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M E E T I N G R E P O R T
Open Access
Microbiome for Mars: surveying
microbiome connections to healthcare with
implications for long-duration human
spaceflight, virtual workshop, July 13, 2020
Michael LaPelusa
1*
, Dorit Donoviel
2
, Sergio E. Branzini
3
, Paul E. Carlson Jr
4
, Stephanie Culler
5
, Amrita K. Cheema
6
,
Rima Kaddurah-Daouk
7
, Denise Kelly
8
, Isabelle de Cremoux
8
, Rob Knight
9
, Rosa Krajmalnik-Brown
10,11
,
Stephen L. Mayo
12
, Sarkis K. Mazmanian
12
, Emeran A. Mayer
13,14,15
, Joseph F. Petrosino
16
and Keith Garrison
17*
Abstract
The inaugural
Microbiome for Mars
virtual workshop took place on July 13, 2020. This event assembled leaders in
microbiome research and development to discuss their work and how it may relate to long-duration human space
travel. The conference focused on surveying current microbiome research, future endeavors, and how this growing
field could broadly impact human health and space exploration. This report summarizes each speaker
s presentation
in the order presented at the workshop.
Keywords:
Microbiome, Spaceflight, Radiation, Multiple sclerosis, Behavior, Gut-brain axis, Metabolome, Sequencing,
Autism spectrum disorder, Fecal microbiota transplants, Live biotherapeutic products
Introduction
An unusual intersection of disciplines took place on July
13, 2020. Microbiome researchers applied their under-
standing of the human microbiome to challenges facing
future long-duration human space flight. The conference
was attended virtually by over 500 unique participants
from around the globe and was sponsored by the Trans-
lational Research Institute for Space Health (TRISH), a
NASA-funded consortium led by Baylor College of
Medicine in partnership with the California Institute of
Technology (Caltech) and the Massachusetts Institute of
Technology (MIT). TRISH identifies and funds potentially
disruptive scientific discoveries and technological ad-
vances that promise to reduce human health risks and
performance in long-duration space missions. It does this
in part by generating scientific content and opportunities
for communities outside of NASA to learn about human
deep-space exploration challenges. Virtual conferences en-
gage a broad and diverse audience for exploring how they
might apply field-specific knowledge to help safeguard
astronauts
health on the way to Mars.
Drs. Sarkis Mazmanian (Caltech) and Stephen Mayo
(Caltech lead for TRISH) developed the conference
agenda and recruited the speakers. This report summa-
rizes the presentations and provides context for space-
flight applications. All presentations were videotaped and
archived on the TRISH website and can be found
here .
Spaceflight imposes many stressors on the human
body, including, but not limited to, exposure to space ra-
diation, physical isolation in a closed and unvaried envir-
onment, a diet restricted to pre-prepared foods and
© The Author(s). 2021
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* Correspondence:
michael.lapelusa@vumc.org
; Keith.R.Garrison@uth.tmc.edu
Michael LaPelusa and Keith Garrison contributed equally to this work.
1
Department of Medicine, Vanderbilt University Medical Center, One
Hundred Oaks
North 719 Thompson Lane Suite 20400, Nashville, TN 37204,
USA
17
Department of Medicine, The University of Texas at Houston Health
Sciences Center, 6431 Fannin St, Houston, TX 77030, USA
Full list of author information is available at the end of the article
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https://doi.org/10.1186/s40168-020-00951-5
recycled fluids, decreased musculoskeletal loading second-
ary to weightlessness, and circadian desynchronization.
These stressors have profound impacts on human health,
physiology, and biology, as documented over decades of
research on astronauts, test subjects participating in ana-
log or simulated missions on Earth, and animal models.
Alterations in different physiological systems occur at
different time points during spaceflight missions. Much
of the knowledge accumulated regarding these changes
is limited to missions shorter than 4 months. As such,
minimal evidence exists regarding what changes to hu-
man health, physiology, and biology occur during (and
after) missions longer than 4 months, and especially for
missions longer than 1 year. Notably, as of June 2020,
only four individuals have completed spaceflight mis-
sions longer than 1 year. Manned missions to Mars
could be up to 3 years long. We must understand the
exposures and risks to humans associated with long-
duration spaceflight so countermeasures can be provided
through vehicle design, crewmember schedule, and ap-
propriate resource allocation. It is also essential to study
and understand the exposures and risks associated with
human spaceflight to improve our understanding of hu-
man health and disease generally, which will continue to
benefit populations here on Earth.
The human microbiome and different space vehicles
environmental microbiomes have been interested in the
human spaceflight community dating back to the 1960s
and 1970s [
1, 2]. Previous analyses of crewmembers
microbiome composition and the microbiome compos-
ition of analog mission study participants suggest that
several changes to the human microbiome occur with
exposure to spaceflight and analog missions. These in-
clude changes to alpha and beta diversity, microbial and
host gene expression, and shifts between dominant
genus [
3
7]. Additionally, analyses showed that crew-
member microbiomes, particularly of the skin, appear to
reflect the space vehicle
s microbiome over time [
6, 8].
Moreover, analyses showed that changes to crewmem-
bers
microbiome composition are reversible upon re-
turn to Earth or completion of analog mission (with at
least partial reversal occurring on the order of days to
weeks) [
4, 7]. These findings
full implications are yet to
be demonstrated, and current research focuses on how
these changes impact human health and performance.
The explosion of research into the human microbiome
over the past two decades has led to associations with
obesity, psychiatric and neurological conditions, cancer,
allergies, specific autoimmune conditions, and much
more. While this field is growing, the current medical
utilization of microbiome manipulation is narrow. Per-
haps the most well-known example is fecal microbiota
transfer (FMT) for recurrent
Clostridium difficile
infec-
tion [
9]. This same treatment modality has also been
used in inflammatory bowel diseases with clinical trials
showing promising results [
10, 11]. While the success of
FMT with
C. difficile
and some inflammatory bowel dis-
ease cases is encouraging, the possibility of further thera-
peutic indications is an area of great intrigue. Other
diseases under investigation include microbiome manipu-
lation in irritable bowel syndrome, obesity, autism, nonal-
coholic fatty liver disease, and eradication of multi-drug-
resistant organisms from colonized individuals [
12
15].
Exploration of space has long been a critical driver of
scientific and technological advancement and, in particu-
lar, has significantly benefited medicine [
16]. Our under-
standing of the microbiome is vital to our continued
exploration of space, and this, in turn, may continue to
provide new medical advancement for disease manage-
ment on Earth.
Workshop goals and objectives
Dr. Stephen Mayo and Dr. Sarkis Mazmanian welcomed
the participants and the speakers and explained the goals
and objectives of the conference:
1. Survey current understanding and evidence for the
effects that the microbiome has on human health.
2. Develop hypotheses about how manipulating the
microbiome might be applied as preventative
measures or countermeasures to the spaceflight
stressors such as weightlessness, isolation, and
ionizing radiation.
A word from the sponsoring organization
Dr. Dorit Donoviel (Baylor College of Medicine), the
TRISH director, gave an overview of human spaceflight
hazards. She explained why TRISH was interested in the
microbiome as an approach to mitigating long-duration
space travel stressors. Dr. Donoviel enumerated the
many research funding and fellowship opportunities
available through TRISH and invited the conference par-
ticipants to explore funding opportunities or participate
as scientific merit reviewers.
Scientific presentations
The workshop included 12 scientific presentations.
Eleven of those presentations are summarized in the fol-
lowing sections. Scientific talk #5,
Microbial pathways
to metabolite production
by Dr. Michael Fischbach
(Stanford), is omitted.
Scientific talk #1: perspective on the field and effects of
radiation on microbiome
The scientific session was opened by Dr. Rob Knight
(University of California, San Diego), who gave an over-
view of the conference topics. Emphasizing the scale of
microbial impact on humans, Dr. Knight briefly touched
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on how microbes affect food and drug metabolism, how
infectious and autoimmune diseases may be related, sea-
sonal microbiome differences, and provided examples of
chronic diseases associated with gut microbes [
17, 18].
One highlighted topic showed that analyzing microbial
rather than human genes could predict over four times
more accurately whether someone was obese or lean
[
19]. Citing studies on skin flora and radiation, antibiotic
usage in mice affecting radiation exposure, and the di-
verse gut flora of voles in Chernobyl, Dr. Knight dis-
cussed how radiation and microbiome relate to human
spaceflight [
20
22]. Another focus was the variance in
weight loss and glycemic response concerning diet
choice, especially regarding plant consumption [
23, 24].
He noted three projects currently underway: American
Gut Project, Microsetta Initiative, and Global FoodO-
mics, all of which study the relationship between what
enters and exits the body and what happens between
these processes.
Dr. Knight also discussed the use of mass spectrometry
in the study of metabolite distribution in mice. Using
germ-free (GF) and specific-pathogen-free (SPF) mice, it
was shown that the metabolomics data of GF and SPF
mice varied drastically throughout the body, and micro-
biome differences were shown to be responsible for new
amino acid conjugations in bile acid [
25]. Adapting the
mass spectrometry technology used in GF and SPF mice,
Dr. Knight showed how the technology could be used to
characterize microbiota present in humans [
26].
Of particular relevance was the description of Katharo-
seq, a new utility for identifying microorganisms present
in a given area using low-biomass samples. With this
technology, it was shown that the Spacecraft Assembly
Facility at the National Aeronautics and Space Adminis-
tration (NASA) Jet Propulsion Laboratory had radiation-
resistant organisms present, including
Deinococcus
radiodurans
[27]. Along with this, he discussed a study
on the microbial communities present on the Inter-
national Space Station [
28]. He detailed how this is im-
portant, given the primary objective of reaching Mars
and preventing the spread of organisms that originated
from Earth. His last discussion topic covered our current
understanding of how our microbiome changes in long-
term space travel in vivo [
6]. Dr. Knight
s concluding re-
marks emphasized the implications of microbiome re-
search on space exploration and how this may benefit
human and environmental microbial research.
Scientific talk #2: gut microbes in multiple sclerosis:
structural, functional, and integrative analysis
Dr. Sergio Baranzini (University of California, San Fran-
cisco) spoke about the relationship between the gut
microbiome and multiple sclerosis (MS). He described
the pathophysiologic link between microbiome dysbiosis,
an abundance of pro-inflammatory microbes or lack of
anti-inflammatory microbes, and immune dysregulation
through pathways that promote T helper 17-cell activity
over regulatory T cell activity [
29]. This led to a discus-
sion of how previous work demonstrated the role that
commensal gut microbes have in triggering immune pro-
cesses that lead to the development of multiple sclerosis
[
30]. Dr. Baranzini also discussed how specific bacterial
taxa found in higher concentrations in the gut micro-
biome of MS patients (compared to people without MS)
induced pro-inflammatory responses in human peripheral
blood T cells, which also likely contributes to the link be-
tween the microbiome, immune system, and MS. [
31]
Dr. Baranzini then spoke about the International Mul-
tiple Sclerosis Microbiome study, an international study
utilizing a unique household case-control design to de-
termine how individual patients
microbiome impacts
multiple sclerosis regarding susceptibility, progression,
and response to treatment. Preliminary results of this
study were shown and included how geography signifi-
cantly influences a person
s gut microbiome, which can
be attributed to many factors, including the relationship
between geography and diet.
Lastly, Dr. Baranzini gave an overview of how know-
ledge network-based multi-model data integration, spe-
cifically using SPOKE (Scalable Precision Medicine
Oriented Knowledge Engine), combines different data
types into one environment and ultimately allows new
connections between data to be identified [
32]. Several
implications for patient care, as well as human space-
flight, were reviewed. Dr. Baranzini outlined how enter-
ing gene expression profiles of space-flown mouse liver,
spleen, and thymus (and comparing to ground-based
controls) in SPOKE could allow users to compare and
contrast gene expression profiles seen in tissues stressed
by disease not previously thought to be related to space-
flight. Thus, SPOKE can elucidate links between
spaceflight-related stress on the human body and com-
mon medical conditions at the molecular level that were
previously unknown and could lead to targets for disease
prevention and therapeutic intervention.
Scientific talk #3: gut-brain connections to behaviors in
mice
Dr. Sarkis Mazmanian (Caltech) began his talk by dis-
cussing the origins of his work on the
gut-brain axis
concerning autism spectrum disorder (ASD). He dis-
cussed using the maternal immune activation (MIA)
mouse model for the study of ASD [
33]. This mouse
model has been shown to display behaviors similar to
those seen in humans with ASD, such as decreased com-
munication, repetitive behaviors, anxiety, and impaired
social interaction. As MIA mice were shown to have
leaky gut
, a gastrointestinal disturbance also seen in
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humans with ASD, mice were given the human com-
mensal
Bacteroides fragilis
to restore gut health. Pro-
biotic treated mice subsequently showed increased
communication, decreased repetitive behaviors, and de-
creased anxiety [
34]. Additionally, MIA mice were
shown to have increased levels of specific serum metab-
olites, including 40-fold higher levels of 4-
ethylphenylsulfate (4-EPS), which also returned to nor-
mal levels after
B. fragilis
treatment [
34]. Recent human
studies have shown up to 9-fold increases in 4-EPS
among some individuals with ASD compared to typically
developing controls [
35]. Subsequently, mouse studies
were devised that compared animals harboring a gut
microbiome that produces 4-EPS (4-EPS+) or does not
(4-EPS
). Mice exposed to 4-EPS in the gut displayed
increased oligodendrocyte precursors (OPC) with de-
creased mature oligodendrocytes and reduced myelin-
ation in their brains compared to mice not treated with
4-EPS. Importantly, 4EPS exposure led to anxiety-like
behaviors and certain ASD-like behaviors in mice.
Chemical maturation of OPCs to mature oligodendro-
cytes restored myelination and behavioral changes.
These studies show that a specific microbial metabolite,
elevated in human ASD, can affect brain activity and
function and complex behaviors in mice. While not ad-
dressed in the talk, these studies may have implications
for behavioral changes associated with spaceflight.
Scientific talk #4: gut-brain connections to behaviors in
humans
Dr. Emeran Mayer (University of California, Los
Angeles) opened his talk emphasizing the complexity
and bidirectional characteristics of the brain-gut micro-
biome (BGM) interactions. He emphasized the import-
ance of circular communication within the BGM system,
illustrated by the fact that stress-induced alterations in
gut function can lead to changes in gut microbial com-
position and production of microbial metabolites. Some
of these neuroactive metabolites signal back to the brain,
potentially affecting emotion regulating and central
autonomic networks. In turn, this feedback regulation
can alter the autonomic nervous system output to the
gut and its microbiome.
He further discussed the detrimental effects the West-
ern diet, chronic stress, and other factors can have on
the integrity of the gut barrier function leading to a re-
duced number of mucus stimulating microorganisms, a
compromised mucus layer, and increased gut permeabil-
ity, allowing access of gut microbes to the gut-based im-
mune system (
leaky gut
)[36]. Such low-grade systemic
immune activation associated with the Western diet and
chronic stress has been implicated in several brain disor-
ders, including depression and neurodegenerative dis-
eases. He emphasized that several large clinical studies
and preclinical evidence strongly support a crucial role of
a diet high in plant-based components favoring gut micro-
bial diversity in preventing and possibly treating some of
these brain disorders. Using the example of interactions
between dietary tryptophan, and the generation of differ-
ent tryptophan metabolites, including serotonin in the
brain-gut microbiome network, he spoke about the differ-
ent windows during development in which gut microbial
metabolites may exert lasting effects on the brain,
highlighting the temporal associations between gut micro-
bial composition and developmental, metabolic, affective,
and neurodegenerative disorders [
37]. Using the example
of depression and the possible role of the gut microbiome
in its pathophysiology, Dr. Mayer briefly discussed a large
study of the relationship between depression and host-
microbiome, noting how this human study, in addition to
many others, can only draw conclusions related to associ-
ation, not causation [
38
42].
Of particular importance was a discussion on neuro-
cognitive studies, particularly in Alzheimer
s and Parkin-
son
s disease [
43
45]. He examined one study in
particular, which showed the coexistence of constipation
with rapid eye movement sleep abnormalities as a pre-
dictor of subsequent development of Parkinson
s disease
onset decades later [
46]. Dr. Mayer concluded his pres-
entation with a note of caution, stating that it is essential
to examine gut microbiome in conjunction with genetic
susceptibility and environmental exposures leading to
disease, not one factor alone [
47]. Not taking into ac-
count this complexity may contribute to the difficulties
encountered when translating the majority of preclinical
studies into clinically relevant and actionable findings.
Scientific talk #6: microbiome sequencing technologies
Dr. Joseph Petrosino (Baylor College of Medicine) talked
about microbiome sequencing technologies. He ex-
plained the role of sequencing in translational micro-
biome research, speaking broadly about the
experimental pipeline that most translational micro-
biome projects follow. This pipeline begins with experi-
mental design and progresses to sample collection,
storage, shipping, and processing (to include microbial
biomass enrichment, deoxyribonucleic acid (DNA), and
ribonucleic acid (RNA) extraction and purification), and
further to library preparation and quality control-
monitored sequencing. The pipeline culminates with the
utilization of bioinformatics tools to assess community
structure, bacterial pangenomes, genome assembly, and
viral detection in samples. He noted that all of these
steps could introduce bias into the experiment, with the
potential for bias highest earlier in the pipeline and less-
ened in steps further along the pipeline.
Dr. Petrosino transitioned into strategies, challenges,
and advances in microbiome sequencing technology and
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analyzed spaceflight
s impact on the microbiome. He
highlighted specific kits designed to facilitate sampling
and storage for challenging cohorts made by Orasure
and Norgen. He also explained how universal microbial
primers are used for amplifying single or multiple vari-
able regions of the 16S rRNA (ribosomal RNA) gene
[
48] and highlighted the 4th variable region (V4), which
offers an ideal length and proper representation of many
bacterial taxa, particularly those that live in the gut.
Other variable regions sometimes provide better reso-
lution for specific niches, such as the use of V1-V3 in
oral and upper respiratory sites. He outlined some spe-
cific sequencing platforms, such as Illumina, PacBio, Ox-
ford Nanopore, and their unique strengths.
Lastly, Dr. Petrosino reviewed The Environmental De-
terminants of Diabetes in the Young (TEDDY) study.
The study investigates the relationship between genetics
and the environment (including the microbiome) in de-
veloping type 1 diabetes mellitus (T1DM). He reviewed
different published data from TEDDY, including how a
temporal developmental pattern in the microbiome of
study participants was identified [
49] and suggested that
similar studies could be undertaken to identify factors
that could mature or progress the microbiome during
spaceflight. He also posited whether viral communities
inhabiting the gut microbiome could serve as a bio-
marker for immune system function. One study identi-
fied that enterovirus B infections might be involved in
the development of islet autoimmunity [
50], a key mech-
anism in the pathogenesis of T1DM.
Scientific talk #7: autism clinical trials
Dr. Rosa Krajmalnik-Brown (Arizona State University)
opened her presentation with an account of a study that
evaluated vancomycin in ASD [
51]. She then noted her
prior research, which showed that autistic children had
lower microbial diversity and fewer
beneficial
organ-
isms, including
Prevotella
species [
52]. Dr. Krajmalnik-
Brown discussed a recently completed clinical trial that
included children with ASD who were given vancomycin
for 2 weeks and microbial transfer therapy using stand-
ard human gut microbiota over 10 weeks. After complet-
ing therapy, subjects were evaluated over 8 weeks and
demonstrated reduced scoring on standardized ASD and
gastrointestinal symptom rating scales. Also, the chil-
dren
s stool analysis showed increased bacterial diversity
[
53]. A follow-up study evaluated gastrointestinal and
autism rating after 2 years post-therapy [
54]. There was
a continued 59% reduction in gastrointestinal symptoms
and gradual improvement in ASD rating. The presenta-
tion concluded with the announcement of a new
double-blind, placebo-controlled clinical trial currently
being conducted to study ASD further and gut micro-
biome interactions in adults.
Scientific talk #8: gut bacteria human co-
metabolism
implications in neuropsychiatric diseases
Dr. Rima Kaddurah-Daouk (Duke) began her presenta-
tion by discussing the metabolome as a
biochemical
readout
to detect metabolic dysregulation influenced by
genome gut microbiome and exposome as a tool to
monitor disease states and to determine the efficacy of
therapeutics. She discussed research showing human
and gut bacteria co-metabolism and partnership in regu-
lating metabolic processes, new technologies to study
this, and transitioned into a summary of global initiatives
in Alzheimer
s disease (AD) research [
55, 56]. Dr.
Kaddurah-Daouk discussed a role of cholesterol and its
metabolism in AD pathophysiology. She highlighted hu-
man enzymes and genes involved in cholesterol biosyn-
thesis and metabolism and gut bacterial enzymes that
regulate its clearance through bile acid production. She
then reviewed recent studies conducted by the Alzhei-
mer Disease Metabolomics Consortium, where altered
bile acid profiles were noted in the blood of Alzheimer
patients [
45]. Several noted changes were catalyzed by
bacterial enzymes leading to increased secondary cyto-
toxic bile acids that correlated with cognitive decline,
amyloid beta and tau brain pathology, and brain neuro-
degeneration [
57]. No bacteria were detected in AD
brains and transcriptomic analysis of 1000 brains
showed no active synthetic route for these compounds,
suggesting that they were transported from blood to
brain [
57]. These findings highlight the importance of
studies that define the gut-brain axis in the pathogenesis
of central nervous system diseases and the relevance of
the blood-brain barrier.
The presentation concluded with studies on selective
serotonin reuptake inhibitors and their impact on
tryptophan-dependent gut microbiome metabolites [
58]
and relevance to the treatment of depression.
Scientific talk #9: radiation effects on microbiome/
metabolome
Dr. Amrita Cheema (Georgetown University Medical
Center) addressed the effects of radiation on the micro-
biome and metabolome. Dr. Cheema started with an
overview of how space-relevant radiation modulates the
gut microbiome. She referenced a study in which fecal
samples from mice exposed to different doses (0.10,
0.25, and 1.0 Gy) of radiation for different amounts of
time were analyzed concerning alpha diversity [
59]. Per-
haps expectedly, alpha diversity was lower in mice that
received any dose of radiation. However, alpha diversity
was relatively similar in mice exposed to no radiation
compared to 1 Gy at 30 days, with less similarity than
the mice exposed to 0.10 and 0.25 Gy at 30 days. Dr.
Cheema floated the hypothesis of a
hypersensitivity
re-
sponse to low doses of radiation. In this hypothesis,
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lower doses of radiation (in this experiment, 0.10 and
0.25 Gy) do not trigger DNA damage repair mechanisms
to the extent seen in higher doses of radiation (in this
experiment, 1 Gy).
Dr. Cheema also gave an overview of the metabolome
and broadly defined metabolomics as the comparative
analysis of endogenous metabolites found in biological
samples. She reviewed data from the previously men-
tioned study, showing how space-relevant radiation can
cause metagenome changes that are observable at a
broader metabolic level. Specifically, pathways involving
central carbon metabolism and nucleotide synthesis,
among others, were directly affected. She concluded her
talk by pointing out the key findings from this study: ex-
posure to low doses of space-relevant radiation shifts the
equilibrium in the gut microbiome towards opportunis-
tic pathogens and causes a functional shift in the metab-
olome towards fermentative metabolism. This leads to
pro-inflammatory states similarly seen in pathologic
conditions like metabolic syndrome and accelerated
aging phenotypes. Dr. Cheema briefly mentioned unpub-
lished data surrounding sulforaphane, a compound
found primarily in cruciferous vegetables being explored
as a potential dietary countermeasure against alterations
induced by space-relevant radiation.
Scientific talk #10: investment in microbiome space
Dr. Denise Kelly (Seventure Partners) discussed the re-
cent scientific progress made in the microbiome space
in her talk focused on the investor landscape in micro-
biome science and market predictions. She described
how the recent history of advances in sequencing in-
creased quality and robustness of data as a result of bet-
ter sample collection and analytic methods, an explosion
in data platforms, and the shift towards more extensive
clinical trials with emphasis on human data from animal
models are changing the trajectory of the field.
Dr. Kelly showed how in 2013 there were tens of start-
ups in the microbiome space whereas in 2020 there are
currently several hundred [
60]. She defined multiple
areas where current market opportunities exist, includ-
ing utilizing microbiota for therapeutic purposes (
bugs
as drugs
), identifying mechanisms in which microbiota
can improve human health (
drugs as bugs
), and how
microbiota can be leveraged to intervene with other mo-
dalities, such as phage therapy (
drugging bugs
). She
noted that there are currently 2540 registered clinical
trials leveraging microbiome science worldwide at the
time of her lecture.
Dr. Kelly introduced Seventure, a European venture cap-
ital firm led by Isabelle de Cremoux that invests in early-
stage startups focusing on life science sectors, digital tech-
nologies, healthcare, pharmaceuticals, medical technology,
biotechnology, nutrition, and food technology. The
company has venture capital financings estimated to be
$1.5 billion (including public funding). Dr. Kelly showed
figures estimating the human microbiome market size to
be $352 million in 2018 with a compound annual growth
rate from 2019 to 2024 of 26. She highlighted probiotics
as the product category currently dominating the market,
but with recent increases in investment in other product
categories, including therapeutics and nutrition-based
modulation of the human microbiome, this will change.
Dr. Kelly then identified recent examples of partner-
ships between startup companies and larger pharma-
ceutical companies, equity raises, and initial public
offerings in the microbiome space. For instance, Gilead
and Second Genome announced a collaboration with a
potential deal size of $1.5 billion. Lastly, Dr. Kelly com-
mented on emerging developments such as the micro-
biome
s role in modulating the immune response to
immune checkpoint inhibitors and integrating tools of
big data, omics, and machine learning to infer function
and provide predictions regarding small molecule targets
and prebiotic therapies.
Scientific talk #11: microbiome in cancer and COVID-19
Dr. Stephanie Culler (Persephone Biosciences) delivered a
presentation on the emerging role of the microbiome in
cancer therapy. She characterized the health and eco-
nomic burden globally and specifically in the USA of non-
communicable diseases such as cardiovascular disease and
cancer. She also identified a few particular challenges to
developing microbiome-leveraging or microbiome-
targeting therapeutics, including the lack of established
clinical endpoints for trials and challenges in the manufac-
turing process (e.g., how an anaerobic growth environ-
ment is difficult to sustain on a large scale).
Dr. Culler introduced
Poop for the Cure
, a project by
Persephone Biosciences aimed at identifying gut microbio-
ta
s role in how patients with cancer respond to cancer
therapies. She outlined how the project is acquiring thou-
sands of stool samples from patients with various types of
diseases, although the project
s initial focus is cancer. After
obtaining samples, whole-genome sequencing is per-
formed. Current areas of study within the project are de-
termining which patients will respond to which therapy
for several types of cancer and understanding if it is pos-
sible to convert cancer therapy non-responders to re-
sponders by shifting the composition of the microbiome.
The final part of Dr. Culler
s presentation touched on
how Persephone Bioscience
s artificial intelligence-based
prediction technologies have the potential to assess
which patients may develop severe disease upon expos-
ure to severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2). She cited several studies indicating how
the microbiome has been shown to play a role in vaccine
immune response [
61
64].
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Scientific talk #12: regulatory considerations for
microbiome-based therapeutics
Dr. Paul Carlson (Food and Drug Administration (FDA)
Center for Biologics Evaluation and Research (CBER)
Office of Vaccines Research and Review - Division of
Bacterial, Parasitic, and Allergenic Products) spoke about
regulatory considerations for microbiome-based thera-
peutics. He first described Investigational New Drug
(IND) applications, which is a request for FDA
authorization to administer an investigational drug to
humans. The FDA
s primary objective in reviewing an
IND is, in all phases of the investigation, to assure the
safety and rights of subjects, and, in phase 2 and 3, to
help ensure the quality of the scientific evaluation. Be-
fore the submission of a Biologics License Application,
there are generally five stages of product development:
discovery and preclinical development, preclinical inves-
tigations, and phase 1, phase 2, and phase 3 human stud-
ies. The IND application and review covers the three
phases of clinical investigation. Dr. Carlson then dis-
cussed that the FDA encourages
pre-IND
meetings.
Typically, for such meetings, the entity which will take
responsibility for and initiate a clinical study under IND
(the sponsor) provides the FDA with a briefing package
including the rationale for the use of the product, prod-
uct description and proposed indication, the proposed
objectives of planned investigations, an overview of the
protocol(s) for a planned study, and specific questions
for CBER 30 days before the pre-IND meeting. CBER
then assembles a review team that comprises diverse sci-
entific expertise and responds in writing to questions
provided in the briefing package. The actual pre-IND
meeting can then focus on the discussion of items that
require further clarification.
Dr. Carlson then spoke about Chemistry, Manufactur-
ing, and Control (CMC) considerations for INDs regard-
ing FMTs and live biotherapeutic products (LBP). He
outlined the challenges of regulation of FMTs and posed
several questions about ensuring safety
both extrinsic
(regarding screening of donors and testing of stool) and
intrinsic (regarding unknown long-term health effects of
changes to the gut microbiome). He touched on the
challenges of safety and mentioned recent safety alerts
on FMT products issued by the FDA to the public, in-
cluding cases of transmission of multi-drug-resistant or-
ganisms, enterotoxigenic
Escherichia coli
, and Shiga
toxin-producing
E. coli
. He also cited the lack of evi-
dence for or against screening stool samples for SARS-
CoV-2. Dr. Carlson then moved to CMC considerations
for LBPs. He defined LBPs as biological products con-
taining live organisms applicable to the prevention,
treatment, or cure of a disease or condition of human
beings that are not vaccines. Specific CMC consider-
ations he mentioned were strain information, antibiotic
resistance profiles, information on cell banking systems,
description of the manufacturing process, stability data,
viable cell data, and bioburden testing (demonstrating
absence of extraneous undesirable bacteria). Dr. Carlson
spoke about LBP INDs and for certain investigations of
commercially available LBPs the process and informa-
tion required to request a waiver of the requirement to
include CMC information in an IND. Sponsors request-
ing a waiver should submit information showing that (1)
the LBP is lawfully marketed as a conventional food or
dietary supplement; (2) the investigation does not in-
volve a route of administration, dose, patient population,
or other factor that significantly increases the risk (or
decreases the acceptability of risk) associated with the
use of the LBP; (3) the investigation is not intended to
support a marketing application of the LBP as a drug for
human use or a biological product for human use; and
(4) the investigation is otherwise conducted in compli-
ance with requirements for INDs. If the waiver is not
granted, then the sponsor must include CMC informa-
tion in the IND application.
Dr. Carlson concluded his talk by providing a comprehen-
sive resource he co-authored with colleagues at the FDA to
help sponsors navigate the I
ND application process [
65].
Dr. Carlson
s participation in the workshop and contri-
butions to this manuscript is an informal communica-
tion and represent his own best judgment. His
comments do not bind or obligate the FDA.
Conclusion
The TRISH-sponsored Microbiome for Mars virtual
workshop held on July 13, 2020, surveyed the micro-
biome field in areas relevant for long-duration human
spaceflight. The workshop covered a broad range of
areas, from basic science aspects to regulatory consider-
ations for the development of therapeutics. The informa-
tion presented by the distinguished panelists through
their presentations and responses to questions offered
by a global audience lays an essential foundation for
TRISH to consider in furtherance of its mission to miti-
gate health and performance risks associated with
human spaceflight.
Abbreviations
FMT:
Fecal microbiota transplant; GF: Germ-free; SPF: Specific pathogen-free;
NASA: National Aeronautics and Space Administration; MS: Multiple sclerosis;
SPOKE: Scalable Precision Medicine Knowledge Engine; ASD: Autism
spectrum disorder; MIA: Maternal immune activation; 4-EPS: 4-
Ethylphenylsulfate; OPC: Oligodendrocyte precursors; DNA: Deoxyribonucleic
acid; RNA: Ribonucleic acid; rRNA: Ribosomal ribonucleic acid; TEDDY: The
Environmental Determinants of Diabetes in the Young; T1DM: Type 1
diabetes mellitus; Gy: Gray; SARS-CoV-2: Severe acute respiratory syndrome
coronavirus 2; FDA: Food and Drug Administration; CBER: Center for
Biologics Evaluation and Research; IND: Investigational New Drug;
CMC: Chemistry, Manufacturing, and Control; LBP: Live biotherapeutic
product
LaPelusa
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Page 7 of 9
Acknowledgments
SLM and DD would like to thank Rachael Dempsey (Baylor College of
Medicine) for her creative and effective outreach efforts and materials. SKM
and SLM would like to thank Lauren Breeyear for the administrative support,
Leslie Maxfield and the Caltech Academic Media Technologies and
Communications team for hosting the webinar, and members of the
Mazmanian laboratory (Reem Abdel-Haq, Joseph Boktor, Jessica Griffiths, and
Henry Schreiber) for moderating questions.
Authors
contributions
KG and ML wrote the manuscript. DD, SKM, and SLM organized the meeting.
RK, SEB, SKM, EAM, JFP, RKB, RKD, AKC, DK, SC, and PEC were speakers. All
authors read, edited, and approved the final manuscript.
Funding
Support for the conference was provided by the Translational Research
Institute for Space Health (TRISH) through NASA Cooperative Agreement
NNX16AO69A. Additional support was provided by Caltech.
Availability of data and materials
Not appliable
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Competing interests
SC declares financial interests in Persephone Biosciences, Inc. DK and IC
declare financial interests in Seventure Partners. RKB received research
funding from Crestovo/Finch Therapeutics. SKM declares financial interests in
Axial Biotherapeutics, Inc. EAM is a scientific advisory board member of
Danone, Axial Biotherapeutics, Viome, Amare, Mahana Therapeutics,
Pendulum, Bloom Biosciences, and APC Microbiome Ireland. The remaining
authors declare that they have no competing interests.
Author details
1
Department of Medicine, Vanderbilt University Medical Center, One
Hundred Oaks
North 719 Thompson Lane Suite 20400, Nashville, TN 37204,
USA.
2
Department of Pharmacology and Chemical Biology, Center for Space
Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030,
USA.
3
Department of Neurology, Weill Institute for Neurosciences, University
of California, San Francisco, CA 94158, USA.
4
Laboratory of Mucosal
Pathogens and Cellular Immunology, Division of Bacterial, Parasitic, and
Allergenic Products, Office of Vaccines Research and Review, Center for
Biologics Evaluation and Research, United States Food and Drug
Administration, Silver Spring, MD 20993, USA.
5
Persephone Biosciences Inc,
JLABS, 3210 Merryfield Row, San Diego, CA 92121, USA.
6
Department of
Oncology, Lombardi Comprehensive Cancer Center, Georgetown University
Medical Center, Washington, DC 20007, USA.
7
Department of Psychiatry and
Behavioral Sciences, Department of Medicine and the Duke Institute for Brain
Sciences, Duke University, Durham, NC 27708, USA.
8
Seventure Partners, 5-7
rue de Monttessuy, 75340 Cedex 07 Paris, France.
9
Departments of Pediatrics,
Bioengineering, and Computer Science & Engineering, University of California
San Diego, 9500 Gilman Drive, MC 0763, La Jolla, CA 92093-0763, USA.
10
Biodesign Center for Health Through Microbiomes, Arizona State University,
Tempe, AZ, USA.
11
School of Sustainable Engineering and the Built
Environment, Arizona State University, Tempe, AZ, USA.
12
Division of Biology
and Biological Engineering, California Institute of Technology, 1200 E.
California Bl, Pasadena, CA 91125, USA.
13
G. Oppenheimer Family Center for
Neurobiology of Stress and Resilience, Ingestive Behavior and Obesity
Program, University of California Los Angeles, Los Angeles, CA, USA.
14
Vatche
and Tamar Manoukian Division of Digestive Diseases, University of California
Los Angeles, Los Angeles, CA, USA.
15
David Geffen School of Medicine,
University of California Los Angeles, Los Angeles, CA, USA.
16
Department of
Molecular Virology and Microbiology, Alkek Center for Metagenomics and
Microbiome Research, Baylor College of Medicine, Houston, Texas, USA.
17
Department of Medicine, The University of Texas at Houston Health
Sciences Center, 6431 Fannin St, Houston, TX 77030, USA.
Received: 19 October 2020 Accepted: 6 December 2020
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