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.