AIDS wasting syndrome as an entero-metabolic disorder: the gut hypothesis

Townsend Letter for Doctors and Patients, June, 2006 by Mitchell Kaminski, Jr., Steven Weil, Jeffrey Bland, Pat Jan

Abstract

There is an interesting relationship between the HIV virus, the health of the gastrointestinal tract, and AIDS wasting syndrome, involving Tumor Necrosis Factor alpha (TNF[alpha]), specific and non-specific immunity in the gut, gut permeability, and oxidative stress. It is hypothesized that the progression of HIV to full-blown AIDS may be impacted by maintaining a healthy gut. A therapeutic protocol that decreases oxidative stress, inhibits TNF[alpha], enhances phase I and II liver detoxification, and improves specific and non-specific immunity in the gut should be part of a therapeutic protocol for HIV-infected individuals. Through a better understanding of the pathophysiology of HIV advancing to AIDS, the practitioner can develop a treatment strategy of nutritional and lifestyle changes which could theoretically prevent an HIV infection from advancing to full-blown AIDS (Alt Med Rev. 1998:3(1):40-53).

Introduction

HIV-infected individuals tend to progress toward AIDS and routinely develop severe nutritional deficiencies. (1-8) "Slim disease" is still commonly used as a synonym for AIDS in Africa. (9) Some AIDS wasting research in the past decade has focused on defining the association between the HIV virus and the gastrointestinal tract. (10-19) When reviewed as a whole, these reports reveal some interesting interrelationships between the HIV virus, Tumor Necrosis Factor alpha (TNF-[alpha]), (20,21) secretory IgA (sIgA), (22) the gastrointestinal tract including the liver, and related pathophysiologic changes at the cellular, subcellular, and molecular levels. (10,23,24) More specifically, HIV replication requires activation of NF-[kappa]B, a viral binding site. (25,26) Activation of this site initiates viral replication and is signaled to proceed by TNF-[alpha]. In fact, HIV has been called a TNF-[alpha] disease. (27) However, NF-[kappa]B transcription is also common to two other immunologic pathways; i.e., antigen/leukocyte induction of protein kinase C28 and gut/ liver pathways associated with oxidative stress. (29,30) (Figure 1) All three are interrelated and play a major role in the progression of HIV to full-blown AIDS. In turn, HIV directly promotes TNF-[alpha] production in the infected CD4 lymphocyte. As these cells die, there is an associated immunodeficiency which is most apparent in the intestine, where potential pathogens are normally present. (31) In addition to pathogens, toxins and other antigens are ready to adhere to leukocyte-binding sites and cause activation of protein kinase C-dependent pathways. Protein kinase C also activates NF-[kappa]B. The net result is HIV replication secondary to local mucosal inflammation. (32) Inflammation also produces a leaky gut which is capable of overwhelming intestinal and hepatic detoxification pathways, resulting in oxidative stress. Oxidative stress then activates NF-[kappa]B, which activates HIV viral replication. These three major HIV transcriptional factors deplete immunologic defenses and result in progression of HIV to AIDS. All three factors more or less center around the gut. The prevalence of pathologic flora in the gut lumen, as well as the competency of intestinal defenses to limit leaky gut and oxidative stress can be assessed. (33) The results of these assessments can then be used to guide therapeutic strategies.

Normal Gastrointestinal Tract Immunity

To understand AIDS wasting syndrome and its effects on the GI tract, it may be helpful to briefly review the role that a normal GI tract, particularly the small intestine, plays in immunity. It is in the small intestine that the majority of exchanges occur between luminal contents, the mucosa, the lamina propria, and the gut-associated lymphoid tissue (GALT). (34-36) The lamina propria houses plasma cells and other immune elements; in fact, the GALT is comprised of several times more immune cell elements than the bone marrow, spleen, and lymph nodes combined. (37) Within and beneath the lamina propria rest the Peyer's patches. Luminal microbes are sampled in the Peyer's patch and inactivated by macrophages. Next, T-cell lymphocytes identify epitopes or protein-binding sites on the foreign organisms. This information is then passed to the B-cell lymphocytes. With this information for antibody production, the B-cells leave the Peyer's patch, become plasma cells, and migrate to various tissues throughout the body that have moist mucosal surfaces, including back to the lamina propria of the gut. (34,35) From here, sIgA is secreted onto the surface to protect the mucosa from adhesion by specific entero-pathogens. (38) If there is no adhesion, then there is no inflammation, and with no inflammation, there is no TNF production or subsequent leaky gut. The antibody-antigen complex is eventually expelled from the GI tract. Secretory IgA does not kill the organism; instead, it neutralizes the binding sites, preventing adhesion and subsequent disease. This precise immunologic activity is known as the specific immunity of the gut.