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Page 2 of 20 Manrique et al. Microbiome Res Rep 2024;3:23 https://dx.doi.org/10.20517/mrr.2023.80

INTRODUCTION
The exploitation of bacteria by humans is a long-time running business, from fermentation of food
products, such as cheese or beer, to heterologous production of compounds with pharmacological means,
including antibiotics or insulin . On top of that, the constant exposure to bacteria - either pathogenic or
[1-4]
[5-7]
commensal bacteria that live in our body - constantly affects our daily lives . In this regard, the scientific
community has been extensively studying the gut microbiota-host relationships for several decades, finding
strong relationships between bacterial composition and health status . Particularly, dysbiosis, defined as
[6-8]
an imbalance of the microbiota composition and functional capacity, has been related to serious health
issues. These include inflammation due to loss of gut homeostasis [9-11] , and infections by opportunistic
pathogens, such as Clostridioides difficile (C. difficile), due to loss of protection conferred by the
microbiota .
[12]

Alterations of the gut microbiome that result in the loss of colonization resistance provided by this
ecosystem often lead to the acquisition of antibiotic resistance genes by C. difficile and subsequent recurrent
[13]
infections, which is a serious issue that affects 500,000 people every year only in the United States . The
lack of solutions for this problem has led to the development of new strategies, which include microbiome-
based therapies that leverage the naive functionality of a healthy microbiota and are one of the most
promising alternatives to date [14-16] . The great success of this story has opened the door to a new generation
of therapies, which can be designed to treat other types of diseases related to the loss of gut microbiota
homeostasis, such as cancer.

In this review, we provide a general overview of how the gut microbiome can be leveraged to treat infectious
diseases and reduce the use of antibiotics worldwide. We summarize what is currently known about the
influence of the microbiota on the development of certain cancers and how they can alter, for good or for
bad, the response to different anticancer treatments. We summarize the past, present, and future of
therapies based on gut microbiota and the regulation issues that have arisen with these therapies. Finally, we
conclude by outlining the direction we believe the field is heading towards.

THE ROLE OF THE MICROBIOTA IN INFECTIOUS DISEASES AND CANCER
Even though it is known that the taxonomical profile of the human microbiome is specific to each
individual, general composition and functional patterns associated with healthy states have emerged in the
human microbiome. Significant alterations in this ecosystem, also known as the dysbiosis state, have been
correlated with multiple diseases, and great research efforts are directed towards understanding how to
return a dysbiotic microbiome back to equilibrium in order to maintain health . The role of the gut
[17]
microbiome in pathogen protection, also known as “colonization resistance”, has been established for
decades and is of most relevance in infections with opportunistic gut pathogens such as Clostridium difficile
(see 2nd Generation Products section) or urinary tract infections (UTIs) often presented after antibiotic
treatment that decimates the gut microbial diversity [18,19] . Similar scenarios have been reported with sexually
transmitted diseases (STDs) and the vaginal microbiome, in which women with a less diverse vaginal
microbiome are generally more susceptible to UTIs and STDs such as human immunodeficiency virus
(HIV), herpes simplex virus (HSV), or papillomavirus . Treatments that reestablish the complexity of the
[20]
microbiome in these environments have shown remarkable results in preventing reinfections [21,22] .

The great influence of the microbiome in many diseases led to the study of the cancer-gut microbiome axis.
In the past decade, data supporting the influence of the gut microbiome on tumor progression and on the
response to oncological treatments have been rapidly growing and have been extensively reviewed
elsewhere [23-25] . In summary, the gut microbiome can have direct and indirect effects on several cancer cells