Introduction

Profile of Human Gut Microbiome: Who are the main microbes? 

Studies have found that each individual has a microbiome that is completely unique and is influenced both by early development in childhood and day-to-day lifestyle. The more diverse the gut microbiome is, the healthier the individual is, with the most diverse microbiomes even decreasing the individual’s chance of developing a number of diseases, both gastrointestinal-related and non-gastrointestinal-related (Rinninella et al., 2019). 

The human gut microbiome’s vast diversity makes it nearly impossible to detail every unique microorganism that plays a role in our gut. Figure 1 shows the typical composition of the human microbiome. A broader perspective allows us to gain a deeper understanding of the three most important groups of microbes at the phylum level of order: Firmicutes, Bacteroidetes, and Actinobacteria. 

Firmicutes
In the Firmicutes phylum, there are five main genera of microorganisms including Lactobacillus, Bacillus, Clostridium, Enterococcus, and Ruminococcus. Increased presence of Firmicutes is linked to consumption of high-fiber carbohydrates during early childhood development. The primary function of Firmicutes in the microbiome is carbohydrate digestion (Ottman et al., 2012). The different genera of the Firmicutes respond varyingly to high animal protein versus high fiber diets. Firmicutes play a large role in the adult microbiome as they are one of the most dominant phyla next to Bacteroidetes and Actinobacteria (Rinninella et al., 2019). 

Bacteroidetes
The most important organisms of the Bacteroidetes phylum are Bacteroides and Prevotella. These microbes are experts at digesting protein and carbohydrates, a mechanism they perform often in the large intestine (Thomas et al., 2011). Bacteroidetes increase when animal proteins are introduced into the childhood diet. High levels of Bacteroides are linked to diets that include more animal protein, which is similar to the standard Western diet. A high-fiber diet is linked to a decreased level of Bacteroides (Rinninella et al., 2019). 

Actinobacteria
Actinobacteria are not as prominent as the other two phyla of microorganisms found in the human gut. Similar to Bacteroidetes, Actinobacteria aid in the digestion of proteins and carbohydrates, mostly in the large intestine (Binda et al., 2018). There is primarily one genus of Actinobacteria of relevance to the gut microbiome, Bifidobacterium. Infants who were breastfed tend to have more diverse Bifidobacterium microbiota than formula-fed infants. Actinobacteria are also increased by a high animal protein diet (Rinninella et al., 2019).  

Within this diverse microbial community, microbes work together to keep us healthy. Different compositions of these key microorganisms have a notable impact on human health. For example, the Bacteroidetes-to-Firmicutes axis is a ratio of the two phyla in the gastrointestinal composition that is being studied as a potential biomarker for obesity among other diseases (Magne et al., 2020). The Bacteroidetes-to-Firmicutes axis is a strong indicator of the level of an individual’s microbiome diversity. On average, diversity is maximized when Firmicutes make up ~80% and bacteroidetes make up ~15% of the microbial population (Manor et al., 2020). 

Naturally, relative microbial diversity is variable, making some individuals more likely to develop certain chronic diseases and conditions. For example, children with obesity have been linked to increased levels of Firmicutes and decreased Bacteroidetes. Furthermore, irritable bowel syndrome patients have been identified with elevated Firmicutes and depleted Bacteroidetes and Actinobacteria (Rinninella et al., 2019). The microbiome has been shown to be indicative of conditions beyond the bowel, including type 2 diabetes, Alzheimer’s, Parkinson’s, autism, and even stress. 
 

Fig. 1. The typical composition of microbes found in the human gut microbiome (Conz et al., 2023).

Diseases at the Forefront

    The main focus of the field of pharmacomicrobiomics is the interactions between these microorganisms and pharmaceuticals. There are a plethora of routes that researchers are taking in an attempt to tackle this project that spans multiple disciplines of medicine. These cases range from oncology to psychiatry, and each brings exciting new approaches to their respective fields. 

Oncology
The gut microbiome has been linked to interactions with traditional cancer therapeutics. In some cases, the drugs begin to accumulate in the microorganisms, and, in other cases, the microbes directly metabolize the drugs into a less effective alternative. Sometimes, however, the microbes benefit the patient. In most cases, the specifics of the mechanisms of drug-microbe interactions are unknown and are currently under investigation (Conti et al., 2022).

Traditional chemotherapy pharmaceuticals take an untargeted approach in their attacks, simply hoping to have a meaningful efficacy against cancer cells. Research has suggested that Bifidobacterium strains may be able to work in conjunction with platinum-based drugs—such as cisplatin and carboplatin—to reduce tumor growth. The bacteria and platinum-based drug work together to boost T cell levels in the body, effectively raising attacks on cancer cells. There are also cases where microbes cause drugs to become reactivated. Drug reactivation can lead to increased microbiome disruption, and even further internal injury (Conti et al., 2022). 

In oncology, researchers are currently applying prebiotic, probiotic, antibiotic, and fecal microbiota transplants in an attempt to boost the efficacy and safety of cancer therapies. These approaches are all meant to alter the gut microbiome composition in order to make it more compatible with therapy (Conti et al., 2022). Attempts to personalize oncology using pharmacomicrobiomics represent another exciting frontier. One group was able to develop a method for mapping drug-microbe interactions within an individual (Javdan et al., 2020). This approach, shown in Figure 2, illustrates how further mapping would allow for individualized patient predictions of drug efficacy.

Parkinson's
Parkinson’s disease is characterized by the loss of dopaminergic neurons, which leads to a deficiency of dopamine in the brain and prevents the brain from executing smooth movements. This loss of fine motor control causes patients to suffer from shaking, stiffness, and instability, significantly impacting their quality of life (National Institute of Neurological Disorders and Stroke, n.d.). The primary drug currently used for Parkinson’s patients is levodopa (L-dopa). Levodopa works against Parkinson’s disease by crossing the blood-brain barrier and becoming dopamine, serving as a replacement for naturally-produced dopamine in patients with Parkinson’s. Often, levodopa is metabolized in the bowel before it can reach the brain, where it is useful. When metabolized outside of the blood–brain barrier, it can no longer cross through to the brain. Even when administered with drugs that are supposed to counteract the metabolism of levodopa, efficacy is still low (Maini Rekdal et al., 2019). 

With the rise of pharmacomicrobiomics, a new solution to levodopa metabolism has also become apparent. One study investigated the drug-microbe interactions present during levodopa metabolism. The study found that Enterococcus faecalis is likely the primary metabolizer of levodopa, even in the complex microbiome. The levodopa can be even further metabolized by Enterococcus lenta (Maini Rekdal et al., 2019). This metabolic process is shown in Figure 3. Knowing that these interactions occur will allow researchers to consider more advanced solutions for preventing the metabolism of levodopa. 

Irritable Bowel Disease
Irritable bowel disease (IBD) is another medical condition commonly treated by medications that can have their efficacies impacted by drug-microbe interactions. IBD is characterized by increased immune activity within the gastrointestinal tract that leads to extreme inflammation, scar tissue buildup, narrowing, and other complications. IBD treatment can be approached using five different classes of therapeutics: aminosalicylates, corticosteroids, immunomodulators, anti-TNF biologics, and small molecule inhibitors. Sometimes, intestinal microbes can activate therapeutics, but gut microbes can often render these drugs completely useless (Becker et al., 2023). 

The immunomodulator class of therapeutics works primarily by repressing the immune system in order to prevent the immune system from attacking the bowel. Thiopurines, a group of immunomodulators, have been connected to microbe interactions that increase the efficacy of the drug and open up a pathway to making thiopurines more localized (Becker et al., 2023). In individuals with IBD, C. concisus, E. coli, and B. fragilis are more common in the microbiome. These strains together are capable of converting the thiopurines into a more active form of the drug (Fig. 4). These microbes could eventually allow the anti-inflammatory effects of thiopurines to be more targeted and their adverse effects to be minimized (Becker et al., 2023).

Biologics—drugs produced by biological mechanisms—are very popular in the IBD treatment space. These therapeutics work to prevent inflammation in IBD patients. In order to do this, they primarily block messages from the immune system. TNF-α inhibitors are a group of therapeutics that both promote healing and block an essential protein in the inflammatory cycle (Biologics and Inflammatory Bowel Disease (IBD), n.d.). Patients often gain antibodies against the medications and must switch. Notably, some microbes may be able to degrade these antibodies naturally (Becker et al., 2023). Furthermore, if doctors had a clear understanding of the microbiome-biologic interactions, it may be easier to predict the most effective treatment.