Probiotics: Finding the Right Regulatory Balance

 

The U.S. Food and Drug Administration (FDA) should consider the unique features of probiotics—bacteria that help maintain the natural balance of organisms in the intestines—in regulating their use and marketing, says Diane Hoffmann, JD, director of the Law and Health Care Program at the University of Maryland Francis King Carey School of Law and lead author of the a newly-released Science article, “Probiotics: Finding the Right Regulatory Balance.”

“The U.S. Food and Drug Administration (FDA) has no definition of probiotics and regulates them based on whether they fall into one of the existing regulated product categories,” says Hoffmann, who along with faculty members from the University of Maryland School of Medicine’s Institute for Genomics Sciences, the University of Maryland School of Pharmacy and the University of Maryland Carey School of Law, investigated how probiotics are being regulated.

The group brought together a working group of scientists conducting microbiome and probiotics research, legal academics, food and drug law attorneys, government representatives, bioethicists and consumer advocates to examine the current regulatory structure to determine if it adequately accounts for the risks of probiotics as well as the accuracy of claims of effectiveness. They also considered whether the regulatory structure is flexible enough to allow for (or at least not discourage) research on new probiotic products that may have therapeutic benefits.

The project was supported by a three year grant from the National Institutes of Health as part of the Ethical, Legal and Social Issues (ELSI) component to the Human Microbiome ProjectClaire Fraser, PhD, and Jacques Ravel, PhD, leading experts in the field of human microbiome science, participated in the study from the Institute for Genome Science at the University of Maryland School of Medicine. 

“One of the outcomes of the Human Microbiome Project is a tremendous interest in targeting these microbial communities with probiotics to both improve health and mitigate disease,” says Fraser, a professor of medicine whose research focuses on the role of the gut microbiome in a number of chronic diseases and its interaction with the immune system. But, according to Ravel, a professor of microbiology and immunology, “There is confusion about the regulatory process, in particular knowing within which product category different types of probiotics fall, and the current regulatory framework discourages the development of probiotic food in preventing disease, improving health or possibly treating disease.”

In their article, the coauthors recommend that FDA consider changing the way it characterizes probiotics and modifying two regulatory pathways. “This will help reduce the number of unsubstantiated probiotic claims and help consumers make more informed decisions as well as encourage more research on probiotics,” says Hoffmann.

Probiotics, which contain live organisms that degrade over time, have been consumed for centuries in the form of yogurts and fermented milks. Supermarket shelves are lined with a variety of probiotics foods and probiotic supplements are being aggressively marketed in retail stores and over the Internet. Although no probiotic has of yet been approved for therapeutic purposes by the FDA, some are undergoing clinical trials and may soon be marketed as biologics or other drugs— a development that prompted Hoffmann and her colleagues to examine the potential regulation of probiotics.

Current FDA regulatory requirements are not customized for probiotics. While probiotics that make drug claims should normally be subjected to the same requirements as other drugs, under “limited circumstances,” Hoffmann and her colleagues recommend an “abbreviated” process for some types of probiotic products. These products include: probiotic foods, dietary supplements and dietary ingredients for which there is adequate evidence of safety in the target population; approved food additives and substances generally recognized as safe (GRAS). An “abbreviated” process would allow probiotics to be excused from Phase l trials, the first step in clinical testing.

“A second recommendation of the working group,” said Frank Palumbo, PhD, JD, professor and executive director of the University of Maryland School of Pharmacy Center on Drugs and Public Policy, “is that the FDA develop a monograph for probiotic foods and dietary supplements similar to that used in Canada or employed by the FDA for over-the-counter drugs. Because all claims in monographs must be substantiated by evidence-based science, requiring a monograph to accompany probiotics should significantly reduce the number of false scientific claims.” Additionally, notes Palumbo, compliance with monograph requirements will lead to expedited review for the application for marketing probiotic products.

The working group report can be found here

The vocabulary used to describe microbial communities: microbiome, metagenome, microbiota

The exponential increase in publications reporting on the analysis of microbial communities inhabiting the human body has been accompanied by confusion in the vocabulary used to describe different aspects of these communities and their environments. In this post, I would like to try to clarify a few terms, which I think tend to be misused: Microbiome, microbiota and metagenomes (and metagenomics). The literature reveals the interchangeable used of these terms, which has led to major confusions in the community and the general public, as each mean something different.

Here is how I would define these specific terms:

Microbiota: The assemblage of microorganisms present in a defined environment. This bacterial census is established using molecular methods relying on the analysis of 16S rRNA gene sequences amplified from a given environment. Taxonomic assignments are performed that allows to assign each sequence to a microbial taxa (bacteria, archaea or lower eukaryotes).

Microbiome: This term refers to the entire habitat, including the microorganisms, their genomes (i.e., genes) and the surrounding environmental conditions. This definition is based on that of "biome", the biotic and abiotic factors of a given environments.

Other in the field limit the definition of microbiome to the collection of genes that are encoded by the members of a microbiota. I would suggest that this is the definition of metagenome not microbiome. 

Metagenome: The collection of genomes and genes from the members of a microbiota.

Therefore, when discussing results from 16S rRNA gene surveys (which describe the community, not the collective genome of the community or the complete habitat) “microbiota” should be used. To re-iterate on Jonathan Eisen's post, when doing such surveys, one doesn't not do metagenomics analysis, and should not use metagenomic sequences when referring to 16S rRNA gene sequences . However, when applying metagenomics to a biological sample (sequencing the community genomes of a microbiota) one generate a collection of genomes and genes. If this set of genomes and genes are discussed in the context of their environments, once can use the word microbiome.

Other terms which I believe are inappropriate and I often find in papers reporting on microbial surveys is "16S survey", "16S sequencing" or "16S analysis". There is no such things as "16S", the proper term is 16S rRNA genes survey, or 16S rRNA genes sequencing/analysis. The "S" in 16S is a non-SI unit for sedimentation rate and stands for Svedberg unit. The Svedberg unit offers a measure of particle size based on its rate of travel in a tube subjected to high g-force. The small subunits of the bacterial and archaeal ribosomes are 30S, and comprise the 16S rRNA (~1540 nucleotide) bound to 21 proteins. 

This post was informed from papers and other communication I have had with colleagues. I hope that a consensus use of these term could be adopted in the near future, so we can all talk about the same thing when using these terms. I would encourage readers to leave comments to stimulate discussions, and may be agree on rules to use these terms. I plan on summarizing these discussion in an editorial article in the journal Microbiome.

Microbiome: a new journal to demystify the role of microbial communities in the biosphere

A new peer-reviewed publication has launched focusing on microbiome research in environmental, agricultural, and biomedical areas. Myself and Eric Wommack from the University of Delaware’s College of Earth, Ocean and Environment are the Editors-in-Chief of Microbiome, a BioMed Central (BMC) publication. The first issue was launched today (www.microbiomejournal.com)

From the press release:

The new publication reflects the growing importance of the need for studying communities of microorganisms – microbiomes –  and their function in their natural environment whether that environment is the human body, the ocean, or any other habitat. 

“Microbiology was once thought of as two exclusive subdisciplines – clinical microbiology and environmental microbiology – but the substantial technological advances, particularly over the past decade in DNA sequencing and analysis, have given scientists new common and interdisciplinary research interests,” explains Dr. Ravel, who is studying the effect of the human microbiome on women’s health, and is part of the NIH-funded Human Microbiome Project (HMP).

 “Microbiome will facilitate the cross-fertilization of ideas, research methods and analyses, and theory between clinical and environmental microbiologists exploring the emergent impacts of microbial communities on the ecosystems they inhabit,” says Dr. Wommack, a University of Delaware professor who researches the inner workings of microbial communities.

The central purpose of Microbiome is to unite investigators conducting research on microbial communities in environmental, agricultural, and biomedical arenas. Topics broadly addressing the study of microbial communities, such as, meta-genomics surveys, bioinformatics, other ‘-omics’ approaches and surveys, and community/host interaction mathematical modeling will be covered.

The first issue of Microbiome features several innovative research papers from scientists at various institutions worldwide. For example, a team from the University of Guelph in Canada, summarized their novel stool substitute transplant therapy research. The team treated two patients with Clostridium difficile using a bacterial strain cocktail in an attempt to alleviate this difficult infection of the lower GI tract.  Other innovative genomic research approaches are also featured in the first issue.

Here are some web coverage of the study:

The journal includes a new section, “Microbiome Announcementsthat will contain short reports describing microbiome datasets and their associated clinical or environmental data.

A prestigious international editorial review board that includes leading interdisciplinary scientists from the U.S., France, Australia, China and other countries, who represent academic centers, private and environmental research centers, as well as federal agencies, has been assembled to work with the journal's editors. 

Microbiome is published online by BioMed Central, based in the UK. The website will also feature many online tools, such as RSS feeds, and robust advanced search capabilities. For more information: http://www.microbiomejournal.com/

The vocabulary used to describe microbial communities: microflora vs microbiota

There has been an explosion of studies that describe microbial communities, mostly spurred by project like the Human Microbiome Project and the democratization of performing high-throughput sequencing. My weekly search for such studies now reveals close to 100 original papers and reviews! This is a good thing as we getting a much better understanding of the role of microbes that live with us and around us. However, this has been accompanied by a ever growing confusion of the terminology associated with describing microbial communities. A recent blog post by Jonathan Eisen highlights one misuse of the word "metagenomics" in the context of marker gene survey, such as 16S rRNA gene sequence-based microbial census. I would like to try to stimulate a conversation to standardize the vocabulary used to describe microbial communities in the scientific literature, and over the next few week, I will write a series of posts dealing with the vocabulary used to describe microbial communities.

I would like to start with one of my pet-peeve, the use of the word "microflora". I fully understand that the word has been used for a long time in the scientific literature, but looking at its definition in all major dictionaries, I feel it is inappropriate to describe any community of microbes.

mi·cro·flo·ra /ˌmīkrōˈflôrə/ noun
1. microscopic plants.
2. the plants or flora of a microhabitat.
origin: 1900–05; micro- + flora

How do these dictionaries define "flora"?
flo·ra [flawr-uh, flohr-uh] noun, plural flo·ras, flo·rae [flawr-ee, flohr-ee]
1. the plants of a particular region or period, listed by species and considered as a whole.
2. a work systematically describing such plants.
3. plants, as distinguished from fauna.
origin: 1655–65; < Neo-Latin, Latin Flōra the Roman goddess of flowers (used from the 17th cent. in the titles of botanical works), derivative of Latin flōr- (stem of flōs ) flower

It is obvious from these definitions and the origins of both words that microflora refers to plants not bacteria. While some dictionaries will include a third definition for microflora that refer to "the aggregate of bacteria, fungi, and other microorganisms normally occurring on or in the bodies of humans and other animals: intestinal flora", this add-on to the definition is the result of over one century of constant misuse of the word driven by a limited understanding of microbes. Our knowledge of microbial communities is now such that we should know better than continuing misusing the word in the scientific literature. I, for one, have contributed to its misuse, as my first grant on human associated microbial communities used the word microflora! Thus, I suggest that to describes the assemblage of microbes living in a microhabitat we use a different term, the word "microbiota", as it is much more encompassing than microflora.

mi·cro·biota [mi″kro-bi-o´tah] noun
1. the microscopic living organisms of a region.
2. the microscopic flora and fauna of a region

Microflora has still its place in the popular literature or in a yogurt advertisement, but microflora does not have its place in the scientific literature anymore.
Let's all stop using the words microflora or flora in scientific papers, conference proceedings, and whenever we can let's educate others. The word microbiota is adequate and appropriate to describe the composition and abundance of microbial communities whether they inhabit the human body or the environment.