In the Journals

Microbiome integral to precision diagnosis, personalized treatment

Advances in microbiome science will play a key role in a new era of patient care, enabling precision diagnostics and personalized treatment strategies, according to a new review article published in Mayo Clinic Proceedings.

“The ability to characterize the microbiome, which includes all the microbes that reside within and upon us and all their genetic elements, using next-generation sequencing, allows us to now incorporate this important contributor to human disease in developing new preventive and therapeutic strategies,” Purna Kashyap, MBBS, review co-author and gastroenterologist at the Mayo Clinic, said in a press release.

The microbiome is dually emerging as both a useful diagnostic and therapeutic tool, according to Kashyap and colleagues, “as it not only contributes to interindividual variability in all aspects of a disease, but also represents a potentially modifiable factor that is amenable to targeting by therapeutics.”

They emphasized that a revolution in sequencing technology has driven the growing appreciation for the microbiome’s role in human health. Continuing advancements in software and algorithms paired with rapidly declining costs have enabled researchers to perform microbial sequencing “on a laboratory bench for about a hundred dollars per sample.” They added that next-generation “multi-omics” approaches to sequencing have enabled in-depth characterization of the gut microbiota, and increased confidence in diagnostic and therapeutic biomarkers.

Microbial biomarkers

One promising application for microbiome sequencing is the use of “microbial fingerprints” as “precise, noninvasive, accessible and economical tools” for “personalized disease diagnosis, including phenotypes, severity, and prognosis,” Kashyap and colleagues wrote.

They described how the gut microbiome has emerged as a particularly useful biomarker for disease phenotype, prognosis and treatment response in inflammatory bowel disease, which “is one of the best-studied conditions associated with dysbiosis.” For instance, there are distinct gut microbial signatures across the three major IBD subtypes — Crohn’s disease, ulcerative colitis and indeterminate colitis — and across disease locations. Gut microbiota signatures have even been found to vary with surgical outcomes in Crohn’s disease, “with an increase in F. prausnitzii in the ileal mucosa associated with decreased disease recurrence at 6 months.”

However, they warned there is a lack of agreement among studies regarding the microbial changes identified in IBD, and called for larger studies of diverse cohorts to account for the effects of disease subtype and environmental factors.

Other GI diseases

The gut microbiome has also been associated with several other gastrointestinal diseases, including colorectal cancer, Clostridium difficile infection and celiac disease, Kashyap and colleagues added.

Fusobacterium nucleatum has been implicated in colorectal cancer through its FadA adhesion serving as both a diagnostic and a therapeutic marker,” they wrote. “Clostridium difficile infection has been associated with decreased microbial diversity and a decrease in secondary bile acid production,” and newly identified microbiome signatures have enabled prediction of outcomes and treatment stratification. Additionally, patients with celiac disease have shown increases in Proteobacteria when they have gastrointestinal vs. extraintestinal symptoms.

Aside from GI diseases, the researchers also noted that the gut microbiota has been implicated in systemic disorders like rheumatoid arthritis. For example, new-onset RA has been associated with increases in Prevotella copri.

“Much work still needs to be done in validating these signatures in large multicenter cohorts, as well identifying potential causative role,” Kashyap and colleagues noted.

Effects on therapeutics

In addition to being a potential therapeutic target, the microbiome also has important effects on traditional therapies, potentially impacting their efficacy, according to the authors.

“The role of the microbiome in the metabolism of many chemical compounds makes it a key player in determining drug availability, efficacy, and toxicity, making it indispensable for developing personalized drug therapies,” they wrote.

For example, studies have shown that competition between acetaminophen and bacteria-generated products could partially explain interindividual variability in analgesic response and differences in adverse events. Additionally, “microbiome markers of drug efficacy ranging from chemotherapeutic agents to statins have been widely described,” and a recent study showed the gut microbiota play a role “in mediating the antidiabetic effects of metformin.”

Thus, “considering the gut microbiota when determining drug responses akin to pharmacogenomics ... will allow us to impart more precise and effective therapeutics while decreasing overall adverse events,” the authors wrote.

Modulating the microbiome

Altering the gut microbiome is emerging as an appealing strategy for developing precision and personalized treatments, Kashyap and colleagues continued.

Developing targeted antibiotics is an important example of precision medicine, they wrote. While traditional antibiotics may have unintended adverse effects on microbial communities and patients, identifying specific pathogens would allow drug developers to “narrow the spectrum of the antibiotic.”

Recent studies have also shown promise for “next-generation probiotics that will be developed using targeted approaches to alter microbial metabolism in a disease-specific manner,” they wrote. “A precision approach using Clostridium scindens to augment resistance to C. difficile infection by targeting secondary bile acid pathway is one such example.”

Further, fecal microbiota transplantation has shown high efficacy for treating recurrent C. difficile infection, and while it has failed to show clinical efficacy in other diseases, “the use of FMT for diseases such as IBD has provided insight into donor specificity in terms of response, suggesting a role of individualizing FMT approaches in multifactorial diseases such as IBD, in contrast to the approach in C. difficile infection.”

Dietary manipulations of the gut microbiome are also promising. The low FODMAPs diet, for example, has been shown to improve symptoms of irritable bowel syndrome, though the authors emphasize that this is only a short-term strategy, as long-term use can have negative health effects. Further, a recent study identified microbiome markers that predict response to the low FODMAPs diet, “with the potential to allow optimization of therapy and minimizing undesirable adverse effects in individuals less likely to respond,” they noted.

Future optimistic despite challenges

While the outlook for the future of microbiome science is optimistic, “there are also substantial challenges in the field,” Kashyap and colleagues wrote.

First, they emphasized that standardized collection, sequencing and analysis are needed to enhance reproducibility of study results across centers.

Second, most microbiome studies rely on disease associations, so to develop more reliable biomarkers, researchers must “better define the mechanisms by which microbiota influence aspects of human disease.”

Further study is also needed on the role of other microorganisms like fungi, bacteriophages and parasites, as well as their interactions, they added.

Finally, a “systems approach” is required to improve understanding of the interaction between diet and the microbiota.

“These challenges apart, the incorporation of microbiome-based diagnostics and therapeutics with other components of precision medicine, such as pharmacogenomics and epigenomics, will be an integral part of the new era in patient care,” Kashyap said in the press release. “This integration will further enhance our ability to find the precise treatments for patient care.” – by Adam Leitenberger

Disclosures: Two of the review authors report they are consultants for Day Two.

Advances in microbiome science will play a key role in a new era of patient care, enabling precision diagnostics and personalized treatment strategies, according to a new review article published in Mayo Clinic Proceedings.

“The ability to characterize the microbiome, which includes all the microbes that reside within and upon us and all their genetic elements, using next-generation sequencing, allows us to now incorporate this important contributor to human disease in developing new preventive and therapeutic strategies,” Purna Kashyap, MBBS, review co-author and gastroenterologist at the Mayo Clinic, said in a press release.

The microbiome is dually emerging as both a useful diagnostic and therapeutic tool, according to Kashyap and colleagues, “as it not only contributes to interindividual variability in all aspects of a disease, but also represents a potentially modifiable factor that is amenable to targeting by therapeutics.”

They emphasized that a revolution in sequencing technology has driven the growing appreciation for the microbiome’s role in human health. Continuing advancements in software and algorithms paired with rapidly declining costs have enabled researchers to perform microbial sequencing “on a laboratory bench for about a hundred dollars per sample.” They added that next-generation “multi-omics” approaches to sequencing have enabled in-depth characterization of the gut microbiota, and increased confidence in diagnostic and therapeutic biomarkers.

Microbial biomarkers

One promising application for microbiome sequencing is the use of “microbial fingerprints” as “precise, noninvasive, accessible and economical tools” for “personalized disease diagnosis, including phenotypes, severity, and prognosis,” Kashyap and colleagues wrote.

They described how the gut microbiome has emerged as a particularly useful biomarker for disease phenotype, prognosis and treatment response in inflammatory bowel disease, which “is one of the best-studied conditions associated with dysbiosis.” For instance, there are distinct gut microbial signatures across the three major IBD subtypes — Crohn’s disease, ulcerative colitis and indeterminate colitis — and across disease locations. Gut microbiota signatures have even been found to vary with surgical outcomes in Crohn’s disease, “with an increase in F. prausnitzii in the ileal mucosa associated with decreased disease recurrence at 6 months.”

However, they warned there is a lack of agreement among studies regarding the microbial changes identified in IBD, and called for larger studies of diverse cohorts to account for the effects of disease subtype and environmental factors.

Other GI diseases

The gut microbiome has also been associated with several other gastrointestinal diseases, including colorectal cancer, Clostridium difficile infection and celiac disease, Kashyap and colleagues added.

PAGE BREAK

Fusobacterium nucleatum has been implicated in colorectal cancer through its FadA adhesion serving as both a diagnostic and a therapeutic marker,” they wrote. “Clostridium difficile infection has been associated with decreased microbial diversity and a decrease in secondary bile acid production,” and newly identified microbiome signatures have enabled prediction of outcomes and treatment stratification. Additionally, patients with celiac disease have shown increases in Proteobacteria when they have gastrointestinal vs. extraintestinal symptoms.

Aside from GI diseases, the researchers also noted that the gut microbiota has been implicated in systemic disorders like rheumatoid arthritis. For example, new-onset RA has been associated with increases in Prevotella copri.

“Much work still needs to be done in validating these signatures in large multicenter cohorts, as well identifying potential causative role,” Kashyap and colleagues noted.

Effects on therapeutics

In addition to being a potential therapeutic target, the microbiome also has important effects on traditional therapies, potentially impacting their efficacy, according to the authors.

“The role of the microbiome in the metabolism of many chemical compounds makes it a key player in determining drug availability, efficacy, and toxicity, making it indispensable for developing personalized drug therapies,” they wrote.

For example, studies have shown that competition between acetaminophen and bacteria-generated products could partially explain interindividual variability in analgesic response and differences in adverse events. Additionally, “microbiome markers of drug efficacy ranging from chemotherapeutic agents to statins have been widely described,” and a recent study showed the gut microbiota play a role “in mediating the antidiabetic effects of metformin.”

Thus, “considering the gut microbiota when determining drug responses akin to pharmacogenomics ... will allow us to impart more precise and effective therapeutics while decreasing overall adverse events,” the authors wrote.

Modulating the microbiome

Altering the gut microbiome is emerging as an appealing strategy for developing precision and personalized treatments, Kashyap and colleagues continued.

Developing targeted antibiotics is an important example of precision medicine, they wrote. While traditional antibiotics may have unintended adverse effects on microbial communities and patients, identifying specific pathogens would allow drug developers to “narrow the spectrum of the antibiotic.”

Recent studies have also shown promise for “next-generation probiotics that will be developed using targeted approaches to alter microbial metabolism in a disease-specific manner,” they wrote. “A precision approach using Clostridium scindens to augment resistance to C. difficile infection by targeting secondary bile acid pathway is one such example.”

Further, fecal microbiota transplantation has shown high efficacy for treating recurrent C. difficile infection, and while it has failed to show clinical efficacy in other diseases, “the use of FMT for diseases such as IBD has provided insight into donor specificity in terms of response, suggesting a role of individualizing FMT approaches in multifactorial diseases such as IBD, in contrast to the approach in C. difficile infection.”

PAGE BREAK

Dietary manipulations of the gut microbiome are also promising. The low FODMAPs diet, for example, has been shown to improve symptoms of irritable bowel syndrome, though the authors emphasize that this is only a short-term strategy, as long-term use can have negative health effects. Further, a recent study identified microbiome markers that predict response to the low FODMAPs diet, “with the potential to allow optimization of therapy and minimizing undesirable adverse effects in individuals less likely to respond,” they noted.

Future optimistic despite challenges

While the outlook for the future of microbiome science is optimistic, “there are also substantial challenges in the field,” Kashyap and colleagues wrote.

First, they emphasized that standardized collection, sequencing and analysis are needed to enhance reproducibility of study results across centers.

Second, most microbiome studies rely on disease associations, so to develop more reliable biomarkers, researchers must “better define the mechanisms by which microbiota influence aspects of human disease.”

Further study is also needed on the role of other microorganisms like fungi, bacteriophages and parasites, as well as their interactions, they added.

Finally, a “systems approach” is required to improve understanding of the interaction between diet and the microbiota.

“These challenges apart, the incorporation of microbiome-based diagnostics and therapeutics with other components of precision medicine, such as pharmacogenomics and epigenomics, will be an integral part of the new era in patient care,” Kashyap said in the press release. “This integration will further enhance our ability to find the precise treatments for patient care.” – by Adam Leitenberger

Disclosures: Two of the review authors report they are consultants for Day Two.

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