Diet, inflammation and the microbiome

A “westernized” diet, including higher animal fat and animal products, increased sugar and ultra-processed foods and overconsumption of calorie-dense, low nutrient and low fiber foods appears to be an important factor in increasing disease rates in many countries around the world[39,40]. Allergic and autoimmune diseases have increased along with the adoption of this diet, but so have cardiovascular diseases, diabetes, obesity and chronic lung diseases[41,42]. This suggests that diet may be playing an important role in these diseases. This is supported by interventional studies in type 2 diabetes mellitus and cardiovascular disease [43,44]. Diet also appears to play a significant role in COPD[45].
Interleukin-6 (IL-6) and C-reactive protein (CRP) are correlated with obesity[46]. CRP has been found to decrease with weight loss independently of the type of diet or weight loss method[47]. Studies have found that the traditional Mediterranean diet, in particular, lowers IL-6, with part of its effect being independent of weight loss[48]. Dietary approaches to stop hypertension (DASH), emphasizes the consumption of low fat, whole foods. The DASH approach has been found to be effective in reversing cardiovascular disease and hypertension[44,49]. Another study showed that a diet with reduced saturated fat and increased fiber, combined with exercise, prevented diabetes in a proportion of patients in a randomized controlled trial of pre-diabetics[50]. Vegetarian or plant-based diets have shown benefit in cardiovascular disease[44] and other inflammatory diseases[51], including inflammatory arthritis[52]. Vegetarian and vegan diets appear to be generally safe, if vitamin B12 is supplemented and adequate attention is paid to other potentially deficient nutrients[53]. Diets that tend to emphasize fruits and vegetables and reduce processed meats and added sugar are associated with better outcomes with regard to lung function in COPD[45]. Typically, these diets cause changes in the microbiota that are beginning to be explored[54]. All tend to increase consumption of fiber, which many studies have found to affect short chain fatty acid production[55] and immune function[5].
Ruminococcus gnavus, a commensal microbe in the intestinal tract, was recently found to be potentially involved in contributing to inflammatory arthritis[56] and inflammatory bowel disease[57]. This may be due to several characteristics, including its ability to degrade mucus, which enhances its translocation across a weakened epithelial barrier. R. gnavus is also increased in those with coronary artery disease[58] and has been found to be decreased by a higher fiber, lower sugar Mediterranean diet[59]. A mutated clade of R. gnavus that tolerates a high-oxygen, pro-inflammatory environment in the intestinal tract has been identified in inflammatory bowel disease[60].
Enterococcus gallinarum, another commensal microbe with pathogenic potential, has been implicated in systemic lupus erythematosus[61]. E. gallinarum can cause disease in a lupus mouse model when the intestinal barrier is weakened, as can happen as a result of dietary factors, certain drugs, hyperglycemia and other factors[62].
There is evidence of a high-fat diet being associated with increases in endotoxin-producing, gram negative Enterobacteriaceae[63]. Endotoxin, as well as the bacteria that produce it, can cross the mucosal barrier of the gut and have systemic inflammatory effects. Lower levels of fiber are thought to increase mucin degrading bacteria that also increase intestinal permeability. Research indicates that this can negatively affect immune function and, therefore, promote respiratory diseases[63].
There is growing support for the view that many of the effects of diet on health arise from the effects of different types of food on the presence of pathogenic species or on the microbial balance in the intestines and elsewhere[12,62,64]. Thus, dietary patterns can lead to inflammation and the overabundance of inflammation-associated microbes, including Enterobacteriaceae or fungal species, such as Candida albicans, that have greater pathogenic potential. It has also been proposed that microbes in food/beverages may have harmful or beneficial effects, and microbes and other substances from ultra-processed foods may be more likely to have harmful effects[12].
The connection between the gut and lungs is increasingly apparent. One example is a study that found Candida albicans overgrowth in the intestinal tract had a negative effect on an inflammatory lung disease[65]. C. albicans may overgrow due to antibiotic use, excessive sugar and refined carbohydrates[66] or low-grade inflammation[67]. Other interactions between the gut and lung microbiotas have been discussed in recent reviews[4,68]
With regard to weight loss interventions, recent evidence from a randomized controlled study of inpatient adults indicates that increased consumption of ultra-processed foods is a key factor that leads to an overconsumption of carbohydrates resulting in weight gain[69]. Whether a diet that focuses on reducing carbohydrates or reducing fat is most beneficial, appears to vary between individuals as a result of still undetermined factors[70]. In fact, recent research using continuous blood sugar monitoring found that the precise foods that will increase blood sugar most, and thus be more likely to cause significant negative metabolic effects, differs among individuals[71,72]. Thus, the best approach to maintaining an optimal weight and blood sugar level may need to be personalized to some degree. However, a common theme in the diet research is the need to favor whole plant foods, particularly fruits and vegetables, and reduce ultra-processed food.
Recent research is showing the benefits of intermittent fasting, time-restricted eating[73] and fasting mimicking diets[74,75]. One benefit of a time-restricted approach appears to be related to it being typically more compatible with human circadian rhythms[76]. This approach may also facilitate reduction of overall caloric intake[73] and may improve sleep[76].
Recently, a carefully-designed diet that restricts overall calories and protein has been developed that is meant to be used for a period of 5 days every few months[77]. This fasting mimicking diet is designed to be easier to follow, yet have most of the benefits of fasting or caloric restriction. Studies suggest that it can increase stem cell production and the beneficial process of autophagy with overall beneficial effects on immune function[78]. There is also evidence that it is beneficial with regard to insulin resistance and diabetes[74] and has positive effects on the microbiota[79].
Besides these benefits and the benefit of weight loss programs in general, there may be other advantages of these types of dietary interventions. Food/beverages from a westernized diet, particularly high levels of high-fat, processed animal products and ultra-processed, high sugar/refined carbohydrate food, could cause imbalances in the microbiome and be a direct or indirect source of increased levels of pro-inflammatory, potentially pathogenic, microbes as discussed above[12]. Thus, dietary interventions that reduce these ultra-processed foods/beverages may help give the immune system a better chance of reducing negative effects of these microbes.
Overall, the various dietary interventions discussed above appear to reduce the tendency of a westernized diet to contribute to insulin resistance, weight gain, microbial imbalances, infections and immune dysregulation. The above research does not determine whether a particular diet will be beneficial for avoiding severe disease from COVID-19, but it does suggest interventions that could help improve and, in some cases, prevent/reverse the diseases that are risk factors for it. Some suggestions for research specific to COVID-19 will be discussed near the end of this article.