The Gut-Brain Axis

Dietary, Probiotic, and Prebiotic Interventions on the Microbiota

Niall Hyland,Catherine Stanton

• Publisher: Academic Press
• Year: 2016
• ISBN:
  9780128025444
• Topic: Medicine
• Subtopic: Physiology

The Gut-Brain Axis: Dietary, Probiotic, and Prebiotic Interventions on the Microbiota examines the potential for microbial manipulation as a therapeutic avenue in central nervous system disorders in which an altered microbiota has been implicated, and explores the mechanisms, sometimes common, by which the microbiota may contribute to such disorders.

• Focuses on specific areas in which the microbiota has been implicated in gut-brain communication
• Examines common mechanisms and pathways by which the microbiota may influence brain and behavior
• Identifies novel therapeutic strategies targeted toward the microbiota in the management of brain activity and behavior

Chapter 1

Regulatory Considerations for the Use and Marketing of Probiotics and Functional Foods

L. Morelli Università Cattolica del Sacro Cuore, Istituto di Microbiologia, Piacenza, Italy

M.L. Callegari, and S. Federici Università Cattolica del Sacro Cuore, Centro Ricerche Biotecnologiche, Cremona, Italy

Abstract

In the last 15 years, the term probiotic has achieved a consensus definition, and two Food and Agricultural Organization/World Health Organization documents have clarified and improved the regulatory profile of probiotics. In contrast, the definition of prebiotic proposed by the Food and Agricultural Organization remains under debate. In the last 5 years growing evidence has supported the suggestion that probiotics/psychobiotics can influence brain function and contribute to the amelioration or prevention of disease and mood disorders. From the regulatory point of view, these exciting results must be considered with prudence because of differences in the approaches and needs of peer reviewers of scientific journals versus examiners of regulatory administration. For conventional probiotics, enrollment of healthy versus unhealthy subjects into trials may define the development of a food or a pharmaceutical product.

Keywords

FAO/WHO guidelines; Gut–brain axis; Prebiotic; Probiotic; Psychobiotic; Regulations

Regulatory Impact of Definitions

Scientific research is the driving force of innovation in nearly all fields of human activity, including nutrition. In the context of nutrition science the management of enteric microbiota to achieve a “health effect” in a human host has enjoyed a long history. During his stay in the early 1900s at the Institute Pasteur, Elie Metchnikoff noticed the “…different susceptibilities of people to the harmful action of microbes and their products. Some can swallow without any evil result a quantity of microbes which in the case of other individuals would produce a fatal attack of cholera. Everything depends upon the resistance offered to the microbes by the invaded organism” (Metchnikoff, 1907). He focused on the sensitivity to low pH of pathogens most commonly isolated from the human gut at that time (Enterobacteriaceae); lactic acid-producing bacteria able to colonize the human gut seemed to Metchnikoff to constitute an ideal tool for inhibiting the growth of pathogens.

The following 50 years witnessed more efforts to develop Metchnikoff’s ideas; for example, in Europe with Escherichia coli strain Nissle 1917 (Möllenbrink and Bruckschen, 1994) and in Japan with Lactobacillus casei Shirota (Morotomi, 1996). In the United States Nicholas Kopeloff studied Lactobacillus acidophilus (1926) (by lucky coincidence with the focus of this book, Kopeloff was an associate professor in bacteriology at the Psychiatric Institute of Ward’s Island, New York), as did Rettger et al. (1935). However, the impact of these investigations on the market was limited, and these studies were ignored by regulatory agencies.

A breakthrough occurred with the appearance in the scientific literature of the term probiotic, which seems to have been coined during the 1950s (Hamilton-Miller et al., 2003) to identify substances able to support the growth of microorganisms; this term appears to have been chosen to oppose the concept of an antibiotic. However, the first clear definition of the term probiotic in relation to beneficial bacteria emerged in the 1960s (Lilly and Stillwell, 1965). At that time research mainly focused on the selection and use of bacteria for use as feed additives. This peculiarity was made evident by Fuller (1989), who proposed to define probiotics as “a live microbial feed supplement which beneficially affects the host animal by improving its intestinal balance.”

Probiotic use was extended to humans by Havenaar and Huis in’t Veld (1992), who proposed the definition “a viable mono or mixed culture of bacteria which, when applied to animal or man, beneficially affects the host by improving the properties of the indigenous flora.” The definition further evolved with the introduction of references to the quantity of viable cells necessary to exert probiotic action. For example, Guarner and Schaafsma (1998) suggested that probiotics be defined as “live microorganisms, which when consumed in adequate amounts, confer a health effect on the host.” A further step was taken by the Food and Agricultural Organization (FAO)/World Health Organization (WHO) Joint Expert Consultation that redefined probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” (FAO/WHO Joint Working Group, 2001). The verb administered was introduced instead of the word consumed to include beneficial bacteria in the urogenital tract or bacteria applied topically, according to studies published at the end of the last century that were the basis for products appearing on the market at the beginning of the 2000s (Ocaña et al., 1999; Parent et al., 1996). Further specification of the term probiotic was provided by the same expert group in 2002 (FAO/WHO Joint Working Group, 2002). Thus it is clear that definitions of the term probiotic have followed the advancement of scientific research, from the quest for substances with actions opposite to those of antibiotics to the selection of bacteria beneficial for humans (not only in the gut).

The two FAO/WHO documents strongly impacted not only science but also regulation, which is relevant for this chapter. Since 2002 these documents have been used as references by health and food-safety agencies all over the world. The European Food Safety Authority, the US Food and Drug Administration, and Health Canada have used them as templates for their own guidelines for probiotics, as have agencies in China, India, Brazil, Argentina, and other nations (Table 1.1). Thus these documents have clarified and improved the regulatory profile of probiotics.

At the time of this writing, the term probiotic has reached a consensus definition with two components: (1) viable bacteria (2) with documented (at the strain level) potential to confer health benefits in the host when administered in the necessary amount; this action could be independent of any effect on the composition of the host’s gut microbiota. It is also assumed that a clear taxonomy has been assigned to the strains and that their intended use is safe. These considerations should be taken together with more general considerations about “active substances” from the regulatory point of view: (1) the need for accurate bacterial identifications, which imply precise definitions of the active substances; (2) the need to assess safety on the basis of a long history of safe use if the product is food or on the basis of specific testing if the product is pharmaceutical; and (3) the need to evaluate efficacy, which should be assessed in healthy people for food and in patients for drugs.

Table 1.1

List of Health and Food Safety Agencies Referring to Food and Agricultural Organization/World Health Organization Guidelines for Probiotic Definition and Evaluation

Regulatory Authority or Author (Country)	Document
US Food and Drug Administration (United States)	Complementary and Alternative Medicine Products and Their Regulation by the Food and Drug Administration (Food and Drug Administration, 2006).
US Pharmacopoeia (United States)	Appendix XV: Microbial Food Cultures Including Probiotics (US Pharmacopoeia, 2012).
Health Canada	Guidance Document : The Use of Probiotic Microorganisms in Food (Health Canada, 2009). The document “clarifies the acceptable use of health claims about probiotics, and provides guidance on the safety, stability and labeling aspects of food products containing probiotic microorganisms.”
Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT; Argentina)	Codigo Alimentario Argentino. Capitulo XVII: Alimentos de Regimen o Dietéticos (A.N.M.A.T.).
Ministry of Health, China Food and Drug Administration (People’s Republic of China)	Regulatory for Probiotic Health Food Application and Examination (interim; China Food and Drug Administration (CFDA), 2005). Most of the Food and Agricultural Organization/World Health Organization guidelines have been adopted. A list of 10 allowed probi...