Basal metabolic rate

From Wikipedia, the free encyclopedia

Basal metabolic rate (BMR) is the rate of energy expenditure per unit time by endothermic animals at rest. It is reported in energy units per unit time ranging from watt (joule/second) to ml O₂/min or joule per hour per kg body mass J/(h·kg). Proper measurement requires a strict set of criteria be met. These criteria include being in a physically and psychologically undisturbed state, in a thermally neutral environment, while in the post-absorptive state (i.e., not actively digesting food). In bradymetabolic animals, such as fish and reptiles, the equivalent term standard metabolic rate (SMR) is used. It follows the same criteria as BMR, but requires the documentation of the temperature at which the metabolic rate was measured. This makes BMR a variant of standard metabolic rate measurement that excludes the temperature data, a practice that has led to problems in defining "standard" rates of metabolism for many mammals.

 

Metabolism comprises the processes that the body needs to function. Basal metabolic rate is the amount of energy per unit time that a person needs to keep the body functioning at rest. Some of those processes are breathing, blood circulation, controlling body temperature, cell growth, brain and nerve function, and contraction of muscles. Basal metabolic rate (BMR) affects the rate that a person burns calories and ultimately whether that individual maintains, gains, or loses weight. The basal metabolic rate accounts for about 60 to 75% of the daily calorie expenditure by individuals. It is influenced by several factors. BMR typically declines by 1–2% per decade after age 20, mostly due to loss of fat-free mass, although the variability between individuals is high.

Description

The body's generation of heat is known as thermogenesis and it can be measured to determine the amount of energy expended. BMR generally decreases with age and with the decrease in lean body mass (as may happen with aging). Increasing muscle mass has the effect of increasing BMR. Aerobic (resistance) fitness level, a product of cardiovascular exercise, while previously thought to have effect on BMR, has been shown in the 1990s not to correlate with BMR when adjusted for fat-free body mass. But anaerobic exercise does increase resting energy consumption (see "aerobic vs. anaerobic exercise"). Illness, previously consumed food and beverages, environmental temperature, and stress levels can affect one's overall energy expenditure as well as one's BMR.

Indirect calorimetry laboratory with canopy hood (dilution technique)

BMR is measured under very restrictive circumstances when a person is awake. An accurate BMR measurement requires that the person's sympathetic nervous system not be stimulated, a condition which requires complete rest. A more common measurement, which uses less strict criteria, is resting metabolic rate (RMR).

BMR may be measured by gas analysis through either direct or indirect calorimetry, though a rough estimation can be acquired through an equation using age, sex, height, and weight. Studies of energy metabolism using both methods provide convincing evidence for the validity of the respiratory quotient (RQ), which measures the inherent composition and utilization of carbohydrates, fats and proteins as they are converted to energy substrate units that can be used by the body as energy.

Phenotypic flexibility

BMR is a flexible trait (it can be reversibly adjusted within individuals), with, for example, lower temperatures generally resulting in higher basal metabolic rates for both birds and rodents. There are two models to explain how BMR changes in response to temperature: the variable maximum model (VMM) and variable fraction model (VFM). The VMM states that the summit metabolism (or the maximum metabolic rate in response to the cold) increases during the winter, and that the sustained metabolism (or themetabolic rate that can be indefinitely sustained) remains a constant fraction of the former. The VFM says that the summit metabolism does not change, but that the sustained metabolism is a larger fraction of it. The VMM is supported in mammals, and, when using whole-body rates, passerine birds. The VFM is supported in studies of passerine birds using mass-specific metabolic rates (or metabolic rates per unit of mass). This latter measurement has been criticized by Eric Liknes, Sarah Scott, and David Swanson, who say that mass-specific metabolic rates are inconsistent seasonally.

In addition to adjusting to temperature, BMR also may adjust before annual migration cycles. The red knot (ssp. islandica) increases its BMR by about 40% before migrating northward. This is because of the energetic demand of long-distance flights. The increase is likely primarily due to increased mass in organs related to flight. The end destination of migrants affects their BMR: yellow-rumped warblers migrating northward were found to have a 31% higher BMR than those migrating southward.

Physiology

The early work of the scientists J. Arthur Harris and Francis G. Benedict showed that approximate values for BMR could be derived using body surface area (computed from height and weight), age, and sex, along with the oxygen and carbon dioxide measures taken from calorimetry. Studies also showed that by eliminating the sex differences that occur with the accumulation of adipose tissue by expressing metabolic rate per unit of "fat-free" or lean body mass, the values between sexes for basal metabolism are essentially the same. Exercise physiology textbooks have tables to show the conversion of height and body surface area as they relate to weight and basal metabolic values.

The primary organ responsible for regulating metabolism is the hypothalamus. The hypothalamus is located on the diencephalon and forms the floor and part of the lateral walls of the third ventricle of the cerebrum. The chief functions of the hypothalamus are:

1. control and integration of activities of the autonomic nervous system (ANS)
   • The ANS regulates contraction of smooth muscle and cardiac muscle, along with secretions of many endocrine organs such as the thyroid gland (associated with many metabolic disorders).
   • Through the ANS, the hypothalamus is the main regulator of visceral activities, such as heart rate, movement of food through the gastrointestinal tract, and contraction of the urinary bladder.
2. production and regulation of feelings of rage and aggression
3. regulation of body temperature
4. regulation of food intake, through two centers:
   • The feeding center or hunger center is responsible for the sensations that cause us to seek food. When sufficient food or substrates have been received and leptin is high, then the satiety center is stimulated and sends impulses that inhibit the feeding center. When insufficient food is present in the stomach and ghrelin levels are high, receptors in the hypothalamus initiate the sense of hunger.
   • The thirst center operates similarly when certain cells in the hypothalamus are stimulated by the rising osmotic pressure of the extracellular fluid. If thirst is satisfied, osmotic pressure decreases.

All of these functions taken together form a survival mechanism that causes us to sustain the body processes that BMR measures.

BMR estimation formulas

Several equations to predict the number of calories required by humans have been published from the early 20th–21st centuries. In each of the formulas below:

• P   is total heat production at complete rest,
• m   is mass (kg),
• h   is height (cm), and
• a   is age (years),

The original Harris-Benedict equation

Historically, the most notable formula was the Harris–Benedict equation, which was published in 1919.

• for men, ${\displaystyle P=\left({\frac {13.7516m}{1~{\mbox{kg}}}}+{\frac {5.0033h}{1~{\mbox{cm}}}}-{\frac {6.7550a}{1~{\mbox{year}}}}+66.4730\right){\frac {\mbox{kcal}}{\mbox{day}}}}$
• for women, ${\displaystyle P=\left({\frac {9.5634m}{1~{\mbox{kg}}}}+{\frac {1.8496h}{1~{\mbox{cm}}}}-{\frac {4.6756a}{1~{\mbox{year}}}}+655.0955\right){\frac {\mbox{kcal}}{\mbox{day}}}}$

The difference in BMR for men and women is mainly due to differences in body weight. For example, a 55 year-old woman weighing 130 lb (59 kg) and 5 feet 6 inches (168 cm) tall would have a BMR of 1272 kcal per day.

The revised Harris-Benedict equation

In 1984, the original Harris-Benedict equations were revised using new data. In comparisons with actual expenditure, the revised equations were found to be more accurate.

• for men, ${\displaystyle P=\left({\frac {13.397m}{1~{\mbox{kg}}}}+{\frac {4.799h}{1~{\mbox{cm}}}}-{\frac {5.677a}{1~{\mbox{year}}}}+88.362\right){\frac {\mbox{kcal}}{\mbox{day}}}}$
• for women, ${\displaystyle P=\left({\frac {9.247m}{1~{\mbox{kg}}}}+{\frac {3.098h}{1~{\mbox{cm}}}}-{\frac {4.330a}{1~{\mbox{year}}}}+447.593\right){\frac {\mbox{kcal}}{\mbox{day}}}}$

It was the best prediction equation until 1990, when Mifflin et al. introduced the equation:

The Mifflin St Jeor Equation

• ${\displaystyle P=\left({\frac {10.0m}{1~{\mbox{kg}}}}+{\frac {6.25h}{1~{\mbox{cm}}}}-{\frac {5.0a}{1~{\mbox{year}}}}+s\right){\frac {\mbox{kcal}}{\mbox{day}}}}$, where s is +5 for males and −161 for females.

According to this formula, the woman in the example above has a BMR of 1204 kcal per day. During the last 100 years, lifestyles have changed and Frankenfield et al. showed it to be about 5% more accurate.

These formulas are based on body weight, which does not take into account the difference in metabolic activity between lean body mass and body fat. Other formulas exist which take into account lean body mass, two of which are the Katch-McArdle formula, and Cunningham formula.

The Katch-McArdle Formula (Resting Daily Energy Expenditure)

The Katch-McArdle formula is used to predict Resting Daily Energy Expenditure (RDEE). The Cunningham formula is commonly attributed as being used to predict RMR instead of BMR, however the formulas provided by Katch-McArdle and Cunningham are the same.

• ${\displaystyle P=370+\left(21.6\cdot \ell \right)}$

where ℓ is the lean body mass (LBM in kg)

• ${\displaystyle \ell =m\left(1-{\frac {f}{100}}\right)}$

where f is the body fat percentage. According to this formula, if the woman in the example has a body fat percentage of 30%, her Resting Daily Energy Expenditure (the authors use the term of basal and resting metabolism interchangeably) would be 1262 kcal per day.

Causes of individual differences in BMR

The basic metabolic rate varies between individuals. One study of 150 adults representative of the population in Scotland reported basal metabolic rates from as low as 1027 kcal per day (4301 kJ/day) to as high as 2499 kcal/day (10455 kJ/day); with a mean BMR of 1500 kcal/day (6279 kJ/day). Statistically, the researchers calculated that 62.3% of this variation was explained by differences in fat free mass. Other factors explaining the variation included fat mass (6.7%), age (1.7%), and experimental error including within-subject difference (2%). The rest of the variation (26.7%) was unexplained. This remaining difference was not explained by sex nor by differing tissue size of highly energetic organs such as the brain.

Differences in BMR have been observed when comparing subjects with the same lean body mass. In one study, when comparing individuals with the same lean body mass, the top 5% of BMRs are 1.28–1.32 times the lowest 5% BMR. Additionally, this study reports a case where two individuals with the same lean body mass of 43 kg had BMRs of 1075 kcal/day (4.5 MJ/day) and 1790 kcal/day (7.5 MJ/day). This difference of 715 kcal/day (67%) is equivalent to one of the individuals completing a 10 kilometer run every day. However, this study did not account for the sex, height, fasting-state, or body fat percentage of the subjects.

Biochemistry

Energy expenditure breakdown
Liver	27%
Brain	19%
Skeletal Muscle	18%
Kidneys	10%
Heart	7%
Other organs	19%

Postprandial thermogenesis increases in basal metabolic rate occur at different degrees depending on consumed food composition.

About 70% of a human's total energy expenditure is due to the basal life processes taking place in the organs of the body (see table). About 20% of one's energy expenditure comes from physical activity and another 10% from thermogenesis, or digestion of food (postprandial thermogenesis). All of these processes require an intake of oxygen along with coenzymes to provide energy for survival (usually from macronutrients like carbohydrates, fats, and proteins) and expel carbon dioxide, due to processing by the Krebs cycle.

For the BMR, most of the energy is consumed in maintaining fluid levels in tissues through osmoregulation, and only about one-tenth is consumed for mechanical work, such as digestion, heartbeat, and breathing.

What enables the Krebs cycle to perform metabolic changes to fats, carbohydrates, and proteins is energy, which can be defined as the ability or capacity to do work. The breakdown of large molecules into smaller molecules—associated with release of energy—is catabolism. The building up process is termed anabolism. The breakdown of proteins into amino acids is an example of catabolism, while the formation of proteins from amino acids is an anabolic process.

Exergonic reactions are energy-releasing reactions and are generally catabolic. Endergonic reactions require energy and include anabolic reactions and the contraction of muscle. Metabolism is the total of all catabolic, exergonic, anabolic, endergonic reactions.

Adenosine Triphosphate (ATP) is the intermediate molecule that drives the exergonic transfer of energy to switch to endergonic anabolic reactions used in muscle contraction. This is what causes muscles to work which can require a breakdown, and also to build in the rest period, which occurs during the strengthening phase associated with muscular contraction. ATP is composed of adenine, a nitrogen containing base, ribose, a five carbon sugar (collectively called adenosine), and three phosphate groups. ATP is a high energy molecule because it stores large amounts of energy in the chemical bonds of the two terminal phosphate groups. The breaking of these chemical bonds in the Krebs Cycle provides the energy needed for muscular contraction.

Glucose

Because the ratio of hydrogen to oxygen atoms in all carbohydrates is always the same as that in water—that is, 2 to 1—all of the oxygen consumed by the cells is used to oxidize the carbon in the carbohydrate molecule to form carbon dioxide. Consequently, during the complete oxidation of a glucose molecule, six molecules of carbon dioxide and six molecules of water are produced and six molecules of oxygen are consumed.

The overall equation for this reaction is:

C₆H₁₂O₆ + 6 O₂ → 6 CO₂ + 6 H₂O

(+38 ATP molecules)

Because the gas exchange in this reaction is equal, the respiratory quotient (R.Q.) for carbohydrate is unity or 1.0:

R.Q. = 6 CO₂ / 6 O₂ = 1.0

Fats

The chemical composition for fats differs from that of carbohydrates in that fats contain considerably fewer oxygen atoms in proportion to atoms of carbon and hydrogen. When listed on nutritional information tables, fats are generally divided into six categories: total fats, saturated fatty acid, polyunsaturated fatty acid, monounsaturated fatty acid, dietary cholesterol, and trans fatty acid. From a basal metabolic or resting metabolic perspective, more energy is needed to burn a saturated fatty acid than an unsaturated fatty acid. The fatty acid molecule is broken down and categorized based on the number of carbon atoms in its molecular structure. The chemical equation for metabolism of the twelve to sixteen carbon atoms in a saturated fatty acid molecule shows the difference between metabolism of carbohydrates and fatty acids. Palmitic acid is a commonly studied example of the saturated fatty acid molecule.

The overall equation for the substrate utilization of palmitic acid is:

C₁₆H₃₂O₂ + 23 O₂ → 16 CO₂ + 16 H₂O

Thus the R.Q. for palmitic acid is 0.696:

R.Q. = 16 CO₂ / 23 O₂ = 0.696

Proteins

Proteins are composed of carbon, hydrogen, oxygen, and nitrogen arranged in a variety of ways to form a large combination of amino acids. Unlike fat the body has no storage deposits of protein. All of it is contained in the body as important parts of tissues, blood hormones, and enzymes. The structural components of the body that contain these amino acids are continually undergoing a process of breakdown and replacement. The respiratory quotient for protein metabolism can be demonstrated by the chemical equation for oxidation of albumin:

C₇₂H₁₁₂N₁₈O₂₂S + 77 O₂ → 63 CO₂ + 38 H₂O + SO₃ + 9 CO(NH₂)₂

The R.Q. for albumin is 63 CO₂/ 77 O₂ = 0.818

The reason this is important in the process of understanding protein metabolism is that the body can blend the three macronutrients and based on the mitochondrial density, a preferred ratio can be established which determines how much fuel is utilized in which packets for work accomplished by the muscles. Protein catabolism (breakdown) has been estimated to supply 10% to 15% of the total energy requirement during a two-hour aerobic training session. This process could severely degrade the protein structures needed to maintain survival such as contractile properties of proteins in the heart, cellular mitochondria, myoglobin storage, and metabolic enzymes within muscles.

The oxidative system (aerobic) is the primary source of ATP supplied to the body at rest and during low intensity activities and uses primarily carbohydrates and fats as substrates. Protein is not normally metabolized significantly, except during long term starvation and long bouts of exercise (greater than 90 minutes.) At rest approximately 70% of the ATP produced is derived from fats and 30% from carbohydrates. Following the onset of activity, as the intensity of the exercise increases, there is a shift in substrate preference from fats to carbohydrates. During high intensity aerobic exercise, almost 100% of the energy is derived from carbohydrates, if an adequate supply is available.

Aerobic vs. anaerobic exercise

Studies published in 1992 and 1997 indicate that the level of aerobic fitness of an individual does not have any correlation with the level of resting metabolism. Both studies find that aerobic fitness levels do not improve the predictive power of fat free mass for resting metabolic rate. However recent research from the Journal of Applied Physiology, published in 2012 Sep. 27, PMCID:PMC3544497, compared Resistance Training and Aerobic training on body mass and fat mass in overweight adults: "STRRIDE AT/RT. When you consider time commitments against health benefits, AT is the optimal mode of exercise for reducing fat mass and body mass as a primary consideration, RT is good as a secondary factor when aging and lean mass are a concern. RT causes injuries at a much higher rate than AT.  Compared to RT, it was found that AET resulted in a significantly more pronounced reduction of body weight by enhancing the cardiovascular system which is what is the principle factor in metabolic utilization of fat substrates. RT if time is available is also helpful in post exercise metabolism, but it is an adjunctive factor because the body needs to heal sufficiently between RT episodes, whereas with AET, the body can accept this every day. RMR, and BMR are measurements of daily consumption of calories. The majority of studies that are published on this topic look at aerobic exercise because of its efficacy for health and weight management.

Anaerobic exercise, such as weight lifting, builds additional muscle mass. Muscle contributes to the fat-free mass of an individual and therefore effective results from anaerobic exercise will increase BMR. However, the actual effect on BMR is controversial and difficult to enumerate. Various studies suggest that the resting metabolic rate of trained muscle is around 55kJ per kilogram, per day. Even a substantial increase in muscle mass, say 5 kg, would make only a minor impact on BMR.

Longevity

In 1926, Raymond Pearl proposed that longevity varies inversely with basal metabolic rate (the "rate of living hypothesis"). Support for this hypothesis comes from the fact that mammals with larger body size have longer maximum life spans (large animals do have higher total metabolic rates, but the metabolic rate at the cellular level is much lower, and the breathing rate and heartbeat are slower in larger animals) and the fact that the longevity of fruit flies varies inversely with ambient temperature. Additionally, the life span of houseflies can be extended by preventing physical activity. This theory has been bolstered by several new studies linking lower basal metabolic rate to increased life expectancy, across the animal kingdom—including humans. Calorie restriction and reduced thyroid hormone levels, both of which decrease the metabolic rate, have been associated with higher longevity in animals.

However, the ratio of total daily energy expenditure to resting metabolic rate can vary between 1.6 and 8.0 between species of mammals. Animals also vary in the degree of coupling between oxidative phosphorylation and ATP production, the amount of saturated fat in mitochondrial membranes, the amount of DNA repair, and many other factors that affect maximum life span.

Organism longevity and basal metabolic rate

In allometric scaling, maximum potential life span (MPLS) is directly related to metabolic rate (MR), where MR is the recharge rate of a biomass made up of covalent bonds. That biomass (W) is subjected to deterioration over time from thermodynamic, entropic pressure. Metabolism is essentially understood as redox coupling, and has nothing to do with thermogenesis. Metabolic efficiency (ME) is then expressed as the efficiency of this coupling, a ratio of amperes captured and used by biomass, to the amperes available for that purpose. MR is measured in watts, W is measured in grams. These factors are combined in a power law, an elaboration on Kleiber's law relating MR to W and MPLS, that appears as MR = W^ (4ME-1)/4ME.^{[clarification needed]} When ME is 100%, MR = W^3/4; this is popularly known as quarter power scaling, a version of allometric scaling that is premised upon unrealistic estimates of biological efficiency.

The equation reveals that as ME drops below 20%, for W < one gram, MR/MPLS increases so dramatically as to endow W with virtual immortality by 16%. The smaller W is to begin with, the more dramatic is the increase in MR as ME diminishes. All of the cells of an organism fit into this range, i.e., less than one gram, and so this MR will be referred to as BMR.

But the equation reveals that as ME increases over 25%, BMR approaches zero. The equation also shows that for all W > one gram, where W is the organization of all of the BMRs of the organism's structure, but also includes the activity of the structure, as ME increases over 25%, MR/MPLS increases rather than decreases, as it does for BMR. An MR made up of an organization of BMRs will be referred to as an FMR. As ME decreases below 25%, FMR diminishes rather than increases as it does for BMR.

The antagonism between FMR and BMR is what marks the process of aging of biomass W in energetic terms. The ME for the organism is the same as that for the cells, such that the success of the organism's ability to find food (and lower its ME), is key to maintaining the BMR of the cells driven, otherwise, by starvation, to approaching zero; while at the same time a lower ME diminishes the FMR/MPLS of the organism.

Medical considerations

A person's metabolism varies with their physical condition and activity. Weight training can have a longer impact on metabolism than aerobic training, but there are no known mathematical formulas that can exactly predict the length and duration of a raised metabolism from trophic changes with anabolic neuromuscular training.

A decrease in food intake will typically lower the metabolic rate as the body tries to conserve energy. Researcher Gary Foster estimates that a very low calorie diet of fewer than 800 calories a day would reduce the metabolic rate by more than 10 percent.

The metabolic rate can be affected by some drugs, such as antithyroid agents, drugs used to treat hyperthyroidism, such as propylthiouracil and methimazole, bring the metabolic rate down to normal and restore euthyroidism. Some research has focused on developing antiobesity drugs to raise the metabolic rate, such as drugs to stimulate thermogenesis in skeletal muscle.

The metabolic rate may be elevated in stress, illness, and diabetes. Menopause may also affect metabolism.

Cardiovascular implications

Heart rate is determined by the medulla oblongata and part of the pons, two organs located inferior to the hypothalamus on the brain stem. Heart rate is important for basal metabolic rate and resting metabolic rate because it drives the blood supply, stimulating the Krebs cycle. During exercise that achieves the anaerobic threshold, it is possible to deliver substrates that are desired for optimal energy utilization. The anaerobic threshold is defined as the energy utilization level of heart rate exertion that occurs without oxygen during a standardized test with a specific protocol for accuracy of measurement, such as the Bruce Treadmill protocol (see metabolic equivalent). With four to six weeks of targeted training the body systems can adapt to a higher perfusion of mitochondrial density for increased oxygen availability for the Krebs cycle, or tricarboxylic cycle, or the glycolitic cycle. This in turn leads to a lower resting heart rate, lower blood pressure, and increased resting or basal metabolic rate.

By measuring heart rate we can then derive estimations of what level of substrate utilization is actually causing biochemical metabolism in our bodies at rest or in activity. This in turn can help a person to maintain an appropriate level of consumption and utilization by studying a graphical representation of the anaerobic threshold. This can be confirmed by blood tests and gas analysis using either direct or indirect calorimetry to show the effect of substrate utilization. The measures of basal metabolic rate and resting metabolic rate are becoming essential tools for maintaining a healthy body weight.

Probiotic

From Wikipedia, the free encyclopedia

A bottle of Yakult, a probiotic drink containing Lactobacillus paracasei.

Probiotics are live microorganisms intended to provide health benefits when consumed, generally by improving or restoring the gut flora. Probiotics are considered generally safe to consume, but may cause bacteria-host interactions and unwanted side effects in rare cases.

The original theory, similar to the modern concept, but not the term, is generally attributed to Nobel laureate Élie Metchnikoff, who postulated that yoghurt-consuming Bulgarian peasants lived longer lives because of that custom. In 1907, he wrote: "[T]he dependence of the intestinal microbes on the food makes it possible to adopt measures to modify the microbiota in our bodies[,] and to replace the harmful microbes by useful microbes."

A growing probiotics market has led to the need for stricter requirements for scientific substantiation of putative benefits conferred by microorganisms claimed to be probiotic. Although there are numerous claimed benefits marketed towards using consumer probiotic products, such as reducing gastrointestinal discomfort, improving immune health, relieving constipation, or avoiding the common cold, such claims are not supported by scientific evidence, and are prohibited as deceptive advertising in the United States by the Federal Trade Commission.

In a clinical setting however, some probiotics have been found to be useful in treating specific medical conditions, such as antibiotic-associated diarrhea in children and Clostridium difficile infection in adults. One concern is that probiotics taken by mouth can be destroyed by the acidic conditions of the stomach. As of 2010, a number of microencapsulation techniques were being developed to address this problem.

Definition

An October 2001 report by the World Health Organization (WHO) defines probiotics as live microorganisms that, "when administered in adequate amounts, confer a health benefit on the host." Following this definition, a working group convened by the Food and Agriculture Organization (FAO)/WHO in May 2002 issued the Guidelines for the Evaluation of Probiotics in Food. A consensus definition of the term probiotics, based on available information and scientific evidence, was adopted after the aforementioned joint expert consultation between the FAO of the United Nations and the WHO. This effort was accompanied by local governmental and supra-governmental regulatory bodies' requirements to better characterize health claims substantiations.

That first global effort was further developed in 2010; two expert groups of academic scientists and industry representatives made recommendations for the evaluation and validation of probiotic health claims. The same principles emerged from those two groups as were expressed in the "Guidelines" of FAO/WHO in 2002. This definition, though widely adopted, is not acceptable to the European Food Safety Authority (EFSA) because it embeds a health claim that is not measurable.

A group of scientific experts assembled in London on October 23, 2013, to discuss the scope and appropriate use of the term probiotic. That meeting was motivated by developments in the field that followed the formation of the 2001 definition, and the panel's conclusions were published in June 2014.

Probiotics in food

Live probiotic cultures are part of fermented dairy products, other fermented foods, and probiotic-fortified foods.

Some fermented products that contain lactic acid bacteria (LAB) include: vegetables such as pickled vegetables, kimchi, pao cai, and sauerkraut; soy products such as tempeh, miso, and soy sauce; and dairy products such as yogurt, kefir, and buttermilk.

Side effects

The manipulation of the gut microbiota is complex and may cause bacteria-host interactions. Though probiotics are considered safe, some have concerns about their safety in certain cases. Some people, such as those with immunodeficiency, short bowel syndrome, central venous catheters, cardiac valve disease and premature infants, may be at higher risk for adverse events. In severely ill people with inflammatory bowel disease there is a risk of the passage of viable bacteria from the gastrointestinal tract to the internal organs (bacterial translocation) as a consequence of bacteremia, which can cause adverse health consequences. Rarely, consumption of probiotics by children with lowered immune system function or who are already critically ill may result in bacteremia or fungemia (i.e., bacteria or fungi in the blood), which can lead to sepsis, a potentially fatal disease.

It has been suggested that Lactobacillus contributes to obesity in humans, but no evidence of this relationship has been found.

Global consumption

In 2015, the global retail market value for probiotics was US$41 billion, including sales of probiotic supplements, fermented milk products, and yogurt, which alone accounted for 75% of total consumption. Innovation in probiotic products in 2015 was mainly from supplements, which produced US$4 billion and was projected to grow 37% globally by 2020. Consumption of yogurt products in China has increased by 20% per year since 2014.

Regulation

The European Food Safety Authority has rejected all petitions by commercial manufacturers for health claims on probiotic products in Europe due to insufficient research, and thus inconclusive proof of effectiveness. Occurring over many years, the scientific reviews established that a cause-and-effect relationship had not been sufficiently proven in the products submitted. The European Commission placed a ban on putting the word "probiotic" on the packaging of products because such labeling misleads consumers to believe a health benefit is provided by the product when no scientific proof exists to demonstrate that health effect.

In the United States, the FDA and Federal Trade Commission have issued warning letters and imposed punishment on various manufacturers of probiotic products whose labels claim to treat a disease or condition. Food product labeling requires language approval by the Food and Drug Administration, so probiotic manufacturers have received warning letters for making disease or treatment claims. The Federal Trade Commission has taken punitive actions, including a US$21 million fine coordinated by 39 different state governments against a major probiotic manufacturer for deceptive advertising and exaggerated claims of health benefits for a yogurt and probiotic dairy drink.

Yogurt labeling

The National Yogurt Association (NYA) of the United States gives a Live & Active Cultures Seal to refrigerated yogurt products that contain 100 million cultures per gram, or frozen yogurt products that contain 10 million cultures per gram at the time of manufacture. In 2002, the US Food and Drug Administration (FDA) and World Health Organization recommended that “the minimum viable numbers of each probiotic strain at the end of the shelf-life” be reported on labeling, but most companies that give a number report the viable cell count at the date of manufacture, a number that could be much higher what exists at consumption. Because of the variability in storage conditions and time before eating, it is difficult to tell exactly how many or how much active culture remains at the time of consumption.

History

Probiotics have received renewed attention in the 21st century from product manufacturers, research studies, and consumers. The history of probiotics can be traced to the first use of cheese and fermented products, that were well known to the Greeks and Romans who recommended their consumption. The fermentation of dairy foods represents one of the oldest techniques for food preservation.

Élie Metchnikoff first suggested the possibility of colonizing the gut with beneficial bacteria in the early 20th century.

The original modern hypothesis of the positive role played by certain bacteria was first introduced by Russian scientist and Nobel laureate Élie Metchnikoff, who in 1907 suggested that it would be possible to modify the gut microbiota and to replace harmful microbes with useful microbes. Metchnikoff, at that time a professor at the Pasteur Institute in Paris, proposed the hypothesis that the aging process results from the activity of putrefactive (proteolytic) microbes producing toxic substances in the large bowel. Proteolytic bacteria such as clostridia, which are part of the normal gut microbiota, produce toxic substances including phenols, indols, and ammonia from the digestion of proteins. According to Metchnikoff, these compounds were responsible for what he called intestinal autointoxication, which would cause the physical changes associated with old age.

It was at that time known that milk fermented with lactic-acid bacteria inhibits the growth of proteolytic bacteria because of the low pH produced by the fermentation of lactose. Metchnikoff had also observed that certain rural populations in Europe, for example in Bulgaria and the Russian steppes, who lived largely on milk fermented by lactic-acid bacteria were exceptionally long lived. Based on these observations, Metchnikoff proposed that consumption of fermented milk would "seed" the intestine with harmless lactic-acid bacteria and decrease the intestinal pH, and that this would suppress the growth of proteolytic bacteria. Metchnikoff himself introduced in his diet sour milk fermented with the bacteria he called "Bulgarian Bacillus" and believed his health benefited. Friends in Paris soon followed his example and physicians began prescribing the sour-milk diet for their patients.

Bifidobacteria were first isolated from a breast-fed infant by Henry Tissier, who also worked at the Pasteur Institute. The isolated bacterium named Bacillus bifidus communis was later renamed to the genus Bifidobacterium. Tissier found that bifidobacteria are dominant in the gut microbiota of breast-fed babies and he observed clinical benefits from treating diarrhea in infants with bifidobacteria.
During an outbreak of shigellosis in 1917, German professor Alfred Nissle isolated a strain of Escherichia coli from the feces of a soldier who was not affected by the disease. Methods of treating infectious diseases were needed at that time when antibiotics were not yet available, and Nissle used the E. coli Nissle 1917 strain in acute gastrointestinal infectious salmonellosis and shigellosis.

In 1920, Rettger and Cheplin reported that Metchnikoff's "Bulgarian Bacillus", later called Lactobacillus delbrueckii subsp. bulgaricus, could not live in the human intestine. They conducted experiments involving rats and humans volunteers, feeding them with Lactobacillus acidophilus. They observed changes in composition of fecal microbiota, which they described as "transformation of the intestinal flora". Rettger further explored the possibilities of L. acidophilus, and reasoned that bacteria originating from the gut were more likely to produce the desired effect in this environment. In 1935 certain strains of L. acidophilus were found very active when implanted in the human digestive tract. Trials were carried out using this organism, and encouraging results were obtained, especially in the relief of chronic constipation.

Contrasting antibiotics, probiotics were defined as microbially derived factors that stimulate the growth of other microorganisms. In 1989 Roy Fuller suggested a definition of probiotics that has been widely used: "A live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance." Fuller's definition emphasizes the requirement of viability for probiotics and introduces the aspect of a beneficial effect on the host.

The term "probiotic" originally referred to microorganisms that have effects on other microorganisms. The conception of probiotics involved the notion that substances secreted by one microorganism stimulated the growth of another microorganism. The term was used again to describe tissue extracts that stimulated microbial growth. The term probiotics was taken up by Parker, who defined the concept as, "Organisms and substances that have a beneficial effect on the host animal by contributing to its intestinal microbial balance." Later, the definition was greatly improved by Fuller, whose explanation was very close to the definition used today. Fuller described probiotics as a "live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance." He stressed two important claims for probiotics: the viable nature of probiotics and the capacity to help with intestinal balance.

In the following decades, intestinal lactic acid bacterial species with alleged health beneficial properties were introduced as probiotics, including Lactobacillus rhamnosus, Lactobacillus casei, and Lactobacillus johnsonii.

Etymology

Some literature gives the word a full Greek etymology, but it appears to be a composite of the Latin preposition pro, meaning 'for', and the Greek adjective βιωτικός (biōtikos), meaning 'fit for life, lively', the latter deriving from the noun βίος (bios), meaning 'life'. The term contrasts etymologically with the term antibiotic, although it is not a complete antonym. The term probiotic comes from the Latin pro, meaning 'supporting', and refers to a substance that is not digested but "promotes the growth of beneficial intestinal microorganisms".

Research

As food products or dietary supplements, probiotics are under preliminary research to evaluate if they provide any effect on health. In all cases proposed as health claims to the European Food Safety Authority, the scientific evidence remains insufficient to prove a cause-and-effect relationship between consumption of probiotic products and any health benefit. There is no scientific basis for extrapolating an effect from a tested strain to an untested strain. Improved health through gut flora modulation appears to be directly related to long-term dietary changes. According to the National Center for Complementary and Integrative Health: "Although some probiotics have shown promise in research studies, strong scientific evidence to support specific uses of probiotics for most health conditions is lacking."

Claims that some lactobacilli may contribute to weight gain in some humans remain controversial.

Allergies

Probiotics are ineffective in preventing allergies in children, with the possible exception of eczema.

Antibiotic-associated diarrhea

Antibiotics are a common treatment for children, with 11% to 40% of antibiotic-treated children developing diarrhea. Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotic therapy. These microbial community alterations result in changes in carbohydrate metabolism, with decreased short-chain fatty acid absorption and osmotic diarrhea as a result. A 2015 Cochrane review concluded that a protective effect of some probiotics existed for AAD in children. In adults, some probiotics showed a beneficial role in reducing the occurrence of AAD and treating Clostridium difficile disease.

Probiotic treatment might reduce the incidence and severity of AAD as indicated in several meta-analyses. For example, treatment with probiotic formulations including L. rhamnosus may reduce the risk of AAD, improve stool consistency during antibiotic therapy, and enhance the immune response after vaccination.

The potential efficacy of probiotics to treat AAD depends on the probiotic strains and dosage. One review recommended for children L. rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony forming units/day, given the modest number needed to treat and the likelihood that adverse events are very rare. The same review stated that probiotic use should be avoided in pediatric populations at risk for adverse events, such as severely debilitated or immune-compromised children.

Bacterial vaginosis

Probiotic treatment of bacterial vaginosis is the application or ingestion of bacterial species found in the healthy vagina to cure the infection of bacteria causing bacterial vaginosis. This treatment is based on the observation that 70% of healthy females have a group of bacteria in the genus Lactobacillus that dominate the population of organisms in the vagina. Currently, the success of such treatment has been mixed since the use of probiotics to restore healthy populations of Lactobacillus has not been standardized. Often, standard antibiotic treatment is used at the same time that probiotics are being tested. In addition, some groups of women respond to treatment based upon ethnicity, age, number of sexual partners, pregnancy, and the pathogens causing bacterial vaginosis. In 2013 researchers found that administration of hydrogen peroxide producing strains, such as L. acidophilus and L. rhamnosus, were able to normalize vaginal pH and rebalance the vaginal microbiota, preventing and alleviating bacterial vaginosis.

Blood pressure

The consumption of probiotics may modestly help to control high blood pressure.

Cholesterol

Preliminary human and animal studies have demonstrated the efficacy of some strains of lactic acid bacteria (LAB) for reducing serum cholesterol levels, presumably by breaking down bile in the gut, thus inhibiting its reabsorption (where it enters the blood as cholesterol).

A meta-analysis that included five double-blind trials examining the short-term (2–8 weeks) effects of a yogurt with probiotic strains on serum cholesterol levels found a minor change of 8.5 mg/dL (0.22 mmol/L) (4% decrease) in total cholesterol concentration, and a decrease of 7.7 mg/dL (0.2 mmol/L) (5% decrease) in serum LDL concentration.

Diarrhea

Some probiotics are suggested as a possible treatment for various forms of gastroenteritis, and a Cochrane Collaboration meta-analysis on the use of probiotics to treat acute infectious diarrhea based on a comprehensive review of medical literature through 2010 (35 relevant studies, >4500 participants) reported that use of any of the various tested probiotic formulations appeared to reduce the duration of diarrhea by a mean of 25 hours (vs. control groups, 95% confidence interval, 16–34 hours), also noting, however, that "the differences between the studies may be related to other unmeasured and unexplored environmental and host factors" and that further research was needed to confirm reported benefits.

Eczema

Probiotics are commonly given to breast-feeding mothers and their young children to prevent eczema, but some doubt exists over the strength of evidence supporting this effect.

Helicobacter pylori

Some strains of lactic acid bacteria may affect Helicobacter pylori infections (which may cause peptic ulcers) in adults when used in combination with standard medical treatments, but no standard in medical practice or regulatory approval exists for such treatment.

Immune function and infections

Some strains of lactic acid bacteria (LAB) may affect pathogens by means of competitive inhibition (i.e., by competing for growth) and some evidence suggests they may improve immune function by increasing the number of IgA-producing plasma cells and increasing or improving phagocytosis, as well as increasing the proportion of T lymphocytes and natural killer cells. LAB products might aid in the treatment of acute diarrhea, and possibly affect rotavirus infections in children and travelers' diarrhea in adults, but no products are approved for such indications. A large study demonstrated that probiotics may decrease dental caries in children. Two reviews reported reduction of the incidence of respiratory-tract infections in adults.

Probiotics do not appear to change the risk of infection in older people.

Inflammatory bowel disease

Probiotics are being studied for their potential to influence inflammatory bowel disease. There is some evidence to support their use in conjunction with standard medications in treating ulcerative colitis and no evidence of their efficacy in treating Crohn's disease.

A live formulation of lyophilized Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus, and Streptococcus thermophilus (VSL#3) has shown effectiveness in the small clinical trials, some of which were not randomized nor double-blinded, that had been done as of 2015; more high-quality clinical trials are needed to determine safety and effectiveness.

Irritable bowel syndrome

Probiotics are under study for their potential to affect irritable bowel syndrome, although uncertainty remains around which type of probiotic works best, and around the size of possible effect.

Lactose intolerance

Ingestion of certain active strains may help lactose-intolerant individuals tolerate more lactose than they would otherwise have tolerated.

Necrotizing enterocolitis

Several clinical studies provide evidence for the potential of probiotics to lower the risk of necrotizing enterocolitis and mortality in premature infants. One meta-analysis indicated that probiotics reduce these risks by more than 50% compared with controls.

Recurrent abdominal pain

A 2017 review based on moderate to low-quality evidences suggests that probiotics may be helpful in relieving pain in the short term in children with recurrent abdominal pain, but the proper strain and dosage are not known.

Urinary tract

There is no good evidence that probiotics are of benefit in the management of infection or inflammation of the urinary tract.

General research

Formulations

Supplements such as tablets, capsules, powders, and sachets containing the bacteria have been studied. However, probiotics taken orally can be destroyed by the acidic conditions of the stomach. As of 2010, a number of microencapsulation techniques were being developed to address this problem.

Multiple probiotics

Preliminary research is evaluating the potential physiological effects of multiple probiotic strains, as opposed to a single strain. As the human gut may contain several hundred microbial species, one theory indicates that this diverse environment may benefit from consuming multiple probiotic strains, an effect that remains scientifically unconfirmed.

Strains

There is only preliminary evidence for most probiotic health claims. Even for the most studied probiotic strains, few have been sufficiently developed in basic and clinical research to warrant approval for health claim status by a regulatory agency such as the Food and Drug Administration or European Food Safety Authority, and, as of 2010, no claims had been approved by those two agencies. Some experts are skeptical about the efficacy of different probiotic strains and believe that not all subjects benefit from probiotics.

Scientific guidelines for testing

First, probiotics must be alive when administered. One of the concerns throughout the scientific literature resides in the viability and reproducibility on a large scale of observed results for specific studies, as well as the viability and stability during use and storage, and finally the ability to survive in stomach acids and then in the intestinal ecosystem.

Secondly, probiotics must have undergone controlled evaluation to document health benefits in the target host. Only products that contain live organisms shown in reproducible human studies to confer a health benefit can actually claim to be probiotic. The correct definition of health benefit, backed with solid scientific evidence, is a strong element for the proper identification and assessment of the effect of a probiotic. This aspect represents a major challenge for scientific and industrial investigations because several difficulties arise, such as variability in the site for probiotic use (oral, vaginal, intestinal) and mode of application.

Thirdly, the probiotic candidate must be a taxonomically defined microbe or combination of microbes (genus, species, and strain level). It is commonly admitted that most effects of probiotics are strain-specific and cannot be extended to other probiotics of the same genus or species. This calls for a precise identification of the strain, i.e. genotypic and phenotypic characterization of the tested microorganism.

Fourthly, probiotics must be safe for their intended use. The 2002 FAO/WHO guidelines recommend that, though bacteria may be generally recognized as safe (GRAS), the safety of the potential probiotic should be assessed by the minimum required tests:

• Determination of antibiotic resistance patterns
• Assessment of certain metabolic activities (e.g. D-lactate production, bile salt deconjugation)
• Assessment of side effects during human studies
• Epidemiological surveillance of adverse incidents in consumers (after market)
• If the strain under evaluation belongs to a species that is a known mammalian toxin producer, it must be tested for toxin production. One possible scheme for testing toxin production has been recommended by the EU Scientific Committee on Animal Nutrition.
• If the strain under evaluation belongs to a species with known hemolytic potential, determination of hemolytic activity is required.

In Europe, the EFSA has adopted a premarket system for safety assessment of microbial species used in food and feed productions to set priorities for the need of risk assessment. The assessment is made for a selected group of microorganisms, which if favorable, leads to a “Qualified Presumption of Safety” status.

Fifthly and finally, probiotics must be supplied in adequate numbers, which may be defined as the number able to trigger the targeted effect on the host. It depends on strain specificity, process, and matrix, as well as the targeted effect. Most of the reported benefits demonstrated with the traditional probiotics have been observed after ingestion of a concentration around 10⁷ to 10⁸ probiotic cells per gram, with a serving size around 100 to 200 mg per day.