Invented by Mark Pimentel, Ruchi Mathur, Christopher Chang, Cedars Sinai Medical Center
The Cedars Sinai Medical Center invention works as followsThe invention described herein describes methods and systems that can be used to determine, select, and/or treat diseases and conditions associated with or caused by high quantities of methylogens or low quantities in a person, or vice versa. In different embodiments, a treatment to inhibit or promote methanogen growth is selected and/or given to a patient in need.
Background for Methods for diagnosis, selection and treatment of diseases or conditions caused by methanogens or associated with them
All publications are incorporated herein by reference in the same degree as if every publication or patent application were specifically and individually stated to be incorporated through reference. This description contains information that can be helpful in understanding the invention. This is not to say that the information contained herein is relevant or prior art, or that the publications specifically or implicitly referred to are prior art.
The human gastrointestinal tract (GI) is home to many microorganisms. These include bacteria, archaea and eukaryotes. At least 70 types of bacteria, 13 types of archaea, and their combined genomes (the microbiome), are believed to have 100 times the number of genes as that of humans (A1,A2). The composition and number microbes found in the intestines depends on a variety of factors (A3,A4). However, most adults reach a relatively stable balance, unique to them, of the types and numbers of bacteria that they have (A5). The microbial community develops with the host through symbiotic relations that favor their coexistence. The full impact of gut microbes will not be known for many years, but the complex interdependent relationship between the gut microbes, and the host, has been the focus of increased scientific interest in the past decade. There is growing evidence that gut microbes may play a role in energy homeostasis and insulin resistance.
This distinct group is a bacterium that grows in anaerobic environments and produces methane as a fermentation by-product. Methanogens have a unique metabolism that increases when other gut microbes produce products (A16), and they use hydrogen and ammonia to generate methane as substrates (A17,A18). Methane is eliminated by the lungs once it has been absorbed into the systemic circulation. Methanobrevibacter is the most common methanogen found in human guts. Methanobrevibacter Smithii is the predominant species (A7). M. smithii can be found in 70 percent of human subjects. Lactulose breath tests are a good way to measure methane production indirectly (A7,A19). Minority of subjects (15%) produced large quantities of gas early in the test, suggesting greater methane potency (A20), while increased methane on breath tests correlates with higher levels of M. Smithii in stools, as determined using quantitative PCR (qPCR).
Introduction of both a Bacteroides species (Bacteroides thetaiotaomicron) and M. smithii into germ-free mice resulted in greater body weights than with B. thetaiotaomicron alone (A22), and methanogens have been shown to increase the capacity of polysaccharide-metabolizing bacteria to digest polyfructose-containing glycans in the colons of germ-free mice (A22), suggesting that methanogens may play a role in caloric harvest. The inventors found in humans that a higher BMI is associated with increased methane in breath tests, in both normal and obese subjects. Methane in the obese population was associated with an astonishing 6.7 kg/m2 higher BMI than non-methane control subjects (P0.05). (A23). These data suggest that methanogens play a role in calorie harvesting and weight gain, but this is undermined by the fact, that colonization of methanogens with humans has only been shown in the large bowel to date (A24-A26).
The inventors also examine the importance of Methanobrevibacter smithii as a determinant of methane production in the breath of humans using quantitative-polymerase chain reaction (PCR) from stool of IBS patients with and without detectable methane on breath testing. Also described herein, the inventors examine the importance of Methanobrevibacter smithii as a determinant of methane production in the breath of humans using quantitative-polymerase chain reaction (PCR) from stool of IBS patients with and without detectable methane on breath testing.
Obesity is a major and rapidly growing public health problem. It’s associated with an increased risk of coronary artery diseases, strokes, type 2 diabetics, cancers and premature deaths (B1,B2). To define preventive measures, it is important to understand the mechanisms that contribute to obesity. Researchers have begun to study the relationship between gut bacteria and metabolism (B3 – B5). Changes in the relative abundances of Bacteroidetes (B6) and Firmicutes (B4) have been associated with changes in metabolism and increased weight in both mice (B6) as well as humans (B4). “Cocolonization of germ-free mice with Methanobrevibacter Smithii results in greater weight gain than infection with B.thetaiotaomicron (B7) alone.
The need to determine the presence of methanogens and their causes and/or associations with various diseases, conditions and diseases, including obesity, pre-diabetes, diabetes, insulin resistant, glucose intolerance and constipation.
The following embodiments are described, and their aspects are illustrated with the compositions and methods that are intended to be illustrative and exemplary in nature and not limitative in scope.
The method includes analyzing a biological sample of a subject for methanogen amount, comparing it to a reference level, and then selecting either a first treatment for the patient if their methanogen value is higher than that value. This is because the first treatment is suitable for patients with a higher methanogen value. Or, a second option is selected if a lower methanogen value is detected.
The present invention provides for various embodiments that provide for a technique that involves analyzing a biological sample of a subject for methanogen amount; comparing that quantity to a standard reference value; selecting either a first treatment for the patient if their methanogen level is higher than that of the standard reference value on the basis that this first therapy would be appropriate for patients with a higher methanogen value than that of the standard reference value or selecting a different therapy for them if they have a lower methanogen based upon recognition that based on recognition that a based on recognition that a the methanogen based on recognition, based on recognition, or a the first based on based on a a a a a lower a lower a lower than a based on a a a based on a based a a based on a a a a based on a a a based based a lower than a reference,
In various embodiments, the method may also include providing the biological specimen. The method can be further incorporated in various embodiments by administering selected therapies.
In various embodiments of the method, a biological sample can be subjected to an analysis for the quantity of a microorganism that produces methane. In some embodiments, a methanogen-producing microorganism may be used. In certain embodiments, a third treatment can be selected to inhibit the growth the methanogen synthtrophic microorganism. In some embodiments, a third therapy can be administered.
In various embodiments, the biological samples can be selected from the stool, mucosal biopsies from a location in the gastrointestinal system, aspirated fluid from a location in the gastrointestinal system, or combinations thereof. In different embodiments, the site of the gastrointestinal system can be the mouth, stomach or small intestine. In different embodiments, the site of the gastrointestinal system can be the duodenum or jejunum. In different embodiments of the technique, the site within the gastrointestinal system can be the cecum, colon rectum or anus, or a combination thereof. The site of the gastrointestinal tract in various embodiments can be the ascending colon or transverse colon. It could also be the descending colon.
In various embodiments, the methanogen amount can be determined by quantitative polymerase-chain reaction (qPCR).
The disease or condition that is caused or associated with a high methanogen amount can be selected in various embodiments from a group including obesity, constipation (NASH), diabetes, pre-diabetes and insulin resistance.
In various embodiments of this method, the disease caused or associated with a low methanogen amount can be Crohn’s or ulcerative colitis.
In various embodiments, the methanogen may be of the Methanobrevibacter genus. In different embodiments, Methanobrevibacter may be selected from a group including M. acididurans (M. arboriphilus), M. curvatus (M. cuticularis), M. filiformis (M. gottschalkii), M. millerae (M. olleyae), M. oralis (M. ruminantium), M. smithii (M. smithii), M. thaueri(M. The Methanobrevibacter in various embodiments can be Methanobrevibacter (M. Smithii).
The reference value in various embodiments can be around 10,000 per ml.
In various embodiments, the first treatment can be an antibacterial or a mixture of two or three antibiotics. In different embodiments, an antibiotic or a combination of antibiotics may be chosen from the group of rifaximin (or neomycin), vancomycin (or metronidazole), or both. In some embodiments, rifaximin can be used as an antibiotic. In different embodiments, neomycin can be used as an antibiotic. Vancomycin can be used in various embodiments. In some embodiments, metronidazole can be used. The combination of two or three antibiotics in various embodiments can be metronidazole and neomycin or rifaximin with metronidazole.
In various embodiments, the first treatment can be a therapeutic probiotic that inhibits the growth of methanogen.
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