US 2020/0027524 A1 · RATIONAL DESIGN OF MICROBIAL-BASED BIOTHERAPEUTICS

Abstract

Methods are provided for the rational design of stable communities of microbes for benefiting the health of a host organism, including human and/or animal health. The methods describe design of microbial consortia based on providing and/or complementing key functionalities lacking or underrepresented in the microbiome of an organism having a disorder or disease as compared to healthy subjects. The consortia are designed to possess metabolic interdependencies for improved engrafting, stability and performance of the consortium. Compositions that include the designed microbial consortia are provided for treatment of disorders/diseases involving chronic inflammation, infection, and the combination of chronic inflammation and infection including inflammatory bowel disease and related disorders. The compositions are also broadly applicable for the treatment of neurological, metabolic and oncology-related conditions.

Claims15

Dependent claims

A method for rational design of microbial consortia for benefiting the health of an organism, the method comprising:

for a plurality of microbial strains each having at least one functionality in a set of functionalities absent or underrepresented in a microbiome of an organism of interest, creating for each strain using genome annotation an in silico metabolic model that predicts an auxotrophic profile for one or a combination of essential nutrients;
integrating in silico the metabolic models for each of the plurality of strains to obtain a combined metabolic model for the plurality of strains;
and
designating a microbial consortium having a metabolic interdependency, including by optionally introducing into the plurality or removing from the plurality one or more microbial strains, wherein the metabolic interdependency of the plurality of strains in the microbial consortium includes each of the strains having at least one auxotrophy for the essential nutrient(s) and each being dependent on at least one of the other strains in the plurality for growthm
wherein the microbial consortium benefits the health of the organism.

2 more elements

A composition for benefiting the health of an animal or a human, the composition comprising i) one or more carriers or excipients and ii) a biologically pure culture of each of:

a) a bacterium having 99% identity to 16S rRNA gene of Blautia producta DSM2950 (SEQ ID NO:
14) and genetic material encoding functionalities for synthesis of butyrate and uptake of a heterologously produced siderophore and uptake of a ferrichrome siderophore;
b) a bacterium having 99% identity to 16S rRNA gene of Megamonas funiformis DSM19343 (SEQ ID NO:
2) and genetic material encoding functionalities for synthesis of proprionate, uptake of a ferrichrome siderophore and an enterobactin siderophore, and β-fructofuranosidase activity for inulin, fructan and sucrose hydrolysis;
c) a bacterium having 99% identity to 16S rRNA gene of Megamonas hypermegale DSM1672 (SEQ ID NO:
3) and genetic material encoding functionalities for synthesis of proprionate, uptake of a ferrichrome siderophore, and β-fructofuranosidase activity for inulin, fructan and sucrose hydrolysis;
d) a bacterium having 99% identity to 16S rRNA gene of Acidaminococcus intestini DSM21505 (SEQ ID NO:
4) and genetic material encoding functionalities for synthesis of butyrate;
e) a bacterium having 99% identity to 16S rRNA gene of Bacteroides massiliensis DSM17679 (SEQ ID NO:
5) and genetic material encoding functionalities for synthesis of proprionate and uptake of a heterologously produced siderophore;
f) a bacterium having 99% identity to 16S rRNA gene of Bacteroides stercoris ATCC43183/DSM19555 (SEQ ID NO:
6) and genetic material encoding functionalities for synthesis of propionate, synthesis of indole, synthesis of indole-3-propionate and indole-3-aldehyde, uptake of a heterologously produced siderophore and uptake of an enterobactin siderophore;
g) a bacterium having 99% identity to 16S rRNA gene of Barnesiella intestinihominis DSM21032 (SEQ ID NO:
7) and genetic material encoding functionalities for synthesis of proprionate, uptake of a heterologously produced siderophore and uptake of an aerobactin siderophore;
h) a bacterium having 99% identity to 16S rRNA gene of Faecalibacterium prausnitzii DSM17677 (SEQ ID NO:
8) and genetic material encoding functionalities for synthesis of butyrate, uptake of a heterologously produced siderophore, synthesis of a bacteriocin, and β-fructofuranosidase activity for inulin, fructan and sucrose hydrolysis;
i) a bacterium having 99% identity to 16S rRNA gene of Subdoligranulum variabile DSM15176 (SEQ ID NO:
9) and genetic material encoding functionalities for synthesis of butyrate and synthesis of a bacteriocin;
j) a bacterium having 99% identity to 16S rRNA gene of Anaerostipes caccae DSM14662 (SEQ ID NO:
10) and genetic material encoding functionalities for synthesis of butyrate, uptake of a heterologously produced siderophore, uptake of a ferrichrome siderophore, synthesis of a yersiniabactin siderophore, deconjugation of bile salt and conversion of bile acid into secondary bile acids, and synthesis of a bacteriocin;
k) a bacterium having 99% identity to 16S rRNA gene of Anaerostipes hadrus DSM 3319/ATCC 29173 (SEQ ID NO:
11) and genetic material encoding functionalities for synthesis of butyrate, synthesis of indole, and synthesis of indole-3-propionate and indole-3-aldehyde;
l) a bacterium having 99% identity to 16S rRNA gene of Clostridium symbiosum ATCC14940 (SEQ ID NO:
12) and genetic material encoding functionalities for synthesis of butyrate, deconjugation of bile salt and conversion of bile acid into secondary bile acids;
m) a bacterium having 99% identity to 16S rRNA gene of Clostridium bolteae ATCC BAA-613 (SEQ ID NO:
13) and genetic material encoding functionalities for synthesis of a siderophore, deconjugation of bile salt and conversion of bile acid into secondary bile acids, and synthesis of a bacteriocin;
n) a bacterium having 99% identity to 16S rRNA gene of Blautia hydrogenotrophica DSM 10507 (SEQ ID NO:
15) and genetic material encoding functionalities for deconjugation of bile salt and conversion of bile acid into secondary bile acids and synthesis of a bacteriocin;
o) a bacterium having 99% identity to 16S rRNA gene of Marvinbryantia formatexigens DSM14469 (SEQ ID NO:
16) and genetic material encoding functionalities for uptake of a heterologously produced siderophore and uptake of a ferrichrome siderophore;
p) a bacterium having 99% identity to 16S rRNA gene of Clostridium scindens ATCC35704 (SEQ ID NO:
17) and genetic material encoding functionalities for conversion of bile acid into secondary bile acids and synthesis of a bacteriocin;
and
q) a bacterium having 99% identity to 16S rRNA gene of Akkermansia muciniphila ATCC BAA-835 (SEQ ID NO:
18) and genetic material encoding functionalities for synthesis of propionate, synthesis of indole, synthesis of indole-3-propionate and indole-3-aldehyde, and uptake of a heterologously produced siderophore.

32 more elements

A composition for benefiting the health of an animal or a human, the composition comprising i) one or more carriers or excipients and ii) a biologically pure culture of each of:

a) a bacterium having 99% identity to 16S rRNA gene of Clostridium saccharogumia DSM17460 (SEQ ID NO:
19) and genetic material encoding functionalities for O-deglycosylation in conversion of secoisolariciresinol diglucoside (SDG) to enterodiol and enterolactone;
b) a bacterium having 99% identity to 16S rRNA gene of Clostridium ramosum DSM1402 (SEQ ID NO:
20) and genetic material encoding functionalities for O-deglycosylation in conversion of secoisolariciresinol diglucoside (SDG) to enterodiol and enterolactone;
c) a bacterium having 99% identity to 16S rRNA gene of Blautia producta DSM2950 (SEQ ID NO:
14) and genetic material encoding functionalities for synthesis of butyrate, uptake of a heterologously produced siderophore, uptake of a ferrichrome siderophore, and O-demethylation in conversion of secoisolariciresinol diglucoside (SDG) to enterodiol and enterolactone;
d) a bacterium having 99% identity to 16S rRNA gene of Clostridium scindens ATCC35704 (DSM5676) (SEQ ID NO:
17) and genetic material encoding functionalities for conversion of bile acid into secondary bile acids, synthesis of a bacteriocin, and dehydrogenation in conversion of secoisolariciresinol diglucoside (SDG) to enterodiol and enterolactone;
e) a bacterium having 99% identity to 16S rRNA gene of Lactonifactor longoviformis DSM17459 (SEQ ID NO:
21) and genetic material encoding functionalities for synthesis of a bacteriocin and dehydrogenation in conversion of secoisolariciresinol diglucoside (SDG) to enterodiol and enterolactone;
f) a bacterium having 99% identity to 16S rRNA gene of Anaerostipes caccae DSM14662 (SEQ ID NO:
10) and genetic material encoding functionalities for synthesis of butyrate, uptake of a heterologously produced siderophore, uptake of a ferrichrome siderophore, synthesis of a yersiniabactin siderophore, deconjugation of bile salt and conversion of bile acid into secondary bile acids, and synthesis of a bacteriocin;
g) a bacterium having 99% identity to 16S rRNA gene of Anaerostipes hadrus DSM3319/ATCC29173 (SEQ ID NO:
11) and genetic material encoding functionalities for synthesis of butyrate, synthesis of indole, and synthesis of indole-3-propionate and indole-3-aldehyde;
h) a bacterium having 99% identity to 16S rRNA gene of Clostridium symbiosum ATCC14940 (SEQ ID NO:
12) and genetic material encoding functionalities for synthesis of butyrate and deconjugation of bile salt and conversion of bile acid into secondary bile acids;
i) a bacterium having 99% identity to 16S rRNA gene of Clostridium bolteae ATCC BAA-613 (SEQ ID NO:
13) and genetic material encoding functionalities for synthesis of a siderophore, deconjugation of bile salt and conversion of bile acid into secondary bile acids, and synthesis of a bacteriocin;
j) a bacterium having 99% identity to 16S rRNA gene of Blautia hydrogenotrophica DSM10507 (SEQ ID NO:
15) and genetic material encoding functionalities for deconjugation of bile salt and conversion of bile acid into secondary bile acids and synthesis of a bacteriocin;
k) a bacterium having 99% identity to 16S rRNA gene of Faecalibacterium prausnitzii DSM17677 (SEQ ID NO:
8) and genetic material encoding functionalities for synthesis of butyrate, uptake of a heterologously produced siderophore, synthesis of a bacteriocin, and β-fructofuranosidase activity for inulin, fructan and sucrose hydrolysis;
l) a bacterium having 99% identity to 16S rRNA gene of Subdoligranulum variabile DSM15176 (SEQ ID NO:
9) and genetic material encoding functionalities for synthesis of butyrate and synthesis of a bacteriocin;
and
m) a bacterium having 99% identity to 16S rRNA gene of Akkermansia muciniphila ATCC BAA-835 (SEQ ID NO:
18) and genetic material encoding functionalities for synthesis of propionate, synthesis of indole, synthesis of indole-3-propionate and indole-3-aldehyde, and uptake of a heterologously produced siderophore.

24 more elements

A composition for benefiting the health of an animal or a human, the composition comprising i) one or more carriers or excipients and ii) a biologically pure culture of each of:

a) a bacterium having 99% identity to 16S rRNA gene of Blautia producta DSM2950 (SEQ ID NO:
14) and genetic material encoding functionalities for synthesis of butyrate and uptake of a heterologously produced siderophore and uptake of a ferrichrome siderophore;
b) a bacterium having 99% identity to 16S rRNA gene of Megamonas funiformis DSM19343 (SEQ ID NO:
2) and genetic material encoding functionalities for synthesis of proprionate, uptake of a ferrichrome siderophore and an enterobactin siderophore, and β-fructofuranosidase activity for inulin, fructan and sucrose hydrolysis;
c) a bacterium having 99% identity to 16S rRNA gene of Bacteroides massiliensis DSM17679 (SEQ ID NO:
5) and genetic material encoding functionalities for synthesis of proprionate, synthesis of GABA, and uptake of a heterologously produced siderophore;
d) a bacterium having 99% identity to 16S rRNA gene of Bacteroides stercoris ATCC43183/DSM19555 (SEQ ID NO:
6) and genetic material encoding functionalities for synthesis of propionate, synthesis of GABA, synthesis of indole, synthesis of indole-3-propionate and indole-3-aldehyde, uptake of a heterologously produced siderophore and uptake of an enterobactin siderophore
e) a bacterium having 99% identity to 16S rRNA gene of Barnesiella intestinihominis DSM21032 (SEQ ID NO:
7) and genetic material encoding functionalities for synthesis of proprionate, synthesis of GABA, uptake of a heterologously produced siderophore and uptake of an aerobactin siderophore;
f) a bacterium having 99% identity to 16S rRNA gene of Faecalibacterium prausnitzii DSM17677 (SEQ ID NO:
8) and genetic material encoding functionalities for synthesis of butyrate, uptake of a heterologously produced siderophore, synthesis of a bacteriocin, and β-fructofuranosidase activity for inulin, fructan and sucrose hydrolysis;
g) a bacterium having 99% identity to 16S rRNA gene of Subdoligranulum variabile DSM15176 (SEQ ID NO:
9) and genetic material encoding functionalities for synthesis of butyrate and synthesis of a bacteriocin;
h) a bacterium having 99% identity to 16S rRNA gene of Anaerostipes caccae DSM14662 (SEQ ID NO:
10) and genetic material encoding functionalities for synthesis of butyrate, uptake of a heterologously produced siderophore, uptake of a ferrichrome siderophore, synthesis of a yersiniabactin siderophore, deconjugation of bile salt and conversion of bile acid into secondary bile acids, and synthesis of a bacteriocin;
i) a bacterium having 99% identity to 16S rRNA gene of Clostridium symbiosum ATCC14940 (SEQ ID NO:
12) and genetic material encoding functionalities for synthesis of butyrate, deconjugation of bile salt and conversion of bile acid into secondary bile acids;
j) a bacterium having 99% identity to 16S rRNA gene of Clostridium bolteae ATCC BAA-613 (SEQ ID NO:
13) and genetic material encoding functionalities for synthesis of a siderophore, deconjugation of bile salt and conversion of bile acid into secondary bile acids, and synthesis of a bacteriocin;
k) a bacterium having 99% identity to 16S rRNA gene of Clostridium scindens ATCC35704 (SEQ ID NO:
17) and genetic material encoding functionalities for conversion of bile acid into secondary bile acids and synthesis of a bacteriocin;
and
l) a bacterium having 99% identity to 16S rRNA gene of Akkermansia muciniphila ATCC BAA-835 (SEQ ID NO:
18) and genetic material encoding functionalities for synthesis of propionate, synthesis of GABA, synthesis of indole, synthesis of indole-3-propionate and indole-3-aldehyde, and uptake of a heterologously produced siderophore.

22 more elements

Dependencies are inferred from the claim text.

Rational design of microbial-based biotherapeutics

Life of this patent

Rational design of microbial-based biotherapeutics

Life of this patent

Abstract

Claims15