Diet, the Intestinal Microbiota and the PHM Hypothesis
There is an increasing appreciation of the role of diet in shaping the
gut microbiota. Many dietary factors have been implicated in
inflammation-related diseases[3]. However, it is proposed here that
PHMs could be an important factor contributing to the effects of
different diets. PHMs in food/beverages might explain the benefits
achieved from apparently contradictory dietary approaches (e.g., low fat
vs low carbohydrate approaches), as will be discussed below.
Evidence supporting the connection between the adoption of a more
westernized diet and CIDs have come from studies in developing
countries[10,192–195]. The asthma rate in a study in India, for
example, was associated with greater consumption of sodas and
sweets[196].
In inflammatory bowel disease research, some promising interventions
involve avoidance of many components of a typical westernized diet. A
recent review found that most environmental factors were only associated
with IBD in certain ethnic groups or countries; however, a westernized
diet was found to be the most ubiquitous environmental factor associated
with IBD incidence[11]. The same group proposed a plant-based diet
approach [197], finding patients that used this approach had a much
lower rate of recurrence after remission.
A Crohn’s disease exclusion diet has been developed that essentially
eliminates gluten, dairy, soy, animal fats, processed meats,
emulsifiers, canned and packaged products, coffee, chocolate and
alcohol[198]. A recent randomized controlled trial[199] found
that this diet combined with partial enteral nutrition was significantly
more effective than exclusive enteral nutrition in Crohn’s disease.
The PHM hypothesis predicts that foods that are consumed a long time
after harvest, food additives, animal products, ultra-processed foods
and fatty foods contain more PHMs. The fermentation of foods and
beverages like alcohol, chocolate, coffee and tea, would give more
opportunity for at least some PHMs to increase, which could be a problem
for some individuals. Food additives and ultra-processed foods provide
conditions for microbes during their processing that are different from
less processed foods. The resulting differences in selective pressures
could lead to increases in PHMs.
Animal agriculture could promote PHM colonization of animals in a manner
analogous to how humans are proposed to be colonized. And since animals
provide an environment similar to human tissue, animals potentially
could contain more PHMs that could colonize humans.
Conventionally-raised farm animals, living an animal version of a
westernized lifestyle, would potentially be even more colonized with
polyextremotolerant PHMs that could affect humans. This has been studied
most extensively in the case of antibiotic resistant microbes that
humans acquire from animal products due to the use of antibiotics in
agriculture[200]. This research supports the idea that modern
agricultural practices are shaping animal microbiotas in a way that
impacts human health.
Vegan or vegetarian diets have been observed to be beneficial in
asthma[201] and rheumatic disease[202,203]. Reduced levels of
animal products are found in the Mediterranean diet, which appears to
have beneficial effects in many diseases[204]. A healthy and long
life span in particular societies consuming low levels of animal
products has also been described[205].
Another food component that might contain more PHMs is fat from animals
and plants. Fats might provide a particularly favorable environment for
microbes adapted to petroleum products. The utilization of hydrocarbons
associated with fossil fuels has been suggested to be linked to
lipophilic and neurotropic tendencies in some polyextremotolerant black
yeast[206]. Bacteria have recently been found in human adipose
tissue, with bacterial abundance associated with inflammatory
parameters[207–209]. It would be interesting to determine if some
of these bacteria are associated with petroleum products or ingested
sources of fats.
There is evidence that a low fat diet is beneficial in heart
disease[210,211] and possibly multiple sclerosis[212,213]. It is
possible that ingested fat and especially animal fat, could contain PHMs
that contribute to disease in humans.
Benefits from avoiding gluten, as recommended by diets like the
above-mentioned diet for Crohn’s disease, could be related to
hypersensitivity to gluten. However, gluten has the potential to
increase intestinal permeability, even in those without celiac
disease[214,215], and may be a problem for that reason as well.
This, and other factors that increase intestinal
permeability[215,216], could facilitate PHM colonization.
Obesity has been linked to a westernized diet[217]. Obesity is also
associated with inflammation and CIDs, such as asthma[218], allergic
rhinitis[219], chronic rhinosinusitis[220] and several
autoimmune diseases[221,222].
Low-fat diets and low-carbohydrate diets have demonstrated essentially
equal success in reversing obesity[223]. A randomized controlled
study comparing low-fat to low-carbohydrate diets found each diet was
successful in a subset of study participants[224]. Analysis of
genetic markers and baseline insulin secretion levels revealed no
predictive relationships. The PHM hypothesis suggests that success in
weight loss on a particular diet might stem from individual differences
in colonizing PHMs.
Individuality was also evident in a study using continuous blood sugar
monitoring since participants differed in the foods that caused the
highest blood sugar increases [225]. The differences in blood sugar
responses appeared to be at least partly related to features of the
intestinal microbiota. According to the PHM hypothesis, the observed
microbiota patterns could be related, directly or indirectly, to PHM
colonization related effects.
Stress is known to increase blood sugar[226]. Thus, a blood sugar
increase in response to a food might result from a stress response to
PHM-related allergens in the food. It should also be noted that air
pollution has also been linked to blood sugar elevation[227] and
type 2 diabetes mellitus incidence[228,229]. According to the PHM
hypothesis, air pollution likely contains PHM.
A recent study by Hall et al[230] showed that inpatient adults given
a diet of ultra-processed food gained more weight than those given
relatively unprocessed food with the same levels of fiber and
macronutrients. The PHM hypothesis proposes that this might be at least
partly due to a higher level of PHMs present in ultra-processed food.
Food cravings can be an important issue in weight loss. It has been
speculated that some intestinal microbes might have an evolutionary
advantage if they cause a craving for foods they use for fuel[231].
The PHM hypothesis suggests that this phenomenon might include a craving
for foods that contain the microbes. In addition, for some people, a
mild stress effect might occur in response to consuming food containing
higher levels of PHMs. This could cause a temporary lift in mood that
could contribute to food craving and overconsumption. Interestingly,
consumption of ultra-processed foods has been linked to food
addiction[232].
Diets that have garnered recent interest include so-called Paleolithic
diets. These diets typically eliminate dairy, grains and legumes and
encourage consumption of fruits, vegetables, nuts, meat and
fish[233].
The autoimmune Paleolithic diet also involves avoidance of certain
proposed inflammatory foods. The foods avoided include gluten, dairy,
legumes, refined sugar, industrial seed oils and nightshade vegetables.
An observational study found an improvement in endoscopic inflammation
and symptoms in patients with IBD who were on this diet[233]. An
approach that included a Paleolithic diet also led to improved
health-related quality-of-life and symptom scores in Hashimoto’s
thyroiditis[234]. A modified Paleolithic diet was associated with
significant improvements in a randomized controlled trial in relapsing
remitting multiple sclerosis[235].
From the PHM hypothesis perspective, the various Paleolithic diet
approaches‘ apparent success in these small initial studies might be due
to reduction of PHMs partly via avoidance of ultra-processed foods.
Encouragement of consumption of fresh fruits and vegetables is also
common in these diets. Presumably, the sooner the food is consumed after
harvesting, the less opportunity for PHMs to increase.
Plant-based or vegan versions of a Paleolithic diet have been
proposed[236]. The previously mentioned findings supporting vegan,
vegetarian, low fat and lower animal product diets would suggest that
these alternative versions of a Paleolithic diet are worth studying.
The role of past PHM colonization should also be considered. If the PHM
hypothesis is correct, the foods/beverages consumed during the majority
of the time prior to illness might contain PHMs that contribute to the
disease. Thus, a diet that differs significantly from the patient’s
previous diet might be most helpful.