Methods of diagnosing and treating small intestinal bacterial overgrowth (SIBO) and SIBO-related conditions

• US 9,358,276 B2
• Filed: 12/16/2014
• Issued: 06/07/2016
• Est. Priority Date: 08/11/1999
• Status: Expired due to Fees

• Current Assignee: Cedars-Sinai Medical Center (Cedars Sinai Health System)
• Original Assignee: Cedars-Sinai Medical Center (Cedars Sinai Health System)
• Inventors: Lin, Henry C., Pimentel, Mark
• Primary Examiner(s): Swartz, Rodney P
• Application Number:
  US14/572,037
• Publication Number:
  US 20150306190A1
• Time in Patent Office: 539 Days
• Field of Search: 424/9.1, 424/9.2, 424/116, 424/278, 424/439, 426/5.71, 426/658, 426/800, 426/801, 435/4, 435/29
• US Class Current: 1/1
• CPC Class Codes: A23L 33/40 Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61B 5/0836 Measuring rate of CO2 production
• CPC Class Codes: A61B 5/412 Detecting or monitoring sepsis
• CPC Class Codes: A61B 5/415 the glands, e.g. tonsils, adenoids or thymus
• CPC Class Codes: A61B 5/418 lymph vessels, ducts or nodes
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/201 having one or two double bonds, e.g. oleic, linoleic acids
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/424 condensed with heterocyclic ring systems, e.g. clavulanic acid
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/65 Tetracyclines
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 31/7048 : having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 36/534 : Mentha (mint)
• CPC Class Codes: A61K 38/1796 : for hormones for neuromediators A61K38/1787
• CPC Class Codes: A61K 38/22 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/225 : Calcitonin gene related peptide
• CPC Class Codes: A61K 38/2271 : Neuropeptide Y
• CPC Class Codes: A61K 38/54 : Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0004 : Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61K 51/1206 : Administration of radioactive gases, aerosols or breath tests
• CPC Class Codes: A61K 9/0053 : Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0087 : Galenical forms not covered by A61K9/02 - A61K9/7023
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: G01N 2033/4977 : metabolic gass from microbes, cell cultures, plant tissues and the like
• CPC Class Codes: G01N 2333/70571 : for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: G01N 2800/06 : Gastro-intestinal diseases
• CPC Class Codes: G01N 33/497 : of gaseous biological material, e.g. breath
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere
• CPC Class Codes: Y10S 426/80 : Geriatric
• CPC Class Codes: Y10S 426/801 : Pediatric
• CPC Class Codes: Y10T 436/145555 : Hetero-N
• CPC Class Codes: Y10T 436/147777 : Plural nitrogen in the same ring [e.g., barbituates, creatinine, etc.]
• CPC Class Codes: Y10T 436/18 : Sulfur containing
• CPC Class Codes: Y10T 436/214 : Acyclic [e.g., methane, octane, isoparaffin, etc.]
• CPC Class Codes: Y10T 436/22 : Hydrogen, per se

Abstract

Disclosed is a method of treating small intestinal bacterial overgrowth (SIBO) or a SIBO-caused condition in a human subject. SIBO-caused conditions include irritable bowel syndrome, fibromyalgia, chronic pelvic pain syndrome, chronic fatigue syndrome, depression, impaired mentation, impaired memory, halitosis, tinnitus, sugar craving, autism, attention deficit/hyperactivity disorder, drug sensitivity, an autoimmune disease, and Crohn'"'"'s disease. Also disclosed are a method of screening for the abnormally likely presence of SIBO in a human subject and a method of detecting SIBO in a human subject. A method of determining the relative severity of SIBO or a SIBO-caused condition in a human subject, in whom small intestinal bacterial overgrowth (SIBO) has been detected, is also disclosed.

Claims

1. A method of treating small intestinal bacterial overgrowth (SIBO) or a SIBO-caused condition in a human subject, said method comprising:

detecting in the subject by suitable detection means, the presence of SIBO, wherein a population of proliferating bacteria is present in the small intestine of the subject, or detecting with said means the absence of SIBO; and

, if the presence of SIBO is detected in the subject,

depriving the bacterial population of nutrient(s) sufficiently to inhibit the growth of said bacteria in the small intestine, and thereby at least partially eradicating SIBO in the human subject.

2. The method of claim 1, further comprising:

in the presence of SIBO in the human subject, causing the subject to consume, for a sustained period, a diet consisting essentially of nutrients that upon arrival in the upper gastrointestinal tract of the subject, are at least partially predigested, said sustained period being sufficient to at least partially eradicate SIBO in the human subject.

3. The method of claim 2, wherein the period is at least about three days.

4. The method of claim 2, wherein the at least partially predigested nutrients are contained in a commestible total enteral nutrition formulation.

5. The method of claim 2, further comprising:

administering to the subject a pancreatic enzyme supplement before or substantially simultaneously with a meal, such that nutrients contained in said meal are at least partially predigested in the upper gastrointestinal tract of the subject by the activity of said pancreatic enzyme supplement.

6. The method of claim 1, further comprising:

in the presence of SIBO in the human subject,

enhancing the digestion and/or absorption of the nutrient(s) in the upper gastrointestinal tract of said human subject by slowing transit of said nutrients across the upper gastrointestinal tract of said human subject, thereby at least partially depriving the bacterial population of the nutrient(s).

7. The method of claim 6, further comprising:

administering a pharmaceutically acceptable composition to said human subject by an oral or enteral delivery route, said human subject having an intrinsic cholinergic afferent neural pathway projecting from a peptide YY-sensitive primary sensory neuron in the intestinal wall of said subject to a prevertebral celiac ganglion and having an adrenergic efferent neural pathway projecting from said ganglion to one or more enterochromaffin cells in the intestinal mucosa and/or to a serotonergic interneuron linked in a myenteric plexus and/or submucous plexus to an opioid interneuron, said opioid interneuron also being linked by an intestino-fugal opioid pathway projecting to said ganglion, with one or more neural connections to the central nervous system and back to the gut projecting from the ganglion,

said pharmaceutically acceptable composition comprising an active agent, said active agent being selected from the group consisting of

(A) active lipids;

(B) serotonin, serotonin agonists, or serotonin-selective reuptake inhibitors;

(C) peptide YY or peptide YY functional analogs;

(D) calcitonin gene-related peptide or functional analogs thereof;

(E) adrenergic agonist;

(F) opioid agonists;

(G) combinations of any of (A), (B), (C), (D), (E) and/or (F); and

(H) antagonists of receptors for any of (B), (C), (D), (E) and/or (F),

said active agent being delivered in an amount and under conditions such that the cholinergic intestino-fugal pathway, at least one prevertebral ganglionic pathway, the adrenergic efferent neural pathway, the serotonergic interneuron and/or the opioid interneuron are activated by the action of any of (A) through (G), whereby the rate of upper gastrointestinal transit in the subject is slowed, thereby enhancing the digestion and/or absorption of the nutrient(s) in the upper gastrointestinal tract of said human subject.

8. The method of claim 6, further comprising:

administering a gastrointestinal transit-slowing composition comprising a carrier and a dispersion consisting essentially of an active lipid in the carrier, the active lipid being selected from the group consisting of saturated and unsaturated fatty acids, fully hydrolyzed fats and mixtures thereof, in an amount and in a form effective to promote contact of the lipid with the subject'"'"'s small intestine and thereby slow gastrointestinal transit and at least partially eradicate SIBO in the human subject.

9. The method of claim 8, wherein the active lipid is selected from the group consisting of:

(A) caprolic acid, caprulic acid, capric acid, lauric acid, myristic acid, oleic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, trans-hexadecanoic acid, elaidic acid, columbinic acid, arachidic acid, behenic acid eicosenoic acid, erucic acid, bressidic acid, cetoleic acid, nervonic acid, Mead acid, arachidonic acid, timnodonic acid, clupanodonic acid, or docosahexaenoic acid;

(B) pharmaceutically acceptable salts of any of (A); and

(C) mixtures of any of (A) or (B).

10. The method of claim 9, wherein the active lipid comprises oleic acid or a pharmaceutically acceptable oleate salt.

11. The method of claim 8, wherein the active lipid comprises fully hydrolyzed fats.

12. The method of claim 8, wherein the active lipid comprises a fatty acid or a pharmaceutically acceptable salt thereof.

13. The method of claim 8, wherein the active lipid is:

(A) a fatty acid selected from the group of (C4-C24) saturated and unsaturated fatty acids;

(B) a pharmaceutically acceptable salt of any of (A);

or

(C) a mixture of any of (A) and/or (B).

14. The method of claim 8, wherein the fatty acid comprises oleic acid, a pharmaceutically acceptable oleate salt, or a mixture of either of these with other fatty acids or salts thereof.

15. The method of claim 7, wherein oral administration is by ingestion of coated or uncoated microspheres or particles, of a dispersible powder or granule formulation, of a suspension, emulsion, solution, syrup, or elixir, or of a coated or uncoated tablet, troche, capsule, caplet, or lozenge.

16. The method of claim 8, wherein oral administration is by ingestion of coated or uncoated microspheres or particles, of a dispersible powder or granule formulation, of a suspension, emulsion, solution, syrup, or elixir, or of a coated or uncoated tablet, troche, capsule, caplet, or lozenge.

17. The method of claim 7, wherein the active agent is selected from the group consisting of serotonin, serotonin agonists, serotonin-selective reuptake inhibitors, 5-HT3 receptor antagonists, and 5-HT4 receptor antagonists.

18. The method of claim 17, wherein the active agent is serotonin, and the serotonin is administered to the human subject, before or substantially simultaneously with a meal, in an amount from about 0.03 to about 0.1 mg/kg body mass.

19. A method of treating irritable bowel syndrome in a human subject, said method comprising:

detecting in the subject by suitable detection means, the presence of SIBO, wherein a population of proliferating bacteria is present in the small intestine of the subject, or detecting with said means the absence of SIBO; and

, if the presence of SIBO is detected in the subject,

depriving the bacterial population of nutrient(s) sufficiently to inhibit the growth of said bacteria in the small intestine, and thereby at least partially eradicating SIBO in the human subject.