Science - USA (2022-05-27)

food-based therapies for this form of mal-

nutrition ( 12 ).

A “healthy”microbiota assemblage of sym-

biotic organisms acts in concert to exclude

harmful invasive species such asSalmonella,

which is a phenomenon known as coloniza-

tion resistance. Hence, an important conse-

quence of dysbiosis is the loss of colonization

resistance to pathogens. For example, anti-

biotic treatment disrupts indigenous microbial

communities and produces an environment

permissive for opportunistic pathogens, such

as Clostridioides difficile, to colonize and ex-

pand in the colon by promoting the germi-

nation of its spores to form vegetative cells.

Two exotoxins secreted by vegetative cells—

toxins A and B—damage the intestine mucosal

barrier, induce a strong inflammatory response,

and cause diarrhea ( 13 ).

Fecal microbiota transplantation (FMT) can

successfully restore a functional microbiome

and mucosal homeostasis inC. difficileinfec-

tion. However, treatment of other intestinal

diseases by FMT, such as inflammatory bowel

disease (IBD), has shown only modest efficacy

in clinical trials. Poor efficacy of FMT in IBD

could be caused by the complexity and hetero-

geneity of the disease or the interpersonal

diversity of donors’fecal microbiota; it could

also occur because the underlying dysbiosis in

IBDpatientsisaneffectofthediseaseprocess.

Other challenges of FMT include the risks of

introducing poorly characterized microbial

material into patients, which may include patho-

bionts, and unreliable long-term establishment

of the transplanted microbiome ( 14 ). Neverthe-

less, the promising results from FMT studies

in patients withC. difficileinfection have in-

spired valuable mechanism-based microbiome

studies on health and disease. Recently, a phase

3, double-blind, randomized, placebo-controlled

clinical trial was conducted to evaluate the ef-

ficacy of oral microbiome (SER-109) therapy for

treatment of recurrentC. difficileinfection.

Compared with the placebo group, the group

given SER-109 showed a superior capacity to

prevent recurrent infection; meanwhile, the

observed safety profile across the groups re-

mained similar ( 15 ). These studies indicate

that a rational design for treatment with de-

fined microbial communities or microbial

metabolites can be therapeutically beneficial.

Monomicrobial- and

polymicrobial-driven phenotypes

Microbiome studies commonly assume that

the association of differentially abundant mi-

crobial taxa with a given phenotype may be

causal. A common goal of such studies has

been the identification of microbial taxa or

products responsible for a phenotype. To do

this, next-generation sequencing of specific

microbes is routinely performed for bacterial

16 S ribosomal RNA (rRNA) genes, eukaryotic

18 S rRNA genes, or preparations that enrich

for viruses (including reverse transcription for

RNA viruses). An“omics-initiated approach”

(e.g., Fig. 2) has successfully identified candi-

date microbes that are associated with a given

phenotype, which are then tested by coloni-

zation experiments in either gnotobiotic or

antibiotic-treated mice.

This approach has been successful in reveal-

ing several key microbial species and functions.

For example, an organism called segmented

filamentous bacterium has been found to be

abundant in mice supplied by Taconic Bio-

sciences but not in mice obtained from The

Jackson Laboratory. These filamentous bacteria

enhance T helper 17 (TH17) cells and immunity

to intestinal bacterial pathogens ( 16 ). Another

example that was identified based on differ-

ences in intestinal intraepithelial lymphocyte

(IEL) abundance within a mouse facility is

Lactobacillus reuteri, which was identified

through sequencing as a biomarker for mice

with increased IELs.L. reuteriwas shown to

drive the IEL phenotype by monoassociation

ingerm-freemice( 17 ). Similarly, the skin bac-

terial symbiontStaphylococcus epidermidis

induces IL-17A+CD8+Tcells,whichimproves

the skin barrier function in a model of epi-

cutaneous infection with the fungal pathogen

Candida albicans( 18 ). Bacterial sequencing

combined with mathematical modeling has

been used to elucidate the effect of antibiotic

treatment ofC. difficile(different antibiotic

treatments showed variation in intestinal dam-

age). This approach also showed that the oc-

currence of a secondary bile acid–producing

bacterial symbiont,Clostridium scindens,pre-

ventedC. difficilecolonization ( 19 ).

Many phenotypes are not the product of a

single organism, and reliance on abundance

alone can be a challenging approach to iden-

tify functional communities of microbes. Here,

functional screening (the screen-initiated ap-

proach shown in Fig. 2) has been successful.

One approach is to make a simplified micro-

biota before engaging in functional low-

throughput screens andtests. This rationale

has been successfully applied to the isolation

of bacterial spores from fecal samples from

healthy human donors. The spores can then

be tested iteratively in germ-free mouse col-

onization experiments. By this method, a con-

sortium of 11 bacterial strains was identified

that induced IFNg+CD8+T cells in mice and

protected them againstListeria monocytogenes

infection. Excitingly, this consortium also en-

hanced antitumor immunity in the MC38 mu-

rine colon carcinoma model ( 20 ). Using a

similar approach, a consortium of 17 bacterial

strains was found to induce FOXP3+regulatory

Tcells(Tregs) that attenuate 2,4,6-trinitrobenze-

nesulfonic acid (TNBS)–induced colitis ( 21 ).

An interesting study on antibiotic resistance has

identified four bacterial symbionts—Bacteroides

sartorii, Parabacteroides distasonis, Clostridium

bolteae,andBlautia producta—that prevented

andeliminatedvancomycin-resistant enterococci

(VRE) colonization in ampicillin-treated mice

( 22 ). What is most interesting is that all four

organisms interact in vivo:B. productasup-

presses VRE growth,C. bolteaeis required for

the colonization ofB. producta,andB. sartorii

Lu et al., Science 376 , 950–955 (2022) 27 May 2022 2of6

Tight junctions

Mucus

Homeostasis Dysbiosis

AMPs SIgA

Lysozyme

Fig. 1. A model of a generic mucosal surface showing microbiota-host interactions at the interface.
In homeostasis, the host provides both physical (epithelial cells) and chemical barriers [mucus, antimicrobial
peptides (AMPs), lysozyme, SIgA, etc.] to segregate symbiotic microorganisms, which usually live in
harmony with the host and form an additional barrier. The tight junctions of epithelial cells are crucial for
maintaining epithelial barrier integrity. Symbiotic bacteria such asE. faeciumandA. muciniphilacan improve
host barrier function through different mechanisms. Microbiota-derived products such as SCFAs and
secondary bile acids are also barrier enhancers. Interruptions in the balance of microbiota can lead to
dysbiosis, which compromises barrier integrity, favors bacterial translocation, and causes expansion of
harmful microbes (e.g.,C. albicansandC. difficile). Thus, dysbiosis has been associated with a wide range
ILLUSTRATION: KELLIE HOLOSKI/ of chronic illnesses, including IBD and asthma.

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