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Manrique et al. Microbiome Res Rep 2024;3:23 https://dx.doi.org/10.20517/mrr.2023.80 Page 9 of 20

2ND GENERATION PRODUCTS - MICROBIOME-BASED THERAPIES A. LBPS
Advances in sequencing technologies have resulted in the identification of new species important for
human health and have led to the characterization of a wide range of genera and species that currently lack
regulatory approval as probiotics. Among these are Akkermansia muciniphila, Faecalibacterium prausnitzii,
Veillonella, Ruminococcus, Christensenella minuta, or Bacteroides fragilis [106,107,115] . These species, which were
formerly referred to as Next Generation Probiotics, are currently defined as LBPs [Figures 1-3].

According to FDA, LBPs are defined as “a biological product that: (1) contains live organisms, such as
bacteria; (2) is applicable to the prevention, treatment, or cure of a disease or condition of human beings;
and (3) is not a vaccine” [116,117] . According to European Pharmacopeia, LBPs are considered “medicinal
products containing live microorganisms such as bacteria or yeasts, which have a positive influence on the
health and physiology of the host”, excluding fecal microbiota transplants and gene therapy agents [118,119] .

As medical products, LBPs must meet several conditions: (1) be effective, with expected benefits that
outweigh its potential risks to patients; (2) be produced under good manufacturing practices (GMPs); (3)
have identified and described the critical parameters that can influence batch reproducibility, product
stability, product performance, and drug product quality [106,107,115] . Both probiotics and LBPs are live
microorganisms, but the latter are included in medicinal products because they have been proven
[117]
therapeutic or prophylactic activity in human diseases [Figure 2]. The development of LBPs is an active
area of research, and the FDA is working to establish a regulatory framework for these products. The FDA-
approved LBPs are a promising step towards the development of microbiome-based therapies. Because
donor-dependent therapeutic products, such as whole or purified FMT, do not contain standardized
composition and are excluded by European Pharmacopeia, we refer to such therapies as microbiota-based
products (MBPs).

FMT
The importance of a balanced gut microbial community has been largely established in recent years. A
decrease in the diversity of this ecosystem, associated with certain health conditions or caused by different
drug treatments, can have a negative impact on our well-being and even lead to infections [69,120-125] . Currently,
one of the most effective treatments to reestablish the gut microbiome composition and diversity is to
repopulate the GI tract with microbiota from a healthy donor [12,126,127] .

FMT involves the inoculation of a patient with the stool microbial community from a healthy individual
[128]
[Figure 3]. The first reported case of FMT dates back to the fourth century , but it was not until 1958 that
this treatment gained popularity to control intestinal infections [14,128,129] . More than 70 clinical trials have
proven the safety and the efficacy of FMT in treating patients with Clostridium difficile infection (CDI),
which is the most common healthcare-associated infection, leading to substantial morbidity and mortality
worldwide [14,130-132] . In this context, restoration of a naïve microbiota and keystone species (e.g.,
Lachnospiraceae and Ruminococcaceae members that are SCFA producers) can reestablish microbiome-
induced colonization resistance by several mechanisms, including inhibition of germination and growth of
C. difficile spores, competition for nutritional and colonization resources, and by reinstatement of the gut
barrier and immune functions [14,127,133,134] .

New FMT approaches
New formulations/strategies
The most common way of administering FMT treatment until now was through the introduction of
homogenized fecal material (either from fresh or frozen samples) via colonoscopy, enema, or naso-oral