As used herein, the term “proximal” can refer to a location that is near or at a target. For example, a device that is located proximal to the abdomen and/or back can refer to a device that is located near the abdomen and/or back but is not directly touching the abdomen and/or back (e.g., the device is located above, below, or in front of the abdomen and/or back), or “proximal” can refer to a device that is located at the abdomen and/or back and is directly touching the abdomen and/or back.
As used herein, the term “direct” refers to the absence of intervening elements. For example, a device that directly contacts the abdomen has no intervening elements between the device and the skin of the abdomen.
As used herein, the term “sufficient” refers to an amount adequate enough to satisfy a condition. For example, “a time sufficient to restore the subject's gut microbiota to a state of health” can refer to LLL being applied to the abdomen for a time adequate enough to restore the subject's gut microbiota to a state of health.
As used herein, the terms “subject” and “patient” can be used interchangeably and refer to any warm-blooded organism including, but not limited to, a human being, a pig, a rat, a mouse, a dog, a cat, a goat, a sheep, a horse, a monkey, an ape, a rabbit, a cow, etc.
Low-level light therapy is commonly used for pain management, to reduce inflammation, and to stimulate photo-biological responses to enhance physiological reactions. The present disclosure relates generally to low-level light therapy (LLLT) and, more specifically, to systems and methods that apply low-level light (LLL) to a subject suffering from gut dysbiosis in order to restore the subject's gut microbiota to a state of health. As used herein, the phrase “restore the subject's gut to a state of health” can mean that (i) at least one aspect of the subject's gut health is improved as compared to the state that the subject's gut health was in before LLL was administered to the subject, and/or (ii) at least one aspect of the subject's gut health is improved as compared to the state that the subject's gut health would be in if no LLL was administered. Aspects of improvement in gut health may include, for example, (i) an increase in abundance of one or more beneficial phyla in the subject's gut, (ii) a decrease in abundance of one or more harmful phyla in the subject's gut, (iii) preserved villus architecture, (iv) restored villus architecture, (v) an increase in villus length, (vi) a decrease in the formation of pyknotic nuclear structures, (vii) preserved crypt depth, and (viii) a decrease in the crypt depth/villus length ratio.
It has been surprisingly found that LLLT can be used to improve gut health in a subject suffering from gut dysbiosis. LLLT provides a safe, non-invasive, and non-pharmacological therapy to patients suffering from the effects of certain conditions that are associated with gut dysbiosis, e.g., chemotherapy induced cachexia. It has been found that applying LLL to a subject suffering from gut dysbiosis can increase the abundance of certain beneficial phylum of bacteria in the subject's gut such as Tenericutes, Verrucomicrobia, and Deferribacteres. The LLLT can be used cumulatively on a subject who is undergoing e.g., multiple rounds of chemotherapy/radiation therapy (CRT). The LLLT can be used alone or in combination with alternative treatments to restore the subject's gut microbiota to a state of health.
It is generally believed that the beneficial effects of LLL can be ascribed to the ability of LLL to enhance mitochondrial function in mammalian cells. However, bacteria do not have mitochondria. While not wishing to be bound by theory, it is possible that certain bacteria may respond to light similar to mitochondria and use light to synthesize ATP because ATP synthase, proton-motive force, and electron transport chain are found within these certain bacteria. Thus, it is possible that LLL can be employed to restore a subject's gut health because individual bacterial phyla respond differently to light and have differing abilities to use light to generate ATP.
The term “low-level light (LLL)” can refer to a procedure that involves exposing at least a portion of a patient's body (e.g., the abdomen or back) to low levels of red and/or near infrared (NIR) light at energy densities that are low compared to other forms of laser therapy (e.g., ablation, cutting, thermal coagulation, etc). It can also be referred to as low-level laser therapy, or “cold laser” therapy. As used herein, the term “low-level light therapy (LLLT)” can be used interchangeably with LLL.
The present disclosure provides a method that includes applying LLL to a subject suffering from gut dysbiosis to restore the subject's gut microbiota to a state of health. The gut dysbiosis may be due to bodily stress, such as chemotherapy. The term “dysbiosis” can refer to a microbial imbalance inside the body. Gut dysbiosis is the disruption of the composition and/or diversity of the gut microbiome. Thursby, E. & Juge, N., Biochem J., 474(11):1823-1836 (2017(. When this balance is disturbed, these colonies exhibit a decreased ability to check each other's growth, which can then lead to overgrowth of one or more of the disturbed colonies which may further damage some of the other smaller beneficial ones in a vicious cycle. The human microbiome is made up of a large number of different strains and species of bacteria. In a healthy gut, the dominant type of bacterial are commensal bacteria. However, when the quantity and proportion of commensal bacteria are reduced, harmful strains and pathogens can grow unchecked causing an imbalance in the microbiota which can lead to dysbiosis.
Examples of harmful bacteria include, but are not limited to Aeromonas hydrophilia, Bacillus cereus, Vibrio parahemolyticus, Vibrio cholerae 01, Vibrio cholera non-01, Vibrio vulnificus, Salmonella enteric, Salmonella typhi, Salmonella paratyphi, Salmonella entertidis, Salmonella cholerasuis, Salmonella typhimurium, Clostridium difficile, Clostridium botulinum, Clostridium perfringens, Staphylococcus aureus, Escherichia coli (—various subclasses), Campylobacter jejuni, Campylobacter coli, Campylobacter lari, Campylobacter fetus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Plesiomonas shigelloides, and Listeria monocytogenes.
There are a number of bodily stresses that can cause gut dysbiosis. For example, certain acute bodily stresses can cause gut dysbiosis, including but not limited to, chemotherapy, radiation therapy, administration of antibiotics, diarrhea, inflammatory bowel disease, and cancer immunotherapy. In other instances, certain chronic bodily stresses can cause gut dysbiosis, including but not limited to, metabolic disorders (e.g., obesity, diabetes), neurodegenerative diseases (e.g., pain, depression, anxiety, autism, multiple sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, stroke) allergies, asthma, and autoimmune diseases (e.g., lupus, ulcerative colitis, Crohn's disease).
The main signs and symptoms of dysbiosis are digestive disturbances. People with the condition may experience frequent gas or bloating. This means that they feel bloated on most days of the week. Also, they suffer from abdominal cramping, diarrhea, and constipation, with mucus in the stool. They may have a combination of diarrhea and constipation, food sensitivities, food intolerances, and chronic bad breath. In some cases, people may experience a difficulty in urinating, vaginal or rectal itching, chest pain, rashes, fatigue, trouble concentrating, depression, anxiety, and brain fog. A doctor can diagnose gut dysbiosis based on the signs and symptoms, medical history, physical examination, and diagnostic tests, such as organic acid tests, comprehensive digestive stool analysis, hydrogen breath test, and biopsy of bacterial tissue from the gut.
It has been discovered that LLLT can be used to restore gut health. LLL is a simple, non-invasive, safe, convenient, and cost-effective modality that has been clinically employed for decades for pain relief and other applications. Chung et al., Ann Biomed Eng., 40(2):516-33 (2012).
In one aspect of the present disclosure, low-level light (LLL) can be applied (in one dose or in multiple doses) to at least a portion of a patient's body at energy densities that are low compared to other forms of laser therapy (e.g., ablation, cutting, thermal coagulation, etc.). For example, the LLL energy density can be from 0.001 J/cm2 to 50 J/cm2. As another example, the LLL energy density can be from 0.001 J/cm2 to 20 J/cm2. In another example, the LLL energy density can be from 0.001 J/cm2 to 3 J/cm2. In a further example, the LLL energy density can be from 0.01 J/cm2 to 0.5 J/cm2. In a specific example, the LLL energy density can be 0.025 J/cm2. In certain instances, the energy density can be measured at the middle of the subject's abdomen. In other instances, the energy density can be measured at different locations along the subject's gut.
The LLL used herein, in some examples, can have a wavelength from 600 nm to 1640 nm. In other examples, the LLL can have a wavelength from 600 nm to 1000 nm, 700 nm to 1000 nm, 800 nm to 1000 nm, or 900 nm to 1000 nm. In still other examples, the LLL can have a wavelength from 650 nm to 750 nm or 800 nm to 900 nm. In one particular example, the LLL can have a wavelength of 980 nm. In another particular example, the LLL can have a wavelength of 660 nm. In a further example, the LLL can have a wavelength of 810 nm.
The power density of the LLL can be from 0.001 W/cm2 to 1 W/cm2. In one example, the power density can be from 0.025 W/cm2 to 0.5 W/cm2. In certain instances the power density can be 0.1 W/cm2 or more. In one instance, the selected or predetermined power density to be delivered to the body can be selected from the range of about 0.01 W/cm2 to about 0.15 W/cm2, including e.g., 0.015, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, and 0.14 W/cm2, and all values there between. In another instance, the selected or predetermined power density to be delivered to the body can be selected from the range of about 0.2 W/cm2 to about 0.5 W/cm2, including, e.g., 0.3 W/cm2 and 0.4 W/cm2, and all values there between. In some instances, higher power densities can be used. To attain subsurface power densities within these ranges in in vivo methods, one skilled in the art would understand that one must take into account attenuation of the energy as it travels through body tissue and fluids from the surface to the target tissue.
In some embodiments, the LLL can be applied in a single dose. In other instances, the LLL can be applied in multiple doses. In some instances, the LLL can be applied multiple times on the same day (e.g., one to five times a day). In further instances, the LLL can be applied over the course of multiple days (e.g., two to ten days). In further instances, the LLL can be applied on consecutive days. In other instances, the LLL can be applied on an intermittent basis, e.g., every other day. In certain instances, the LLL can be applied e.g., once or twice a day for 1-10 days. In one example, the LLL can be applied once a day for four days. In another example, the LLL can be applied once a day for five days. In another example, the LLL can be applied twice a day for four days. In a further example, the LLL can be applied twice a day for five days.
The LLL can be applied to the subject for a period of 10 minutes to 3 hours. In one example, the LLL can be applied for a period of 30 minutes to 2 hours. In one specific instance, the LLL can be applied for a period of about 30 minutes. In an additional instance, the LLL can be applied for about 1 hour. In another specific instance, the LLL can be applied for a period of about 2 hours. The period of time that the LLL is administered to the subject can be based in part on the body mass index (BMI) of the subject. For example, subjects having a lower BMI may only require LLL administration for a period of 30 minutes, whereas subjects with a higher BMI may require that the LLL be administered for a period of 2 or 3 hours.
In some instances the LLL can be applied to at least a portion of a subject's body. One skilled in the art will understand that in each instance the LLL can be applied proximally to the subject's body. In certain instances the LLL can be applied directly to the subject's body. In one aspect, the LLL can be applied to the subject's abdomen and/or back. In one instance, the LLL can be applied to the subject's abdomen. In another instance, the LLL can be applied to the subject's back. In one particular example, the LLL can be applied to the subject's lower back. In another example, the LLL can be applied to the subject's middle back. In yet another instance, the LLL can be applied along the middle of the subject's back. In other instances, the LLL can be applied to the subject's abdomen and the subject's back. In one instance the LLL can be applied to the subject's abdomen and the subject's lower back. In a further instance, the LLL can be applied to the subject's abdomen and the subject's middle back.
Applying LLL to a subject suffering from gut dysbiosis can restore the subject's gut microbiota to a state of heath. Restoring the subject's gut to a state of health can mean that (i) at least one aspect of the subject's gut health is improved as compared to the state that the subject's gut health was in before LLL was administered to the subject and/or (ii) at least one aspect of the subject's gut health is improved as compared to the state that the subject's gut health would be in if no LLL was administered. Aspects of improvement in gut health may include, for example, (i) an increase in abundance of one or more beneficial phyla in the subject's gut, (ii) a decrease in abundance of one or more harmful phyla in the subject's gut, (iii) preserved villus architecture, (iv) restored villus architecture, (v) an increase in villus length, (vi) a decrease in the formation of pyknotic nuclear structures, (vii) preserved crypt depth, and (viii) a decrease in the crypt depth/villus length ratio.
In one instance, restoring the subject's gut microbiota to a state of health can include increasing the abundance of one or more of the phyla consisting of Tenericutes, Verrucomicrobia, and Deferribacteres. In another instance, restoring the subject's gut microbiota to a state of health can include increasing the abundance of the Tenericutes and Verrucomicrobia phyla in the subject's gut. In a further instance, restoring the subject's gut microbiota to a state of health can include increasing the abundance of the Tenericutes, Verrucomicrobia, and Deferribacteres phyla in the subject's gut. In another example, restoring the subject's gut microbiota to a state of health can include increasing the abundance of the Tenericutes phyla in the subject's gut. In a further example, restoring the subject's gut microbiota to a state of health can include increasing the abundance of the Verrucomicrobia phyla in the subject's gut. In yet another example, restoring the subject's gut microbiota to a state of health can include increasing the abundance of the Deferribacteres phyla in the subject's gut. In another instance, restoring the subject's gut microbiota to a state of health can include decreasing the abundance of harmful phyla in the subject's gut. In other instances, restoring the subject's gut microbiota to a state of health can include restoring and/or preserving villus architecture. In certain instances, restoring the subject's gut microbiota to a state of health can include preventing the shortening of villus length, and/or preventing the formation of pyknotic nuclear structures, and/or preserving crypt depth.
In some embodiments, the LLLT can be used in conjunction with other treatments. For example, LLLT can be used in conjunction with other treatments that help restore a healthy microbiota in the gut. For instance, LLLT can be used in conjunction with various diets, supplements, nutritional plans, and probiotic treatments.
In one aspect, the present disclosure includes a method that includes applying LLL to a subject suffering from gut dysbiosis caused by a bodily stress. In one instance, the method can include placing a subject's abdomen and/or back proximal to a light source device wherein the light source device is configured to apply LLL at a certain wavelength. The method can further include applying the LLL to the subject's abdomen and/or back at a power density and for a time sufficient to restore the subject's gut microbiota to a state of health.
In another aspect, the present disclosure includes a method that includes applying LLL to a subject's abdomen and/or back at a certain wavelength wherein the subject has previously undergone chemotherapy and/or radiation therapy. In one instance, the LLL can be applied at a power density and for a time sufficient to restore the subject's gut microbiota to a state of health.
Another aspect of the invention provides a fecal preparation. The fecal preparation is made by a process comprising the steps of obtaining a fecal sample from a subject diagnosed with gut dysbiosis and applying low level light (LLL) to the fecal sample at a certain wavelength and at a certain power density and for a time sufficient to restore the gut microbiota to a state of health. In some embodiments, restoring the subject's gut microbiota to a state of health comprises increasing the abundance of one or more of the phyla consisting of Tenericutes, Verrucomicrobia, and Deferribacteres in the subject's gut.
Feces is the solid or semisolid remains of food that was not digested in the small intestine, and has been broken down by bacterial in the large intestine. Methods of obtaining a fecal sample are known to those skilled in the art, and can be obtained by a medical practitioner or by the subject themselves. Typically, the subject defecates into a bedpan or commode, and the feces are then transferred into a specimen container.
Low level light is then applied to the fecal sample to convert it to a fecal preparation. The wavelength, power density, and time for the administration of the LLL can be any of the values described herein. However, because of the lack of penetration issues when the LLL is applied directly to feces, the illumination can be for a shorter period of time. For example, the LLL can be applied for a period of one second to 2 hours, a period of one second to one hour, or a period of one second to 10 minutes. In some embodiments, the certain wavelength is from 600-1640 nm, in further embodiments, the certain power density is from 0.001-1 W/cm2, and in yet further embodiments the LLL is applied for a period of one second to 2 hours at a fluence from 0.1 J/cm2 to 1 J/cm2 for a 980 nm laser, or 1 to 10 J/cm2 for a 810 nm laser at cellular levels.
Another aspect of the invention provides a method of treating gut dysbiosis using a fecal preparation. The method comprises the steps of administering treated feces to a subject that has undergone bodily stress, wherein the treated feces comprise feces obtained from the same or a different subject before the subject has undergone bodily stress to which low level light (LLL) has been applied at a certain wavelength and at a certain power density and for a time sufficient to restore the feces obtained from the subject to a state of health. The bodily stress can be any of the types of bodily stress described herein. For example, in some embodiments, the bodily stress is chemotherapy and/or radiation therapy. In some embodiments, the treated feces are obtained from the same subject being treated, while in other embodiments the treated feces are obtained from a different subject.
The fecal preparation can be administered to the subject using any of the methods know for use in fecal transplantation procedures. For example, the fecal preparation can be made into a suspension which is then given through nasogastric and nasoduodenal tubes, or through a colonoscope or as a retention enema. See Franzos et al., Clinical Gastroenterology and Hepatology, 9 (12): 1044-9 (2011). The fecal preparation may be administered once, or it may be administered sequentially as part of a treatment regimen.
As shown in
The controller 14 can be configured to generate and transmit a control signal (e.g., including dosage parameters for LLL) to the light source device 12. The controller 14 can be a computing device (e.g., a general purpose computer, special purpose computer, and/or other programmable data processing apparatus) that can include or be otherwise associated with a non-transitory memory storing instructions (e.g., computer program instructions) that, upon execution by a processor, can create a mechanism for implementing the functions of the controller 14 (e.g., generating and transmitting the control signal to the light source device 12). For example, one or more of the dosage parameters (e.g., time of application) can be pre-set within the controller 14. As another example, one or more of the dosage parameters can be input by a user via a user interface associated with the controller 14.
The controller 14 and the light source device 12 can be communicatively coupled (e.g., via a wired connection and/or a wireless connection) to facilitate the transmission of the control signal. An example of a method 20 that the light source device 12 can utilize to apply the LLL according to the control signal is shown in
At 24, the light source device 12 can obtain the dosage parameters for the LLL from the control signal. At 26, the light source device can deliver the LLL according to the dosage. In some instances, the dosage can include a desired power density (e.g., selected from 0.001 W/cm2 to 1 W/cm2) to be delivered to the intestines. In one specific instance, the dosage can include a desired power density of 300-400 mW/cm2. To deliver the desired power density into the intestines, a relatively higher surface power density of LLL may be required, depending on subject's skin pigmentation and the depth of the intestines relative to the skin surface. In some instances, super pulsed gallium arsenide (GaAs) lasers can be employed to generate super pulses of LLL with extremely short duration (100 to 300 nanoseconds), that can penetrate into tissue depths of 3 to 13 cm and deeper.
The term “light source device” can refer to a mechanical implement that can deliver a light signal of LLL to a portion of the subject's body. Examples of the light source devices include a probe, a flexible array device, or the like.
The term “light source” can refer to a component of a light source device that delivers one or more lights of different wavelengths. For example, the light source can be a low-level laser source (e.g., a laser light emitting diode (LED)) that generates coherent light. As another example, the light source can be an incoherent light source, such as a traditional LED or light bulb. The wavelength of the light can include a wavelength corresponding to the visible range of the electromagnetic spectrum (e.g., red light). In another example, the wavelength can correspond to the near-infrared or infrared range of the electromagnetic spectrum.
The light source device 12 can be configured to apply LLL to a subject's body (e.g., the whole body or a portion of the body including the abdomen and/or the back). In some instances, the light source device 12 can include a monochromatic laser that radiates light in the red or NIR wavelengths (λ=600 nm-1640 nm). In other instances, the light source device 12 can include a light emitting diode (LED) that radiates light in the red or NIR wavelengths (λ=600 nm-1640 nm). In one particular instance, the light source device 12 can radiate light at a wavelength of 980 nm (NIR).
In some instances, the light source device 12 can be configured to apply the LLL to the subject's body according to the control signal. In some instances, the LLL can be applied to a portion of the subject's body (e.g., abdomen and/or back). One skilled in the art will appreciate that any known light source device can be used to apply LLL to at least a portion of the subject's body. The light source device 12 can be configured in any shape that facilitates indirect delivery of LLL to at least a portion of the subject's body or facilitates the direct delivery of LLL to at least a portion of the subject's skin. In one instance the light source device 12 can be a mobile or a stationary device. In another instance, the light source device 12 may be a probe, e.g., a mobile probe or a handheld probe. One example of the light source device 12 that can deliver the LLL to least a portion of the subject's body is a LLL blanket (
In one aspect, the present disclosure includes a light source device configured to apply LLL to a subject's abdomen and/or back. The device can include a light source configured to generate a light signal with a wavelength from 600 nm to 1640 nm and a power density of from 0.001-1 W/cm2. The light source device can also include a processing unit preprogrammed with a time for application of the light signal to the abdomen and/or back, wherein the time for application is sufficient to restore the subject's gut microbiota to a state of health, and a power source.
In some instances, the light signal can have a wavelength from 600 nm to 1000 nm, 700 nm to 1000 nm, 800 nm to 1000 nm, or 900 nm to 1000 nm. In still other examples, the light signal can have a wavelength from 650 nm to 750 nm or 800 nm to 900 nm. In one particular example, the light signal can have a wavelength of 980 nm. In another particular example, the light signal can have a wavelength of 660 nm. In a further example, the light signal can have a wavelength of 810 nm.
In further instances, the power density of the light signal can be from 0.001 W/cm2 to 1 W/cm2. In one example, the power density of the light signal can be from 0.025 W/cm2 to 0.5 W/cm2. In certain instances, the power density of the light signal can be 0.1 W/cm2 or more. In one instance, the power density of the light signal can be selected from the range of about 0.01 W/cm2 to about 0.15 W/cm2, including e.g., 0.015, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, and 0.14 W/cm2, and all values there between. In some instances, higher power densities can be used. For example, power density of the light signal can be selected from the range of about 0.2 W/cm2 to about 0.5 W/cm2, including, e.g., 0.3 W/cm2 and 0.4 W/cm2, and all values there between.
The following examples are included for the purpose of illustration only and are not intended to limit the scope of the appended claims. The examples demonstrate the use of LLL as a non-pharmacological tool for restoring a subject's gut health.
Study Design
Two individual studies were carried out, each study using fourteen C57BL/6 (B6) female mice at 12 weeks of age. The mice were first intraperitoneally (i.p.) administered a radiosensitizer drug, carboplatin (56.2 mg/kg). Three hours later the mice were subject to 5 Gy total body -irradiation (TBI) (a cytoablative therapy for cancer and leukemia). In each individual study, LLL at 980 nm was applied to 7 mice and sham light was applied to the other 7 mice. The LLL and the sham light were applied to a shaved, awake mouse noninvasively 3 hours post-TBI as illustrated in
Analysis
CRT caused lower intestine tract damage (
Histopathological studies confirmed that administration of LLL better-preserved villus architecture and villus lengths. In contrast, significant villus loss, destruction, and shortening, and pyknotic nuclear structures in the crypt were found in mice treated with CRT alone (
Co-Housing
Co-housing of LLL-treated mice with CRT sham-treated mice reciprocally affected the healthy status of these two groups of mice. As can be seen in
To corroborate the importance of gut microbiota in LLL-mediated protection against gut injury induced by CRT, mice were treated for two weeks with an antibiotic cocktail containing ampicillin (1 mg/mL), streptomycin (5 mg/mL) and vancomycin (0.25 mg/mL) (designated A+ in -irradiation (TBI). The mice were then subjected to either LLL or sham light 3 hours post-TBI (LLL used a laser at 980 nm which delivered 0.025 J/cm2 into the intestines). The laser density was adjusted to 17.4 mW/cm2 to illuminate the shaved abdomen of the mice for 123 seconds (assuming a penetration rate at 1.3% based on measurements of deceased mice). The LLL and sham light treatments were repeated daily for 4 consecutive days. The body weight of the mice was recorded every other day for 35 days post-CRT. It was found that elimination of gut microbes greatly protected the gut from CRT-induced damage, showing no significant body weight decreases relative to day 0, although a weight loss was noticed on day 7 after CRT (
Feces were collected from LLL-treated and the sham-treated CRT-mice during the final week of the experiment described in Example 1 (days 13-20). The fecal samples were weighed and frozen immediately in liquid nitrogen and then stored at −80° C. The frozen fecal pellets were resuspended at a concentration of 100 mg/1.2 mL sterile phosphate-buffered saline (PBS) under anaerobic conditions, homogenized, and filtered through a 70 μm strainer. The recipient mice were irradiated with 5 Gy TBI as described in Example 1 and gavaged with 400 μL of the resultant fecal suspension 3-5 hours after irradiation. The fecal suspension (400 μL) was gavaged once a day for additional four days. As can be seen in
The effect of LLLT on the abundance of specific phyla in the gut microbiota was investigated. To this end, the total DNA of fecal samples collected from LLL-mice and CRT-treated mice, as described in Example 1, were extracted using a fecal genomic DNA extraction kit according to the manufacturer's instructions. Relative expression of seven different groups of bacteria at phylum level (Bacteroidetes, Firmicutes, Actinobacteria, Deferribacteres, Verrucomicrobia, Tenericutes, Delta- and Gammaproteobacteria) was investigated by qPCR. The primers for each phylum are listed in Table 1. An increase of Tenericutes, Verrucomicrobia, and Deferribacteres by 50-fold, 15-fold or 5-fold, respectively was found in LLL-mice as compared with CRT-mice (-proteobacteria in the presence or absence of LLL were seen. Three-well known probiotic bacteria, specifically Bifidobacterium spp. belonging to the phylum of Actinobacteria, and Lactobacillus spp. and Bacillus subtilis both within the phylum of Firmicutes, were not affected by LLL at a genus level when evaluated by qPCR (
Feces were collected from normal C57BL/6 (B6) female mice at age of 12 weeks. The fecal samples were weighed and frozen immediately in liquid nitrogen and then stored at −80° C. The frozen fecal pellets were resuspended at a concentration of 0.1 g/0.9 mL sterile phosphate-buffered saline (PBS) under anaerobic conditions, homogenized for 30 s using a vortex, and filtered through a 70 μm strainer. The fecal samples were either left untreated or treated with 0.2% H2O2 for 30 min, and then treated with 980 nm light for 75 s, 45 s, 30 s and 0 s, corresponding to light energy 0.025 J/cm2, 0.015 J/cm2, 0.01 J/cm2 and 0 J/cm2, respectively. The treated bacteria, along with controls, were cultured on Remel Brucella Agar plate containing 5% sheep blood in triplicate. After 72 h strictly anaerobic culture at 37° C., bacterial 16s RNA was collected and quantified as
As shown in
H2O2 treatment mimics the stress or reactive oxygen species (ROS) induced by various pathological etiologies, leading to gut dysbiosis. The data indicates that LLL directly affects bacterial growth under anerobic conditions to preserve the diversity and probiosis of the gut microbiota.
From the above description, those skilled in the art will perceive improvements, changes and modifications. Such improvements, changes and modifications are within the skill of one in the art and are intended to be covered by the appended claims. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety.
This application claims the benefit of U.S. Provisional Application No. 62/985,557, filed Mar. 5, 2020. This provisional application is hereby incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/021078 | 3/5/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62985557 | Mar 2020 | US |
