Assessing the Beneficial Effects of the Immunomodulatory Glycan LNFPIII on Gut Microbiota and Health in a Mouse Model of Gulf War Illness

Abstract

The microbiota’s influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the gut–brain–immune axis. This study examined short- and long-term effects of GWI-related chemicals on gut health and fecal microbiota and the potential benefits of Lacto-N-fucopentaose-III (LNFPIII) treatment in a GWI model. Male C57BL/6J mice were administered pyridostigmine bromide (PB; 0.7 mg/kg) and permethrin (PM; 200 mg/kg) for 10 days with concurrent LNFPIII treatment (35 μg/mouse) in a short-term study (12 days total) and delayed LNFPIII treatment (2×/week) beginning 4 months after 10 days of PB/PM exposure in a long-term study (9 months total). Fecal 16S rRNA sequencing was performed on all samples post-LNFPIII treatment to assess microbiota effects of GWI chemicals and acute/delayed LNFPIII administration. Although PB/PM did not affect species composition on a global scale, it affected specific taxa in both short- and long-term settings. PB/PM elicited more prominent long-term effects, notably, on the abundances of bacteria belonging to Lachnospiraceae and Ruminococcaceae families and the genus Allobaculum. LNFPIII improved a marker of gut health (i.e., decreased lipocalin-2) independent of GWI and, importantly, increased butyrate producers (e.g., Butyricoccus, Ruminococcous) in PB/PM-treated mice, indicating a positive selection pressure for these bacteria. Multiple operational taxonomic units correlated with aberrant behavior and lipocalin-2 in PB/PM samples; LNFPIII was modulatory. Overall, significant and lasting GWI effects occurred on specific microbiota and LNFPIII treatment was beneficial.

Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness

“…Giving mice butyrate during exposure with PB and permethrin resulted in increased butyrogenic bacteria, and decreased TLR4 activation 73 . Lacto‐N‐fucopentaose‐III is a glycan in human milk and also increased butyrate producer bacteria such as Butyricoccus and Ruminococcous in mice exposed to GW chemicals 74 . These treatments to mediate butyrate producing bacteria resulted in improved gut health and decreased inflammation.…”

“…In clinical situation, changes in the types of diet can be easy for some people patients but hard for others. The development of supplements that contain various phytochemicals with anti-inflammatory effects 77,80,85 or milk glycan that improves gut microbiota profile 74 may help reducing the symptoms and/or can ameliorate the impacts of high-fat diet. Many studies have been done on the potential pharmaceutical treatments for GWI.…”

“…73 to GW chemicals. 74 These treatments to mediate butyrate producing bacteria resulted in improved gut health and decreased inflammation.…”

Evaluation of delayed LNFPIII treatment initiation protocol on improving long-term behavioral and neuroinflammatory pathology in a mouse model of Gulf War Illness

“…Considering the immune dysfunction in GWI, recent preclinical studies have explored the efficacy of several immune-targeted compounds that have shown some promising results ( Joshi et al, 2018 ; Kodali et al, 2018a ; Ribeiro et al, 2020 ; Shetty et al, 2020 ). In our studies, we have focused on one potent immunomodulatory and anti-inflammatory treatment, Lacto-N-fucopentaose III (LNFPIII), that may be an advantageous treatment option for GWI as demonstrated in two, chemically distinct GWI models ( Brown et al, 2021a , 2021b ; Carpenter et al, 2020 , 2021 ; Mote et al, 2020 ). LNFPIII is a Lewis(X)-containing immunomodulatory glycan found in human breast milk and on parasitic helminths that, to date, has had no documented adverse effects ( Atochina et al, 2008 ; Bhargava et al, 2012 ; Srivastava et al, 2014 ; Tundup et al, 2015 ; Zhu et al, 2012 ).…”