Gut microbiota diversity: the cornerstone of human health
The human gastrointestinal tract is colonized by approximately 100 trillion prokaryotic
cells, most of them being obligate anaerobic bacteria (Fig. 1). Among these bacteria,
three main phyla, the Bacteroidetes, Firmicutes, and Actinobacteria, totalize more
than 90% of the community and dominate the gut microbiota of healthy subjects. However,
the composition of this microbiota is highly diverse and variable at low taxonomical
levels (genus and species) between individuals. Indeed, studies based on next-generation
sequencing (NGS) approaches demonstrated that the gut microbiota harbors between 1000
and 1150 different bacterial species at the population level, with each individual
carrying at least 160 species [1].
Fig. 1
The gut microbiota: from massive bacterial diversity to focused therapeutic target
This microbial diversity results from the co-evolution between microbial communities
and their hosts. In healthy subjects, this close symbiotic relationship is highly
beneficial for both parties (Fig. 1) [2]. Indeed, gut microbiota exerts essential
functions in digestive metabolism, protection from pathogen colonization, immune system
stimulation, and trophic functions at epithelium level. Thus, the balance of commensal
microorganisms in the gut microbial ecosystem is essential for the maintenance of
host-microbiota homeostasis and barrier effect against pathogens.
Disruption of this balance, called dysbiosis, can alter this mutualistic relationship
and promote pathological conditions involving uncontrolled local immune responses
and potentially systemic inflammation (Fig. 1) [3]. Dysbiosis often arises from iatrogenic
factors such as surgery or oncology-associated treatments, and particularly drugs,
including chemotherapy and broad-spectrum antibiotics, which dramatically alter the
structure of the microbial ecosystem [4]. This shift in gut microbiota composition
is characterized by a reduction of overall microbial diversity, a disruption of beneficial
bacteria that support host defenses (e.g., Firmicutes), and a rise in dominance of
bacterial species usually subdominant, including some pathogens and pathobionts (e.g.,
Clostridium difficile, some Enterobacteriaceae) and multidrug-resistant (MDR) bacteria.
We herein highlight the evidence that microbial diversity is the cornerstone of a
good health, while a decreased diversity is often related to poor clinical outcomes,
and especially in graft-versus-host disease (GvHD) patients.
Higher gut microbial diversity is strongly associated with increased survival in GvHD
patients
Allogenic hematopoietic stem cell transplant (allo-HSCT) is an effective treatment
for hematopoietic malignancies and inherited hematopoietic disorders, and is considered
to be the most effective tumor immunotherapy available to date [5]. However, T lymphocytes
derived from transplanted stem cells can attack tissues of the recipient host resulting
in GvHD, one of the major complications of allo-HSCT associated with significant mortality
(15–25% of deaths after allo-HSCT). Patients undergoing allo-HSCT can be simultaneously
exposed to cytotoxic chemotherapy, total-body irradiation, immunosuppressors, and
broad-spectrum antibiotics that can cause dramatic alterations of the intestinal microbiota
and varying degrees of damage to the intestinal mucosa, leading to breaches in host
defences [4, 6–8].
Examination of the intestinal microbiota of patients before allo-HSCT, using NGS,
demonstrated that the gut microbiota composition of recipients correlates with the
approximate microbiota profiles of healthy individuals in terms of species richness
and diversity [9–11] (Fig. 2). Over the course of allo-HSCT, patients show profound
shifts in microbial communities marked by a significant reduction in overall microbial
diversity, with an approximate decrease of 30% of species richness [11–13]. Indeed,
a significant shift toward Enterococcaceae is usually observed in patients after allo-HSCT,
and interestingly, this shift is particularly prominent in patients that subsequently
develop GvHD. Similarly, increases in Lactobacillales and decreases in Clostridiales
also happen after allo-HSCT for GvHD subjects [10, 12, 14].
Fig. 2
Disruption of the gut microbiota over the course of allo-HSCT
This loss of microbial diversity often results in a reduced range of microorganisms
in dominance, or even a single bacterial species that supplants the previously rich
and complex consortium of microorganisms. As a result, bacteria such as vancomycin-resistant
Enterococcus, viridans group Streptococcus, and various Proteobacteria, commonly encountered
dominating, can enter the bloodstream and cause septicemia, particularly in times
of neutropenia and gut mucosal barrier injury [9, 15]. Moreover, a study conducted
on pediatric patients demonstrated that the gut microbiota of GvHD patients before
allo-HSCT shows lower species diversity and richness than non-GvHD patients, with
specific gut microbiota signatures and notably a reduced abundance of members of Bacteroidetes
phylum and a loss in the abundance of health-associated bacteria such as Faecalibacterium
and Ruminococcus [13]. Thus, these results demonstrate that the diversity of the gut
microbiota of patients correlates with the occurrence of medical complications resulting
from allo-HSCT, especially the risk of infection and GvHD.
The diversity of the gut microbiota also plays a key role in overall survival after
allo-HSCT, and in GvHD patient outcome. Indeed, despite the medical treatment administered,
approximately 30% of patients undergoing allo-HSCT maintain a high microbial diversity
throughout the course of transplantation. A major study conducted on 80 allo-HSCT
patients showed that a high diversity of the intestinal microbiota at the time of
engraftment is associated with an increase of overall survival and a reduced non-relapse
mortality, independent of known predictors such as pre-transplant comorbidity and
disease status [15]. Indeed, the overall survival at 3 years was 67% for patients
with a high microbial diversity at the time of engraftment, 60% for patients with
an intermediate diversity, and 36% for patients with a low microbial diversity. Similarly,
another study demonstrated that a low microbial diversity after allo-HSCT is associated
with an increased non-relapse mortality and a reduction of overall survival [14].
The importance of a high microbial diversity is confirmed by studies on GvHD patients
for whom an increased microbial diversity between allo-HSCT and development of GvHD
is associated with a reduced GvHD-related mortality [16]. These studies also evidenced
that in addition to diversity, composition of the gut microbiota of patients who remain
alive after allo-HSCT significantly differs from the microbiota of patients who do
not survive. Indeed, increased amounts of bacteria belonging to the genus Blautia
and to the Lachnospiraceae and Actinomycetaceae families are observed in patients
who survived during the follow-up period, whereas greater abundance of Gammaproteobacteria,
including Enterobacteriaceae is observed in deceased patients [15, 16]. Thereby, diversity
and composition of the gut microbial community clearly appear to harbor reliable predictors
of the overall survival after allo-HSCT and in GvHD patients (Fig. 2).
Confirming these results, administration of high loads of broad-spectrum antibiotics,
which dramatically modify the bacterial diversity, was shown to be negatively correlated
with overall survival of patients [17, 18]. Indeed, a cumulative exposure to antibiotics
has been associated with an increased GvHD-related mortality at 5 years when using
antibiotics effective against anaerobic bacteria such as piperacillin and tazobactam
(19.8% mortality for treated patients versus 11.9% for untreated patients). Piperacillin
and tazobactam, which are highly active against obligate anaerobic bacteria, accentuate
the perturbation of the gut microbiota composition, with greater loss of several major
bacterial populations such as Bacteroidetes and Lactobacillales. On the contrary,
antibiotics like cefepime and aztreonam, with a reduced activity against anaerobes
and a lower impact on microbial communities, are significantly correlated with reduced
GvHD-related mortality [17]. Thus, this study indirectly points out a correlation
between GvHD-related mortality and reduced microbiota diversity. Similarly, a study
conducted on 621 patients who underwent allo-HSCT demonstrated that an antibiotic
treatment before allo-HSCT was associated with a higher transplant-related mortality
(34%) compared with an antibiotic treatment post allo-HSCT (21%) or no antibiotherapy
(7%) [19]. These results suggest that differences in the spectrum of activity of antibiotics
used and the timing of antibiotic treatment might modulate the severity of GvHD and
its outcome through modifications of the gut microbiota, highlighting once again the
role of microbial diversity in clinical outcome of these patients.
Fecal microbiota transfer: toward health improvement through the restoration of a
diverse gut microbiota
As illustrated with allo-HSCT treatment and GvHD complication studies, given the importance
of the intestinal microbiota, solutions to maintain a high microbial diversity could
lead to significantly improved clinical outcomes in many diseases. First, it can be
hypothesized that limiting administration of broad-spectrum antibiotics could reduce
the dramatic disruptions of the gut microbiota composition, consequently diminish
the severity of many diseases including GvHD, and thereby reduce mortality. Then,
modulating the gut microbiota to restore the diverse commensal microbial populations
lost during disease treatment could offer novel therapeutic possibilities.
The establishment of bacteriotherapies such as fecal microbiota transfer (FMT), consisting
in administering fecal material from a healthy donor to a patient with an altered
gut microbiota, could be an efficient tool for dysbiosis correction. The purpose of
FMT is to increase microbial diversity and restore a healthy microbiota [1], to re-establish
a symbiotic dialog between intestinal microbiota and the host, and consequently to
improve clinical outcomes and overall health (Fig. 1). For instance, treating dysbiotic
GvHD patients with FMT using a fecal sample associated with a highly diverse microbial
community could be a relevant strategy to restore a healthy gut microbiota and improve
their health (Fig. 2). Thus, in case of allogeneic FMT, the selection of donors could
therefore be guided by the richness and diversity of their intestinal microbiota in
order to maximize the expected benefits of FMT for the patient. Moreover, this strategy
could promote the reintroduction in the gut ecosystem of health-promoting microorganisms
that might reduce the severity of GvHD and the risk of death, such as Blautia or the
Lachnospiraceae and Actinomycetaceae [15, 16]. This could be achieved by conventional
FMT but also by FMT using fecal material enriched with specific health-promoting microorganisms.
These potential beneficial effects of FMT are supported by two recent small case series,
which illustrated that FMT is effective in GvHD patients, with an improvement of gastrointestinal
symptoms and a reduction or disappearance of diarrhea, associated with a reconstruction
of the gut microbiota [20, 21]. Another recent report confirmed and extended the 7
cases reported so far with 5 complete responses and 3 partial responses among 11 treated
patients, with excellent safety profiles [22]. Finally, with the restoration of a
diverse microbiota, FMT could limit pathobiont domination and consequently enhance
resistance to infection by intestinal pathogens through a restored barrier effect
of the gut microbiota. FMT is currently used for treatment of infections with C. difficile
or for MDR bacteria decolonization, and has started to demonstrate its safety and
efficiency on allo-HSCT patients [23–26]. Alternative sterile FMT approaches, which
consist in using filtered stool supernatants free of any microorganism, could also
be very effective and safe for the treatment of immunocompromised GvHD patients [27].
Thus, growing evidence suggests that through the restoration of a rich and diverse
gut microbiota, FMT could be a promising treatment for many digestive or extra-digestive
pathologies involving the gut microbiota symbiosis. As it could be used for the treatment
of GvHD as illustrated here, FMT could also be of interest for the treatment of patients
undergoing cancer therapy for whom the diversity of the gut microbiota significantly
influences the efficiency of immunotherapies [28–30], in patients suffering from severe
alcoholic hepatitis for whom the gut microbiota diversity is related to clinical outcome
[31], or even for patients admitted in intensive care units for whom a diverse gut
microbiota could prevent bacterial infections and sepsis [32, 33].
Furthermore, new therapeutic strategies combining bacteriotherapies such as FMT that
modulates the gut microbiota, and conventional drugs targeting the host physiology
and immune system, offer promising perspectives for effective patient care through
the bilateral restoration of the host-microbiota homeostasis.