BACTERIA ENGINEERED TO TREAT METABOLIC DISEASES

1 . An engineered bacterium comprising a gene sequence or gene cassette for producing one or more aryl hydrocarbon receptor (AhR) agonist(s), wherein the gene sequence or gene cassette is operably linked to a directly or indirectly inducible promoter that is not associated with the gene sequence or gene cassette in nature.

2 . The engineered bacterium of claim 1 , wherein the engineered bacterium comprises gene sequence for producing indole-3-acetonitrile.

3 . The engineered bacterium of claim 2 , wherein the engineered bacterium comprises gene sequence encoding cyp79B2 (tryptophan N-monooxygenase).

4 . The genetically engineered bacteria of claim 2 or claim 3 , wherein the engineered bacterium comprises gene sequence encoding cyp71a13 (indoleacetaldoxime dehydratase).

5 . The genetically engineered bacteria of any of claims 2 - 4 , wherein the engineered bacterium comprises gene sequence encoding cyp79B3 (tryptophan N-monooxygenase).

6 . The genetically engineered bacteria of claim 5 , wherein the cyp79B2, cyp71a13, and cyp79B3 are from Arabidopsis thaliana.

7 . The bacterium of any of claims 1 - 6 , wherein the bacterium comprises a gene or gene cassette for producing indole-3-propionic acid.

8 . The genetically engineered bacteria of claim 7 , wherein the engineered bacterium comprises gene sequence encoding tryptophan ammonia lyase.

9 . The genetically engineered bacyteris of claim 8 , wherein the tryptophan ammonia lyase is from Rubrivivax benzoatilyticus.

10 . The genetically engineered bacterium of any of claims 7 - 9 , wherein the engineered bacterium comprises one or more gene sequences encoding indole-3-acrylate reductase.

11 . The genetically engineered bacterium of claim 10 , wherein the ndole-3-acrylate reductase is from Clostridum botulinum.

12 . The genetically engineered bacterium of any of claims 7 - 11 , wherein the engineered bacterium comprises gene sequence encoding Tryptophan dehydrogenase (trpDH).

13 . The genetically engineered bacteria of claim 12 , wherein the trpDH is from Nostoc punctiforme NIES-2108.

14 . The genetically engineered bacterium of any of claims 7 , claim 12 and claim 13 , wherein the engineered bacterium comprises gene sequence encoding fldA (indole-3-propionyl-CoA:indole-3-lactate CoA transferase).

15 . The genetically engineered bacterium of claim 14 , wherein the fldA is from Clostridium sporogenes.

16 . The genetically engineered bacterium of any of claims 7 and claims 12 - 15 , wherein the bacterium comprises gene sequence(s) encoding fldB and fldC (indole-3-lactate dehydratase).

17 . The genetically engineered bacterium of claim 16 , wherein the fldB and fldC is from Clostridium sporogenes.

18 . The genetically engineered bacterium of any of claims 7 and claims 12 - 17 , wherein the engineered bacterium comprises gene sequences encoding fldD (indole-3-acrylyl-CoA reductase).

19 . The genetically engineered bacterium of claim 18 , wherein the fldD is from Clostridium sporogenes.

20 . The genetically engineered bacterium of any of claims 7 and claims 12 - 19 , wherein the engineered bacterium comprises gene sequences encoding Acul (acrylyl-CoA reductase).

21 . The genetically engineered bacteria of claim 20 , wherein the Acul is from Rhodobacter sphaeroides.

22 . The genetically engineered bacterium of any of claims 7 and claims 12 - 21 , wherein the engineered bacterium comprises gene sequence encoding fldH1 (3-lactate dehydrogenase 1).

23 . The genetically engineered bacterium of claim 22 , wherein the fldH1 is from Clostridium sporogenes.

24 . The genetically engineered bacterium of any of claims 7 and claims 12 - 23 , wherein the engineered bacterium comprises gene sequence encoding fldH2 (indole-3-lactate dehydrogenase 2).

25 . The genetically engineered bacteria of claim 24 , wherein the fldH2 is from Clostridium sporogenes.

26 . The genetically engineered bacterium of claim 12 , wherein the engineered bacterium comprises gene sequences encoding trpDH, fldA, fldB, flD, and fldH1.

27 . The genetically engineered bacterium of claim 12 , wherein the engineered bacterium comprises gene sequences encoding trpDH, fldA, fldB, flD, and fldH2.

28 . The genetically engineered bacterium of claim 12 , wherein the engineered bacterium comprises gene sequence encoding trpDH, fldA, fldB, acuI and fldH1.

29 . The genetically engineered bacterium of claim 12 , wherein the engineered bacterium comprises gene sequence encoding trpDH, fldA, fldB, acuI and fldH2.

30 . The genetically engineered bacterium of any of claims 1 - 29 , wherein the engineered bacterium comprises gene sequence for producing tryptamine.

31 . The engineered bacteria of claim 30 , wherein the engineered bacterium comprises gene sequence encoding Tryptophan decarboxylase.

32 . The engineered bacterium of claim 31 , wherein the Tryptophan decarboxylase is from Catharanthus roseus.

33 . The engineered bacterium of any of claims 1 - 32 , wherein the engineered bacterium comprises gene sequence for producing producing indole-3-acetaldehyde.

34 . The genetically engineered bacterium of claim 33 , wherein the engineered bacterium comprises gene sequence encoding aro9 (L-tryptophan aminotransferase).

35 . The genetically engineered bacterium of claim 33 or claim 34 , wherein the engineered bacterium comprises gene sequence encoding aspC (aspartate aminotransferase.

36 . The genetically engineered bacterium of any of claims 33 - 35 , wherein the engineered bacterium comprises gene sequence encoding taal (L-tryptophan-pyruvate aminotransferase.

37 . The genetically engineered bacterium of any of claims 33 - 36 , wherein the engineered bacterium comprises gene sequence encoding staO (L-tryptophan oxidase).

38 . The genetically engineered bacterium of any of claims 33 - 37 , wherein the engineered bacterium comprises gene sequence encoding trpDH (Tryptophan dehydrogenase).

39 . The genetically engineered bacterium of any of claims 33 - 38 , wherein the engineered bacterium comprises gene sequence encoding ipdC (Indole-3-pyruvate decarboxylase).

40 . The genetically engineered bacterium of claim 33 , wherein the engineered bacterium comprises gene sequence encoding tdc (Tryptophan decarboxylase).

41 . The genetically engineered bacterium of claim 33 or claim 40 , wherein the engineered bacterium comprises gene sequence encoding tynA (Monoamine oxidase).

42 . The genetically engineered bacterium of any of claims 1 - 41 , wherein the engineered bacterium comprises gene sequence for producing indole-3-acetic acid.

43 . The genetically engineered bacterium of claim 42 , wherein the bacterium comprises gene sequence encoding one or more of the following: aro9 (L-tryptophan aminotransferase), aspC (aspartate aminotransferase), taal (L-tryptophan-pyruvate aminotransferase), staO (L-tryptophan oxidase), trpDH (Tryptophan dehydrogenase), iad1 (Indole-3-acetaldehyde dehydrogenase), AAO1 (Indole-3-acetaldehyde oxidase), ipdC (Indole-3-pyruvate decarboxylase), ipdC (Indole-3-pyruvate decarboxylase), tdc (Tryptophan decarboxylase), tynA (Monoamine oxidase), yuc2 (indole-3-pyruvate monooxygenase), IaaM (Tryptophan 2-monooxygenase), and iaaH (Indoleacetamide hydrolase).

44 . The genetically engineered bacterium of any of claims 1 - 43 , wherein the bacterium further comprises gene sequence for producing tryptophan.

45 . The genetically engineered bacterium of any of claims 1 - 44 , wherein the bacterium further comprises gene sequence encoding one or more tryptophan transporters.

46 . The genetically engineered bacterium of claim 45 , wherein the tryptophan transporter is selected from mtr, aroP, and tnaB.

47 . The bacterium of any of claims 1 - 46 , wherein the bacterium further comprises gene sequence for producing kynurenine.

48 . The bacterium of any of claims 1 - 47 , wherein the bacterium further comprises a gene sequence for producing kynurenic acid.

49 . The bacterium of any of claims 1 - 48 , wherein the bacterium further comprises a gene sequence for producing an indole.

50 . The genetically engineered bacterium of any of claims 1 - 49 , wherein the bacterium further comprises gene sequence encoding a non-native metabolic or satiety effector molecule.

51 . The bacterium of claim 50 , wherein the metabolic or satiety effector molecule is selected from a a short-chain fatty acid, butyrate, propionate, acetate, GLP-1, IL-22, IL-10, bile salt hydrolase, n-acyl-phophatidylethanolamine (NAPE), a n-acyl-ethanolamines (NAE), a ghrelin receptor antagonist, peptide YY3-36, a cholecystokinin (CCK), CCK58, CCK33, CCK22, CCK8, a bombesin, gastrin releasing peptide (GRP), neuromedin B (P), glucagon, GLP-1, GLP-2, apolipoprotein A-IV, amylin, somatostatin, entero statin, oxyntomodulin, pancreatic peptide, a serotonin receptor agonist, nicotinamide adenine dinucleotide (NAD), nicotinamide mononucleotide (NMN),nucleotide riboside (NR), nicotinamide, and nicotinic acid (NA).

52 . The bacterium of claim 51 , wherein the metabolic or satiety effector molecule is a short-chain fatty acid.

53 . The bacterium of claim 52 , wherein the metabolic or satiety effector molecule is butyrate.

54 . The bacterium of claim 52 , wherein the metabolic or satiety effector molecule is propionate.

55 . The bacterium of claim 52 , wherein the metabolic or satiety effector molecule is GLP1.

56 . The bacterium of any of claims 1 - 55 , wherein the gene sequence is operably linked to a directly or indirectly inducible promoter that is induced by exogenous environmental conditions.

57 . The bacterium of claim 56 , wherein the promoter is directly or indirectly induced by exogenous environmental conditions found in the mammalian gut.

58 . The bacterium claim 57 , wherein the promoter is directly or indirectly induced by low-oxygen or anaerobic conditions.

59 . The bacterium of claim 58 , wherein the promoter is selected from a FNR-inducible promoter, an ANR-inducible promoter, and a DNR-inducible promoter.

60 . The bacterium of claim 59 , wherein the promoter is a FNR-inducible promoter.

61 . The bacterium of any of claims 1 - 57 , wherein the promoter is regulated by a reactive nitrogen species (RNS).

62 . The bacterium of any of claims 1 - 57 , wherein the promoter is regulated by a reactive oxygen species (ROS).

63 . The bacterium of any one of claims 1 - 62 , wherein the gene sequence and operatively linked promoter are present on a plasmid in the bacterium.

64 . The bacterium of any one of claims 1 - 62 , wherein the gene sequence and operatively linked promoter are present on a chromosome in the bacterium.

65 . The bacterium of any one of claims 1 - 64 , wherein the bacterium is an auxotroph comprising a deletion or mutation in a gene required for cell survival and/or growth.

66 . The genetically engineered bacterium of claim 65 , wherein the bacterium is an auxotroph in diaminopimelic acid or an enzyme in the thymidine biosynthetic pathway.

67 . The bacterium of any one of claims 1 - 66 , wherein the bacterium comprises a kill switch.

68 . The bacterium of any of claims 1 - 67 , wherein the bacterium is a non-pathogenic bacterium.

69 . The bacterium of claim 68 , wherein the bacterium is a probiotic or a commensal bacterium.

70 . The bacterium of claim 69 , wherein the bacterium is selected from the group consisting of Bacteroides, Bifidobacterium, Clostridium, Escherichia, Lactobacillus, and Lactococcus.

71 . The bacterium of claim 70 , wherein the bacterium is Escherichia coli strain Nissle.

72 . A pharmaceutically acceptable composition comprising the bacterium of any one of claims 1 - 71 ; and a pharmaceutically acceptable carrier.

73 . The pharmaceutically acceptable composition of claim 72 , wherein the composition is formulated for oral or rectal administration.

74 . A method of treating a metabolic disease in a subject in need thereof comprising the step of administering to the subject the composition of claim 72 or claim 73 .

75 . The method of claim 74 , wherein the disorder of condition is selected from the group consisting of: type 1 diabetes; type 2 diabetes; metabolic syndrome; Bardet-Biedel syndrome; Prader-Willi syndrome; non-alcoholic fatty liver disease; tuberous sclerosis; Albright hereditary osteodystrophy; brain-derived neurotrophic factor (BDNF) deficiency; Single-minded 1 (SIM1) deficiency; leptin deficiency; leptin receptor deficiency; pro-opiomelanocortin (POMC) defects; proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency; Src homology 2B1 (SH2B1) deficiency; pro-hormone convertase 1/3 deficiency; melanocortin-4-receptor (MC4R) deficiency; Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome; pseudohypoparathyroidism type 1A; Fragile X syndrome; Borjeson-Forsmann-Lehmann syndrome; Alstrom syndrome; Cohen syndrome; and ulnar-mammary syndrome.