The Functional Medicine Approach to COVID-19: Nutrition and Lifestyle Practices for Strengthening Host Defense.

The developing symptoms of COVID-19, as well as the progression of illness and fatality, are a clearly a function of the overall health status of the individual. Complex, chronic diseases such as obesity, hypertension, and diabetes are directly correlated with risk of disease severity and mortality. We explore lifestyle interventions that have specifically been demonstrated to strengthen host defense, reduce the probability and mitigate the severity of viral infection. Lifestyle interventions, from a Functional Medicine perspective, include nutrition, sleep, exercise, stress reduction, and connection. These factors, when in balance, provide a foundation for optimal health and immune function.

A Systems Medicine Approach: Translating Emerging Science into Individualized Wellness.

In today's aging society, more people are living with lifestyle-related noncommunicable diseases (NCDs) such as cardiovascular disease, type 2 diabetes, obesity, and cancer. Numerous opinion-leader organizations recommend lifestyle medicine as the first-line approach in NCD prevention and treatment. However, there is a strong need for a personalized approach as "one-size-fits-all" public health recommendations have been insufficient in addressing the interindividual differences in the diverse populations. Advancement in systems biology and the "omics" technologies has allowed comprehensive analysis of how complex biological systems are impacted upon external perturbations (e.g., nutrition and exercise), and therefore is gradually pushing personalized lifestyle medicine toward reality. Clinicians and healthcare practitioners have a unique opportunity in advocating lifestyle medicine because patients see them as a reliable source of advice. However, there are still numerous technical and logistic challenges to overcome before personal "big data" can be translated into actionable and clinically relevant solutions. Clinicians are also facing various issues prior to bringing personalized lifestyle medicine to their practice. Nevertheless, emerging ground-breaking research projects have given us a glimpse of how systems thinking and computational methods may lead to personalized health advice. It is important that all stakeholders work together to create the needed paradigm shift in healthcare before the rising epidemic of NCDs overwhelm the society, the economy, and the dated health system.

Intestinal absorption and postabsorptive metabolism of linoleic acid in rats with short-term bile duct ligation.

We investigated in bile duct-ligated (BDL) and sham-operated control rats whether the frequent presence of essential fatty acid deficiency in cholestatic liver disease could be related to linoleic acid malabsorption, altered linoleic acid metabolism, or both. In plasma of BDL rats, the triene-to-tetraene ratio, a biochemical marker for essential fatty acid deficiency, was increased compared with controls (0.024 +/- 0.004 vs. 0.013 +/- 0.001; P < 0.05). Net and percentage of dietary linoleic acid absorbed were decreased in BDL rats compared with control rats (1.50 +/- 0.16 mmol/day and 81.3 +/- 3.3% vs. 2.08 +/- 0.07 mmol/day and 99.2 +/- 0.1%, respectively; each P < 0.001). At 24 h after [(13)C]linoleic acid administration, BDL rats had a similar ratio of plasma [(13)C]arachidonic acid to plasma [(13)C]linoleic acid concentration compared with control rats. Delta(6)-Desaturase activity was not significantly different in hepatic microsomes from control or BDL rats. At 3 h after [(13)C]linoleic acid administration, plasma appearance of [(13)C]linoleic acid and cumulative expiration of (13)CO(2) were decreased in BDL rats, compared with controls (by 54% and 80%, respectively). The present data indicate that the impaired linoleic acid status in cholestatic liver disease is mainly due to decreased net absorption and not to quantitative alterations in postabsorptive metabolism.

Detection of impaired intestinal absorption of long-chain fatty acids: validation studies of a novel test in a rat model of fat malabsorption.

BACKGROUND: Classic fat balance studies detect fat malabsorption but do not discriminate between the potential causes of malabsorption, such as impaired intestinal lipolysis or reduced uptake of fatty acids. OBJECTIVE: We aimed to validate a novel test for the specific, sensitive detection of impaired intestinal uptake of long-chain unesterified fatty acids in an appropriate rat model of fat malabsorption. DESIGN: The absorption and appearance in plasma of [(13)C]palmitic acid were determined in control rats and in rats with fat malabsorption due either to chronic bile deficiency (permanent bile diversion) or to oral administration of the lipase inhibitor orlistat (200 mg/kg diet). [(13)C]Palmitic acid results were compared with the percentage absorption of ingested dietary fat determined by fat balance. RESULTS: Between 1 and 6 h after intraduodenal administration, plasma [(13)C]palmitate concentrations in control rats were 4-10-fold higher than in bile-deficient rats (P < 0.05) but were not significantly different between orlistat-supplemented rats and their controls. In control and bile-deficient rats, plasma [(13)C]palmitate concentrations allowed complete discrimination between normal (>92%) and reduced (<92%) fat absorption, whereas the percentage absorption of [(13)C]palmitate over 48 h appeared to be highly correlated with the percentage absorption of ingested dietary fat (r = 0.89, P < 0.001). CONCLUSIONS: The [(13)C]palmitic acid absorption test detects impaired intestinal absorption of long-chain fatty acids selectively and sensitively in a rat model of fat malabsorption due to bile deficiency. Our data strongly support the use of the [(13)C]palmitic acid absorption test for the diagnosis of clinical fat malabsorption syndromes.

Postprandial chylomicron formation and fat absorption in multidrug resistance gene 2 P-glycoprotein-deficient mice.

BACKGROUND & AIMS: It has been proposed that biliary phospholipids fulfill specific functions in the absorption of dietary fat from the intestine, but the physiological significance has not been established. The aim of this study was to evaluate the role of biliary phospholipids in dietary fat absorption in vivo by using mice homozygous or heterozygous for disruption of the Mdr2 gene (Mdr2((-/-)), Mdr2((+/-))) and control (Mdr2((+/+))) mice. Mdr2((-/-)) mice do not secrete phospholipids and cholesterol into bile, and bile salt secretion is not impaired. Mdr2((+/-)) mice show only impaired (-40%) phospholipid secretion. METHODS: Methods included an analysis of time dependency of intestinal uptake and plasma appearance of intragastrically administered (radiolabeled) triglycerides and measurement of 3-day fecal fat balance with low- and high-fat diets. RESULTS: Intragastric administration of olive oil resulted in a rapid increase in plasma triglycerides in Mdr2((+/+)) and Mdr2((+/-)) but not in Mdr2((-/-)) mice. The "postprandial response" of plasma triglycerides could be partially restored in Mdr2((-/-)) mice by intraduodenal infusion of whole rat bile. After intragastric [(3)H]triolein administration in Triton WR1339-pretreated animals, the appearance of (3)H-triglycerides in plasma was reduced by 70% in Mdr2((-/-)) compared with Mdr2((+/+)) mice, excluding accelerated lipolysis as the cause of defective triglyceride response in Mdr2((-/-)) mice. (3)H-triglycerides accumulated in enterocytes in Mdr2((-/-)) mice. Surprisingly, the efficacy of fat absorption as derived from balance studies was not affected and was only minimally affected in Mdr2((-/-)) mice fed low (14 energy percent)- and high (35 energy percent)-fat diets, respectively (all >95%). CONCLUSIONS: The results show that biliary lipid secretion is necessary for postprandial appearance in plasma of chylomicrons in vivo but not for quantitative absorption of dietary lipids.

Biliary phospholipid secretion is not required for intestinal absorption and plasma status of linoleic acid in mice.

Biliary phospholipids have been hypothesized to be important for essential fatty acid homeostasis. We tested this hypothesis by investigating the intestinal absorption and the status of linoleic acid in mdr2 Pgp-deficient mice which secrete phospholipid-free bile. In mice homozygous (-/-) for disruption of the mdr2 gene and wild-type (+/+) mice, dietary linoleic acid absorption was determined by 72 h balance techniques. After enteral administration, [(13)C]-linoleic acid absorption was determined by measuring [(13)C]-linoleic acid concentrations in feces and in plasma. The status of linoleic acid was determined in plasma and in liver by calculating the molar percentage of linoleic acid and the triene:tetraene ratio. Although plasma concentration of [(13)C]-linoleic acid at 2 h after enteral administration was significantly lower in (-/-) compared to (+/+) mice (P

Bile diversion in rats leads to a decreased plasma concentration of linoleic acid which is not due to decreased net intestinal absorption of dietary linoleic acid.

Decreased bile secretion into the intestine has been associated with low plasma concentrations of essential fatty acids (EFA) in humans. We studied the mechanism behind this relationship by determining the status and absorption of the major dietary EFA, linoleic acid (LA), in control and 1-week bile-diverted rats. The absorption of LA was quantified by a balance method and by measuring plasma concentrations of [13C]LA after its intraduodenal administration. Absolute and relative concentrations of LA in plasma were decreased in bile-diverted rats (P<0.01 and P<0.001, respectively). Fecal excretion of LA was increased at least 20-fold in bile-diverted rats (0.72+/-0.11 vs. 0.03+/-0.00 mmol/day; P<0.0001). Due to increased chow ingestion by bile-diverted rats, net intestinal absorption of LA was similar between bile-diverted and control rats (1.96+/-0.14 vs. 1.91+/-0.07 mmol/day, respectively; P>0.05). After intraduodenal administration of [13C]LA, plasma concentrations were approximately 3-4-fold lower in bile-diverted rats for at least 6 h (P<0.001). Plasma concentrations of both [12C]arachidonic acid and [13C]arachidonic acid were increased in bile-diverted rats (P<0.05). We conclude that decreased plasma concentrations of LA in 1-week bile-diverted rats are not due to decreased net intestinal absorption of LA, but may be related to increased metabolism of LA.

Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids.

BACKGROUND: Pancreatic enzyme replacement therapy frequently fails to correct intestinal fat malabsorption completely in cystic fibrosis (CF) patients. The reason for this failure is unknown. OBJECTIVE: We investigated whether fat malabsorption in CF patients treated with pancreatic enzymes is caused by insufficient lipolysis of triacylglycerols or by defective intestinal uptake of long-chain fatty acids. DESIGN: Lipolysis was determined on the basis of breath 13CO2 recovery in 10 CF patients receiving pancreatic enzyme replacement therapy after they ingested 1.3-distearoyl,2[1-13C]octanoyl glycerol ([13C]MTG). Intestinal uptake of long-chain fatty acids was determined by analyzing plasma [13C]linoleic acid ([13C]LA) concentrations after patients ingested [13C]LA. For 3 d, dietary intakes were recorded and feces were collected. RESULTS: Fecal fat excretion ranged from 5.1 to 27.8 g/d (mean+/-SD: 11.1+/-7.0 g/d) and fat absorption ranged from 79% to 93% (89+/-5%). There was no relation between breath 13CO2 recovery and dietary fat absorption (r = 0.04) after ingestion of [13C]MTG. In contrast, there was a strong relation between 8-h plasma [13C]LA concentrations and dietary fat absorption (r = 0.88, P < 0.001). CONCLUSION: Our results suggest that continuing fat malabsorption in CF patients receiving enzyme replacement therapy is not likely due to insufficient lipolytic enzyme activity, but rather to incomplete intraluminal solubilization of long-chain fatty acids, reduced mucosal uptake of long-chain fatty acids, or both.

Intestinal absorption of essential fatty acids under physiological and essential fatty acid-deficient conditions.

The adequate supply of essential fatty acids (EFA) to the body depends upon sufficient dietary intake and subsequent efficient intestinal absorption. Lipid malabsorption is not only a leading cause of EFA deficiency (EFAD), but also occurs secondarily to EFAD. Understanding the relationship between EFAD and lipid malabsorption may be helpful in the development and optimization of oral treatment strategies. Sequential steps involved in EFA absorption, including lipolysis, solubilization by bile, uptake into the enterocyte, and chylomicron secretion into lymph are reviewed, both under physiological and EFAD conditions. EFAD in itself affects the deficiency state by impairment of EFA absorption due to its effects on bile formation and on chylomicron secretion. These processes may be interrelated as decreased phosphatidylcholine secretion into the bile (a consequence of EFAD) is known to result in decreased chylomicron assembly and secretion. Possible treatments of EFAD include increasing dietary amounts of triacylglycerols and/or specifically tailoring lipids (structured triacylglycerols, EFA-rich phosphatidylcholines, EFA-ethyl esters). It is forseen that insights into the relationship between lipid malabsorption and EFAD will refine rational approaches to prevent and treat EFAD in specific patient groups.

The metabolic importance of unabsorbed dietary lipids in the colon.

Digestion and absorption of lipids is a highly efficient process. From Western diets about 95% will be absorbed. This implies that together with lipids from endogenous sources 6-8 g of lipids will enter the colon daily. This input significantly increases during various lipid malabsorption syndromes. It has long been assumed that the biological fate of unabsorbed lipids is physiologically not relevant. However, significant microbial lipid metabolism occurs. Circumstantial evidence is arising which supports a role of unabsorbed lipid metabolites in the development of colonic diseases. Lipid metabolites may act as detergents in the colon, leading to mucosal injury and reactive hyperproliferation, which in its turn could promote tumour development. Lipid metabolites could also be transformed in biological active metabolites, which have a tumour promoting potency. More mechanistic information is needed on the colonic metabolic fate of lipids in order to develop strategies for manipulating colonic flora in the prevention of lipid related colonic diseases.