Shorts


Jule Klotter

Gut Microbiota in Liver Disease

Gut microorganisms have a direct effect on liver health, according to an article by David A. Brenner and colleagues.1 While chronic alcohol consumption is known to damage the liver, what is less recognized is alcohol’s effect on microbes in the GI tract and how these changes affect the liver. Chronic alcohol consumption boosts intestinal bacterial overgrowth by reducing intestinal antibacterial peptides (particularly Reg 3g) and changes the composition of the gut microbiome. People with cirrhosis have bacterial overgrowth in the small intestine, increased bacteremia, and increased intestinal permeability.

In studies in which mice were given alcohol, Lactobacillus decreased markedly, as did bacterial synthesis of long chain fatty acids, the primary fuel for Lactobacillus. Firmicutes and Bacteroidetes also declined. As the populations of these anti-inflammatory bacteria declined, intestinal inflammation and gut permeability increased, allowing bacterial products to enter portal blood and damage the liver. Alcohol-fed mice that were also given saturated long chain fatty acids showed less steatosis, lower ALT, and decreased oxidative stress, compared to controls. They also had a higher level of Lactobacillus and less intestinal permeability.

When bacterial products, such as lipopolysaccharide (LPS), travel to the liver via portal blood, they activate Toll-like receptors (TLRs) on macrophages, dendritic cells, and other immune cells, instigating innate immune responses. Brenner et al explain, “…different TLRs have been assessed for their roles of liver disease. For each TLR, the presumed ligand is a bacterial product from the gut microbiota. In particular, hepatic stellate cells (HSC) have TLRs 2, 4, and 9. Kupffer cells, the resident macrophage in the liver, have TLRs 2, 3, 4, and 9, and hepatocytes have TLRs 1-9.” LPS from Gram-negative bacteria activate TLR4. CpG DNA from bacteria activate TLR9. Experiments with TLR4 knockout mice (no TLR4 receptors) and TLR9 knockouts have shown that TLR activation sets off a series of reactions that lead to liver inflammation, hepatic steatosis, and fibrosis.           

In addition to dysbiosis and intestinal permeability, some gut microbiota can contribute to phosphatidylcholine deficiency by converting choline to TMA, rendering the choline useable for making phosphatidylcholine. Phosphatidylcholine is needed to prevent lipid accumulation in liver cells. Choline-deficient diets are known to produce non-alcoholic steatohepatitis (NASH). Also, some polymorphisms in the human PEMT gene result in less phosphatidylcholine production and are associated with non-alcoholic fatty liver disease.

Healing the liver cannot occur without addressing gut dysbiosis. As an aside, FDA approved Heplisav®, a hepatitis B vaccine, in November 2017, and the CDC’s Advisory Committee on Immunization Practices (ACIP) panel added the vaccine to its vaccine schedule at its February 2018 meeting (available on YouTube). Heplisav is the first approved vaccine to use the TLR9 agonist 1018 ISS as an adjuvant. Adverse effects in the Heplisav group, occurring within seven days of vaccination, were reportedly similar to adverse effects reported in the “control” group, which received the aluminum-adjuvant hepatitis vaccine Engerix B. A case of autoimmune Wegener’s granulomatosis, two cases of hypothyroidism and one of vitiligo occurred in the Heplisav groups, and no autoimmune diseases were reported in the aluminum-adjuvant groups: “…although due to small numbers and 4:1 randomization ratio this difference was not significant,” Nikolai Petrovsky writes.2 At the ACIP hearing, panel members voiced concern about reports of myocardial infarction in Heplisav recipients. Heplisav is the first approved vaccine in the world to use a TLR agonist as an adjuvant.

Vagus-Nerve Stimulation

Vagus-nerve stimulation (VNS) using an implanted device that emits electrical pulses is an FDA-approved treatment for drug-resistant depression and epilepsy. VNS may also be therapeutic for autoimmune and inflammatory disorders, such as rheumatoid arthritis and Crohn’s disease, in which the inflammatory protein tumor necrosis factor-alpha (TNFα) is a key factor, according to a review by Bruno Bonaz, MD, PhD, and French colleagues.3 Gold standard treatments for these conditions aim to counteract TNFα’s effects. VNS aims to prevent TNFα’s release in the first place.

Bonaz et al say that recent investigations show that the vagus nerve has an anti-inflammatory role in addition to homeostatic regulation of organs. Vagal nerve fibers mediate the cholinergic anti-inflammatory pathway in which acetylcholine is released at synaptic junctions with macrophages. The acetylcholine inhibits macrophage release of  TNFα. Vagal stimulation of the splenic nerve’s anti-inflammatory pathway may be another route by which macrophage release of TNFα decreases.

Yaakov Levine told Nature journalist Douglas Fox that macrophages are unable to produce TNFα for up to 24 hours after being exposed to acetylcholine.4 In animal studies, Levine found that just 250-millionths of an amp—“one-eighth the amount often used to suppress seizures”—is enough vagus-nerve stimulation to reduce inflammation. Levin works for SetPoint Medical, a company founded to develop and market vagus-nerve stimulation as a medical treatment.

The first VNS clinical study for inflammation began in 2011 when 18 people with rheumatoid arthritis agreed to be implanted with stimulators. Twelve of the participants experienced symptom improvement at six weeks. Also, their blood levels of TNFα and inflammatory IL-6 decreased. These improvements disappeared when the device was deactivated for 14 days and returned with VNS (Koopman FA et al. Proc Natl Acad Sci USA. 2016;113:8284-8289).

Raul Coimbra and Todd Costantini at the University of California-San Diego have found evidence that some people are resistant to vagus-nerve stimulation, according to Nature. Humans, unlike other animals, have genome codes for an extra acetylcholine receptor protein: “…if the abnormal receptor is produced in sufficient quantities, it can disrupt signaling and render macrophages unresponsive to acetylcholine. They may then continue releasing TNF-α despite vagal stimulation.”4

Bonaz and colleagues report that non-invasive VNS devices are entering the market. Instead of requiring general anesthesia to implant an electrode around the left vagus nerve in the neck and a bipolar pulse generator subcutaneously in the left chest wall or axilla, new devices use an earphone-like device to stimulate the vagus nerve in the ear; or they transmit proprietary electrical signals through the skin. The Bonaz article also notes ways other than VNS to decrease TNF-α levels via the cholinergic anti-inflammatory pathway: fat nutrition, choline, ghrelin, acupuncture, hypnosis, meditation, and tai chi. Physical activity and exercise stimulate vagal efferent nerve fibers and the cholinergic anti-inflammatory pathway.

Treating Mitochondrial Dysfunction with Natural Supplements           

Mitochondrial dysfunction, resulting in impaired cellular energy production, produces excess fatigue, making the simplest tasks feel onerous. It occurs in aging and in all kinds of chronic diseases: neurodegenerative, cardiovascular, metabolic, autoimmune, gastrointestinal, chronic infections, neurobehavioral, and cancers. Non-genetic, acquired mitochondrial dysfunction responds to treatment with natural supplements, writes Garth L. Nicolson, PhD, in a 2014 article.5 Dr. Nicolson is founder, president, and research professor at the Institute for Molecular Medicine’s department of molecular pathology (Huntington Beach, California).

During the process of creating energy, mitochondria also produce damaging free radicals that cause oxidative damage to cellular and mitochondrial membranes. As a result, function is impaired and inflammation ensues. Nicolson explains that people with chronic fatigue typically show signs of excess oxidative stress in blood tests, including elevated peroxynitrite levels. He considers alpha-lipoic acid, L-carnitine, coenzyme Q10, and phospholipid therapy to be among the “most promising supplements” for improving mitochondrial function and reducing fatigue.

Alpha-lipoic acid is a necessary co-factor for important mitochondrial enzymes. In addition, it helps reduce oxidative stress by stimulating the production of glutathione. Alpha-lipoic acid has the added benefit of being able to remove excess metals associated with hemochromatosis, Parkinson’s, and other chronic diseases. Although α-lipoic acid’s effect on chronic fatigue had not yet been studied in controlled clinical trials (as of 2014), Nicolson said, “…its widespread use as a safe supplement (usually 200-600 mg/d) to support mitochondrial function and reduce oxidative stress has justified its incorporation into various supplement mixtures.”5

L-carnitine transports fatty acids into the mitochondria for oxidation and removes excess acyl groups. It also increases the rate of mitochondrial oxidative phosphorylation, which tends to decline with age. Reduced phosphorylation impairs energy production and increases damaging reactive oxygen species and reactive nitrogen species. Nicolson cites a study in which 70 centenarians who took L-carnitine for six months experienced significant improvement in physical and mental fatigue. They also showed improved cognitive function, increased muscle mass, and better endurance (Malaguarnera M, et al. Am J Clin Nutr. 2007;86(6):1738-1744). Studies involving L-carnitine, most of which have focused on insulin resistance and cardiovascular disease, indicate doses up to 2 grams per day are safe.

Coenzyme Q10 is vital for electron transport along the mitochondrial electron transport chain. It also affects the expression of genes associated with cell signaling and metabolism. Coenzyme Q10 has the added benefit of being a strong antioxidant in its reduced form. Nicolson says, “Clinically, it has been used in doses up to 1200 mg per day, but most studies used lower doses.”5

Lipid replacement therapy provides the molecules needed to replace damaged phospholipids in mitochondrial membranes, thereby improving mitochondrial function. Oral phospholipid supplementation, in doses ranging from 500 to 2000 mg per day, have decreased fatigue in people with Gulf War illness, chronic fatigue syndrome, fibromyalgia as well as fatigue associated with aging.

In addition to the supplements discussed by Nicolson, the pineal hormone melatonin is useful for mitochondrial dysfunction, according to Reza Sharafati-Chaleshtori and colleagues.6 Melatonin helps regulate mitochondrial function. It also stimulates antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase; and it inhibits lipoxygenase, an enzyme that takes part in oxidation of unsaturated fatty acids. The authors say melatonin is an inexpensive, safe medication with mild adverse effects. Drug interactions, however, have occurred with anticoagulants, immunosuppressants, anti-diabetes, and birth control pills.

Acetaminophen-Induced Liver Damage

Acetaminophen (Tylenol (US); paracetamol (Europe)) is widely used for headache and mild pain. While very safe if taken in limited doses, overdose leading to liver damage is common, as William M. Lee explains in his 2017 article.7 About 500 US deaths each year are due to acetaminophen dose-related hepatocellular necrosis. Acetaminophen overdose also is responsible for 50,000 emergency room visits and 10,000 hospitalizations.

People can have a hard time keeping track of dosage because acetaminophen is present in over-the-counter products like Nyquil and in opioid combination medications like Vicodin and Norco. In most cases, patients have ingested 6-10 grams per day for several days to relieve postoperative pain, low back pain, or other painful conditions before experiencing signs of overdose: nausea, vomiting, abdominal pain, and eventually drowsiness. In a 2005 study of patients with acute liver failure 275 of 662 (41.5%) had overdosed on acetaminophen; seven percent of them reported taking less than 4 grams. Lee reports that alcohol, starvation, or other factors that decrease glutathione may account for their increased sensitivity to the drug. “Current package labeling mentions severe liver injury as a possible outcome if one takes more than 4000 mg in 24 h or with other APAP-containing compounds or with alcohol,” Lee writes.7 About two-thirds of patients with acetaminophen-related acute liver failure recover, with or without the recommended antidote, N-acetylcysteine. Patients who receive N-acetylcysteine within 12-18 hours usually avoid severe liver injury.

Because acetaminophen is such a common cause of acute liver failure, Constantine J. Karvellas, MD, and colleagues sought a more reliable means of assessing outcome.8 They conducted a study with 198 patients with acetaminophen-induced acute liver failure and focused on serum liver-type fatty acid binding protein (FABP1), which transports long-chain fatty acids in tissues with active fatty acid metabolism, including liver cells. Patients with liver damage due to alcohol or drug toxicity are known to show elevated levels of FABP1.

In this study, the researchers found that people who survived acetaminophen-associated liver failure had “significantly lower serum FABP1 levels early [day 1] (238.6 vs. 690.8 ng/ml, p<0.0001) and late [day 3-5] (148.4 vs 612.3 ng/ml, p<0.0001) compared with non-survivors.”8 Patients with FABP1 levels greater than 350 ng/ml, either early or late, had a significantly higher risk of death. The authors recommend that FABP1 be studied further as a prognostic tool for acetaminophen-related liver injury.

This column was first published in Townsend Letter, June 2018.

References

  1. Brenner DA, Paik Y-H, Schnabi B. Role of Gut Microbiota in Liver Disease. J Clin Gastroenterol. 2015;49(0 1): S25-S27.
  2. Petrovsky N. Comparative safety of vaccine adjuvants: a summary of current evidence and future needs. Drug Saf. 2015 November;38(110:1059-1074.
  3. Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol. 2016;594(20):5781-5790.
  4. Fox D. The shock tactics set to shake up immunology. Nature. May 3, 2017.
  5. Nicolson GL. Mitochondrial Dysfunction and Chronic Disease: Treatment with Natural Supplements. Integrative Medicine. August 2014;13(4):35-43.
  6. Sharafati-Chaleshtori R, et al. Melatonin and human mitochondrial diseases. J Res med Sci. 2017;22:2.
  7. Lee WM. Acetaminophen (APAP) hepatotoxicity—Isn’t it time for APAP to go away? Journal of Hepatology. 2017;67:1324-1331.
  8. Karvellas CJ, et al. Elevated FAB1 serum levels are associated with poorer survival in acetaminophen-induced acute liver failure. Hepatology. March 2017;65(3):938-949.

Published February 24, 2024

About the Author

Jule Klotter has a master’s in professional writing from the University of Southern California. She joined Townsend Letter’s staff in 1990. Over the years, she has written abstract articles for “Shorts” and many book reviews that provide information for busy practitioners. She became Townsend Letter’s editor near the end of 2016.