BACKGROUND

[0002] 1. Field of the Invention

[0003] The present invention relates to the field of treatment of gastrointestinal disorders, hyperlipidemia, autoimmune diseases and obesity. More particularly, the present invention relates to a probiotic composition, and a method for treatment of obesity using the composition.

[0004] 2. Background of the Invention

[0005] Gastrointestinal disease includes many disorders, including but not limited to, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, infectious enteritis (viral, bacterial, parasitic), antibiotic associative diarrhea, clostridium difficile colitis, microscopic or lymphocytic colitis, collagenous colitis, colon polyps and familial polyp syndromes (e.g., familial polyposis syndrome, Gardner's Syndrome), helicobacter pylori, irritable bowel syndrome, nonspecific diarrheal illnesses, and intestinal cancers. Moreover, obesity is the most common and costly nutritional problem in the United States.

[0006] The cause of many of these diseases is unknown. Such is the case with inflammatory bowel disease (“IBD”), the general term for diseases that cause inflammation in the intestines. For example, ulcerative colitis (“UC”) is an IBD that causes inflammation of the mucosa lining of the large intestine. The inflammation usually occurs in the rectum and lower part of the colon, but it may affect the entire colon.

[0007] The most common symptoms of UC include abdominal pain, tenesmus, fecal urgency, and bloody diarrhea. A person with UC may also experience fatigue, weight loss, loss of appetite, rectal bleeding, and loss of body fluids and electrolytes. Although UC is generally not itself fatal, a more severe form of the disease may lead to the formation of toxic megacolon leading to bowel perforations or bowel obstruction. UC may also increase the risk of colon cancer depending on the duration, extent and severity of the disease.

[0008] Despite the prevalence of IBD, including UC and Crohn's disease, no theories regarding the cause have yet been proven. In fact, as stated in U.S. Pat. No. 5,932,214, even the broader category of diseases known as IBD have “no cure, and exact causes of IBD are not yet understood.” (Col. 1, lines 40-41). Yet, advances in UC have shown, however, that it is possible to control the inflammation without knowing the etiology of the disease. Present methods of treatment for UC depend upon the extent of the disease and the severity of the symptoms. To distinguish the amount of colonic surface involved in the inflammation process, UC is divided into subgroups, including ulcerative proctitis, proctosigmoiditis, left sided UC and pancolitis. The locations of each of these subgroups of UC are illustrated in FIG. 1.

[0009] Present treatments for gastrointestinal disorders, in general, and for UC specifically, rely on drug therapy and, where such drug therapy is not effective, surgery is required. For example, initial treatment for mild to moderate UC may include the 5-ASA agents, including sulfasalazine, oral or rectal mesalamine, or olsalazine as well as conventional corticosteroid enemas. Another treatment for UC is disclosed in U.S. Pat. No. 5,932,214. This method of treatment involves administration of an antibody, polypeptide or other molecule recognizing VLA-4 (very late antigen-4). Patients with persistent mild to moderate symptoms of active UC, in spite of these therapies (treatment—refractory), may require conventional corticosteroids orally. Patients with still persistent symptoms or those with severe UC may require immunosuppressive agents such as azathioprine or 6-MP. Cyclosporin may be considered for those who do not respond. If conventional treatment is successful, remission is usually maintained with sulfasalazine and/or oral or rectal mesalamine or olsalazine, and, in some cases with azathioprine/6-MP.

[0010] Crohn's disease like UC is an inflammatory disease of the intestinal tract, but unlike UC, may involve any part of the GI tract, from mouth to anus. The terminal ilcum is a common site of involvement in active Crohn's disease and may result in malabsorption syndromes. Symptoms include diarrhea, abdominal pain, nausea, weight loss, and growth retardation. Active disease may lead to intestinal obstruction, bleeding, fistula formation, rectal abscesses, bowel perforation and peritonitis, and increased susceptibility to bowel cancer. Treatment of Crohn's disease involves use of 5-aminosalycilic acids, corticosteroids, and immunosuppressive drugs. Antibiotics are necessary for infections and surgery may be required for refractory Crohn's or the complications that may develop from the disease. 5-ASA compounds may cause headache, nausea, fatigue, abdominal pain, worsening diarrhea, and in some cases, hypersensitivity reactions leading to rash, fever hepatitis, pneumonitis, hemolytic anemia, and bone marrow suppression.

[0011] Long term use of corticosteroids may cause Cushing's Syndrome hyperglycemia, acne, muscle weakness, osteoporosis, and cataract formation, among other things. Immunosuppressive agents may cause hepatic toxicity, bone marrow suppression, and pancreatitis among other things. Response to therapy is measured by improvement in clinical signs/symptoms of the disease along with improvement in disease activity on gastrointestinal imaging, using endoscopy and barium x-ray studies.

[0012] With respect to infectious enteritis, there are a variety of viruses, bacteria, and parasites that can infect the digestive tract and cause sudden and sometimes violent symptoms, including nausea/vomiting, diarrhea (sometimes bloody), abdominal pain and cramping, fever, weakness, and loss of appetite. Among the viral causes, most are due to the Rotaviruses and the enteric caliciviruses such as Norwalk virus. Among the bacterial causes, Salmonella, Shigella, and Camphylobacter are the most common, but other pathogens like pathogenic E. Coli, Vibrio and Yersinia can occur in endemics both inside and outside the United States. Parasitic infection can be due to protozoal organisms like Entamoeba histolytica, Giardia, and Cryptosporidium.

[0013] Treatment of these infections include general supportive measures like bed rest, hydration, and nutritional support. Some require antibiotics or antiparasitic agents. These drugs can cause allergic reactions and can affect the normal bowel flora and cause superinfections with harmful bacteria like Clostridium difficile. Some may also effect other organ systems like the liver and kidneys. Clinical improvement can be monitored by the white blood count, and clearing of the offending pathogen on serial stool analysis.

[0014] Antimicrobial agents are responsible for 25% of drug induced diarrhea. The rates of antibiotic associated diarrhea (“AAD”) vary from 5 to 39% depending on the specific type of antibiotic used. The mechanism of AAD may be due to functional disturbance of intestinal carbohydrate or bile acid metabolism, an allergic or toxic effect on the intestinal mucosa, a pharmacologic effect on motility, or a disruption of the normal intestinal flora causing an overgrowth of harmful bacteria like Clostridium difficile, Clostridium peringes, Staphylococcus aureus, Klebsiella oxytoca, Candida species, or Salmonella species. About 10 to 20% of all cases of AAD are caused by Clostridium difficile, an anaerobic bacteria that secretes 2 enterotoxins, A and B, which can induce a severe colitis of the intestinal lining. Symptoms, at one end of the spectrum include a mild diarrhea, which resolves after discontinuation of the antibiotic, to severe disease causing high fever, leukocytosis, abdominal pain, profuse diarrhea, hypoalbuminemia, dehydration, and electrolyte disturbances. In rarer cases, toxic megacolon with perforation and death may occur.

[0015] The impact of AAD is reflected by higher medical costs, increased hospital stays, and increased rates of comorbidities. Treatment involves discontinuing the antibiotic, general supportive measures, bed rest, hydration, electrolyte and nutritional support, and in some cases, treatment with other antibiotics like metronidazole and vancomycin, to help restore the normal balance of the intestinal flora. In the more severe cases, surgery and colectomy may be necessary. Parameters used to measure improvement include resolution of symptoms, restoration of fluid and electrolyte balance, normalization of the white blood count, and clearing of toxins on serial stool analysis. In some cases, endoscopic evaluation of mucosal damage is necessary.

[0016] Microscopic or lymphocytic colitis and collagenous colitis may represent variants of the same disease. The disease is characterized by a waxing and waning watery diarrhea that usually affects middle-aged females. Colonoscopy shows normal appearance of the mucosa but biopsy shows infiltration of the lamina propria with inflammatory cells and intraepithelial lymphocytes. It is only in collagenous colitis that a subepithelial band of collagen is present. The pathogenesis of the disorder remains a mystery but there is evidence, much like UC and Crohn's disease, that the inflammatory process may be triggered by a luminal agent. The disease is treated much like IBD with 5-ASA drugs and corticosteroid. 5-ASA products may cause headache, nausea, fatigue, abdominal pain and worsening diarrhea. Hypersensitivity reactions may lead to rash, fever, hepatitis, pneumonitis, hemolytic anemia, and bone marrow suppression. Long term use of corticosteroids may cause Cushing's disease, hyperglycemia, acne, muscle weakness, osteoporosis, and cataracts, among other things.

[0017] The majority of colorectal cancers, regardless of etiology, are believed to arise from adenomatous polyps. These polyps protrude from the mucosa and are visible endoscopically. Regular lower GI screening and removal of polyps remains, by far, the best way to prevent colon cancer. Unfortunately, colon cancer still remains the second leading cause of cancer death in the U.S. primarily because of an unsatisfactory adherence to a regimented screening program. Certain hereditary syndromes (like Familial Polyposis) are characterized by the appearance of thousands of adenomatous polyps throughout the large bowel. If left surgically untreated, colorectal cancer will develop in almost all patients prior to age 40. To prevent colon cancer in these individuals, a total colectomy is usually required. There is currently no other hard and fast way to prevent colon polyps and thus colorectal cancer, but dietary factors, like enhancing fiber and lowering saturated fat intake, might help. Nonsteroidal anti-inflammatory drugs like sulindac and celecoxib hold some promise. Many times though, these nonsteroidal agents may produce adverse GI side effects, renal failure, edema, and hypertension.

[0018] Irritable bowel syndrome (“EBS”) is the most common gastrointestinal disease in clinical practice, and although not life threatening, it causes great distress. The patient with IBS may present with one of 3 clinical variants: patients with spastic colitis complain primarily of chronic abdominal pain and constipation. A second group has chronic intermittent diarrhea, often without pain, and a third group has features of both and complain of alternating constipation and diarrhea. The cause of the disease is thought to be due to an altered intestinal motility and increased visceral perception leading to reflex intestinal motor activity. Significant psychologic disturbances may be seen in some patients with IBS. Depression, hysteria, and obsessive compulsive traits are common. Fiber supplements, tranquilizers, and anticholinergic agents are the mainstay of treatment. Unfortunately, no specific drug or dietary regimen affords good relief in all patients, and, thus, a number of therapeutic maneuvers need to be tried. Response to treatment is based solely on relief of distressing symptoms. There are no laboratory studies used to monitor IBS.

[0019] Nonspecific diarrheal illnesses usually fall into one of five categories: 1

[0020] Treatment and monitoring vary according to the specific cause of the diarrhea.

[0021] Helicobacter pylori is a micro-aerophilic gram negative bacillus that invades the gastric mucosa inducing an inflammatory response in the epithelial cell layer causing an infiltration of polymorphonuclear leukocytes. It can cause gastritis that can lead to erosions and even ulceration of the stomach and duodenum. It is the most common cause of ulcer disease in the U.S. Eradication of this organism usually requires a proton pump inhibitor in combination with clarithromycin and either amoxicillin or metronidazole. For many patients, this combination is poorly tolerated and gastrointestinal side effects are common. Antibiotic associated diarrhea along with hypersensitivity reactions can also occur. Eradication of H. pylori can be confirmed with either UGI endoscopy with biopsy and special staining for H. pylori or by the breath urea nitrogen test.

[0022] Hyperlipidemia is detected by finding an elevated cholesterol or triglyceride in fasting plasma. There are 6 types that have been described: I, IIa, IIb, III, IV, and V, and are distinguished by the pattern of lipoprotein elevation in plasma. Each type may be inherited or secondary to other disorders like diabetes mellitus or hypothyroidism. Left untreated, hyperlipidemia can lead to atherosclerotic vascular disease or in some cases acute pancreatitis. Treatment involves a low fat diet, exercise, restriction of alcohol, and lipid lowering drugs. The pharmacologic agents used include the “statins” (which may cause constipation, hepatitis, myositis, and GI disturbances), bile acid sequestrants (which may cause constipation, heartburn, nausea, and bloating), nicotinic acid (which may cause flushing, GI distress, or hyperuricemia), and fibrates (which may cause cholelithiasis, hepatitis, or myositis). Monitoring response usually involves checking fasting plasma LDL, HDL, and triglycerides levels.

[0023] Autoimmune disease are characterized by production of either antibodies that react with host tissue or immune effector T cells that are autoreactive to endogenous self peptides. Genetic factors likely play a role in the genesis toward auto antibody formation or in the case of Major Histcompatability Complex antigen association with autoimmune diseases via presentation of self or foreign peptides that stimulate inappropriate antiself response. Examples of autoimmune diseases include systemic lupus crythematosus, rheumatoid arthritis, and the vasculitis syndromes.

[0024] Treatment of these conditions usually include the use of corticosteroids and immunosuppressive agents. Long term use of corticosteroids may cause Cushing's syndrome, hyperglycemia, acne, muscle weakness, osteoporosis, cataracts, among other things. Immunosuppressive drugs may cause hepatic toxicity, bone marrow suppression, and pancreatitis, among other things. Monitoring of response is based on improvement in clinical signs/symptoms, improvement in parameters of inflammation like the westergren sedimentation rate and c reactive protein levels, and in some cases, reduction in blood levels of auto antibodies.

[0025] Obesity is the most common and costly nutritional problem in the U.S., affecting approximately 33% of adults. Kuezmarski R J, Flegal K M, Campbell S M, Johnson C L. Increasing Prevalence of Overweight Among US Adults. JAMA 1994; 272:205-11. The underlying causes of obesity are complex and generally cannot be simplified to mere “overeating”. Both physiological and psychological factors may be involved.

[0026] Unfortunately, the prevalence of obesity is on the rise, increasing by approximately 30% between 1980 and 1994. Id. Health care costs directly attributed to obesity amount to $68 billion per year, and an additional $30 billion per year is spent on weight reduction programs and special foods. Long-Term Pharmacotherapy in the Management of Obesity: National Task Force on the Prevention and Treatment of Obesity. JAMA 1996; 276-1907-15. Even so, treatment directed toward the long-term reduction of body weight is largely ineffective, and 90 to 95% of persons who lose weight subsequently regain it. Wadden T A. Treatment of Obesity by Moderate and Severe Caloric Restriction: Results of Clinical Research Trials. Ann Intern Med 1993; 229:688-93; Rosenbaum M, Leibel R L, Pathophysiology of Childhood Obesity. Adv Pediatr 1988; 35:73-137.

[0027] Obesity is associated with increased morbidity and mortality. It has been linked to a number of diseases including type 2 diabetes mellitus, hypertension, coronary artery disease, stroke, hypercholesterolemia, cholelithiasis, fatty liver disease, certain cancers (postmenopausal breast cancer and cancers of the colon, endometrium and kidney), musculoskeletal disorders (osteoarthritis), obstructive sleep apnea, and infertility, not to mention the social consequences and isolation that many patients with obesity experience. Department of Agriculture, Department of Health and Human Services. Nutrition and Your Health: Dietary Guidelines for Americans, 4th Ed. Home and Garden Bulletin No. 232. Washington, D.C.: Government Printing Office, 1995.

[0028] Current treatment strategies have been disappointing and largely ineffective for long-term success. Certainly every effort is made to set short-term goals and recognize the importance of lifestyle alterations in the form of increased exercise and decreased caloric intake. Drug therapy is now limited since fenfluramine and dexfenfluramine have been taken off the market due to their possible link to valvular heart disease. Two new agents, sibutramine (Meridia), a catecholaminergic and serotonergic agonist, and orlistat (Xenical), a lipase inhibitor, have recently been approved by the FDA. Unfortunately, sibutramine causes dry mouth, headaches, insomnia, constipation, and dose related increases in heart rate and blood pressure. Sibutramine for Obesity. The Medical Letter 1998; 40:32. Orlistat can cause flatulence, oily stools, and fecal urgency and interferes with the absorption of the fat soluble vitamins (A, D, E, and beta carotene). Orlistat for Obesity. The Medical Letter 1999; 41:55-6. Both drugs are only indicated for short term treatment and weight gain after cessation is common.

[0029] Surgical therapy is reserved for patients with severe obesity or those with lesser obesity who have coexisting conditions. Jejunal-ileal shunting can be effective but is costly and frequently results in symptoms related to a blind loop. The more common gastroplasty procedure is also costly and can cause “dumping” associated with the passage of gastric contents into the intestine. These patients need to be followed carefully for intestinal obstruction and electrolyte disturbances. Excess consumption of liquid or semisolid foods can negate the benefits of both procedures. Browenll K D, Fairbum C G, eds. Eating Disorders and Obesity: A Comprehensive Handbook. New York: Guilford Press, 1995.

[0030] Generally, conventional treatment methods for most gastrointestinal disorders, autoimmune diseases and obesity are expensive for the patient. In addition, while the symptoms may be relieved by conventional treatments, there are known side effects resulting from conventional treatments. For example, the side effects associated with treatment of UC using 5-ASA agents include nausea, vomiting, heartburn, diarrhea, and headache. For immunosuppressive agents, side effects include pancreatitis, fever, rash, arthralgia, nausea, leukopenia, infection, and hepatitis. Side effects resulting from surgery relate to problems common to the use of any invasive procedure, QOL issues, and complications. Further, many current treatment methods do not appear to play a beneficial role, such as reduction in the risk of colon cancer.

[0031] Recently, a number of diseases are being treated by probiotics. The term “probiotic” implies use of bacteria which performs beneficial functions for the human organisms when they are present and alive in viable form.

[0032] Consider, for example, the composition of U.S. Pat. No. 3,988,440 for treatment of gastritis, and for gastric and duodenal ulcers. This particular composition contains 4-5.5% lactic acid bacteria or, more specifically, Lactobacillus bulgaricus, which is cultivated in a soya media. Kawai, et al., U.S. Pat. No. 4,710,379, discloses an agent that contains bacteria cells obtained from microorganisms belonging to the genius Streptococcus, but not the species thermophilus. Kawai, et al., also claims the method for stimulating growth of intestinal lactic acid flora by administering a microorganism belonging to the genius Streptococcus to a person recognized as being deficient in intestinal lactic acid bacteria.

[0033] Cavaliere Veseley, et al., U.S. Pat. No. 5,716,615, discloses a method of treatment of gastrointestinal disorders and for treatment of hypercholesterolemia. The composition contains 10-95% of Streptococcus thermophilus and 90-5% L. plantarum, and L. sasei, and other bacteria (see Col. 2, line 30-Col. 3, line 12). Cavaliere Veseley, et al., also suggests treatment for chronic hepatitis, high cholesterol, and irritable bowel syndrome with this composition.

[0034] Paul, U.S. Pat. No. 5,531,988, discloses an invention which comprises a bacteria and whey-containing composition, which is a mixture of an immunoglobulin and a bacterium, such as Lactobacilli or Bifidobacterium or mixtures thereof. This composition is used to treat diarrhea, constipation, and gas/cramps.

[0035] Ford, U.S. Pat. No. 5,636,202, discloses micro-encapsulated Lactobacilli bacteria orally administered to treat or present antibiotic associated or other chronic or acute diarrhea. Ford suggests use of Lactobacillus bulgaricus. Interestingly, the claims of Ford are directed only to treatment of skin infections.

[0036] Reddy, et al., U.S. Pat. No. 6,080,401, discloses a medicinal preparation for treatment of a disease or disorder in humans and animals combining a drug in a dosage sufficient for effective treatment of a disease or disorder, and a viable probiotic in a quantity sufficient to increase the efficacy of the drug. Reddy discloses a combination of probiotics and herbal preparations for aiding in weight loss. The weight loss preparation includes probiotics having Lactobacillus acidophilus and Bifidobacterium bifidus.

[0037] Each of these probiotic treatments is limited in its application and effectiveness. It is desired to treat the aforementioned gastrointestinal and autoimmune diseases, hyperlipidemia and obesity in an effective and cost efficient manner using a single probiotic composition. Therefore, a new composition and method of treatment is needed that is effective in reducing symptoms, reasonable in cost to the patient, does not exhibit significant adverse side effects, and which may be beneficial in reducing the risk of colon cancer. Of course, it is also desirable that the composition be easy to manufacture and deliver to the patient.

SUMMARY

[0038] In accordance with the present invention, a probiotic composition and method for the treatment of obesity is provided that solves the deficiencies inherent in traditional treatments. The present invention provides an effective treatment for obesity that avoids adverse side effects, is reasonable in cost for the patient, and may be beneficial in reducing the risk of obesity related diseases. Further, the present invention is relatively easy to manufacture and deliver to the patient.

[0039] In accordance with the present invention, a probiotic composition for the treatment of obesity is provided. The probiotic composition comprises a mixture having Lactobacillus bulgaricus and Streptococcus thermophilus lactic acid bacteria. The probiotic composition further comprises a carbohydrate enriched media whereby the mixture and media are combined and allowed to ferment until a desired ratio of the Lactobacillus bulgaricus and Streptococcus thermophilus organisms as well as a desired number of total organisms per gram are achieved. The desired ratio of Lactobacillus bulgaricus and Streptococcus thermophilus organisms ranges from about 1:1 to about 10:1. The desired number of Lactobacillus bulgaricus per gram ranges from about 3×10⁸ to about 2×10¹¹. Once the desired ratios and number of organisms are achieved, the composition may be freeze dried.

[0040] The present invention further includes a method for treating obesity using the lyophilized probiotic composition. The method comprises the steps of providing a probiotic composition comprising a mixture of Lactobacillus bulgaricus and Streptococcus thermophilus lactic acid bacteria. The composition further comprises a carbohydrate enriched media where the mixture and the media are combined and allowed to ferment until a desired ratio of Lactobacillus bulgaricus and Streptococcus thermophilus organisms as well as a desired number of total organisms per dose (10 grams/dose) are achieved. Next, the lyophilized probiotic composition is administered to a patient.